GROWTH DIFFERENTIATION FACTOR COMBINATION THERAPY 15

Abstract

This disclosure provides combination therapy with GDF15 molecules. In some embodiments, the GDF15 molecule is a GDF15-Fc fusion, wherein a GDF15 region is fused to an Fc region, optionally via a linker. In one embodiment, the combination therapy comprises the administration of a GDF15 molecule with a GLP-1R agonist. In another embodiment, the combination therapy comprises the administration of a GDF15 molecule with a GIPR antagonist.

Description

GROWTH DIFFERENTIATION FACTOR COMBINATION THERAPY 15 RELATED APPLICATIONS This application claims the benefit of United States Provisional Application No. 62 / 815,866, filed on March 8, 2019, which is incorporated herein by reference in its entirety. LIST OF SEQUENCES This application is submitted together with a Sequence List in electronic format. The Sequence List is provided as a file named A-2298-WOPCT_SeqList.txt, created on March 2, 2020, which has a size of 166 KB. The information in the electronic Sequence List is incorporated herein by reference in its entirety. FIELD OF INVENTION This disclosure relates to GDF15 molecules such as GDF15 fusion proteins, compositions thereof, and methods for the preparation and use of such proteins, such as their use in combination therapy. BACKGROUND Growth differentiation factor 15 (GDF15), also cited as macrophage inhibitory cytokine 1 (MIC1) (Bootcov MR, 1997, Proc Nati Acad Sel 94:11514-9), placental bone morphogenetic factor (PLAB) (Hromas R 1997, Biochim Biophys Acta. 1354:404), placental transforming growth factor beta (PTGFB) (Lawton LN 1997, Gene. 203:17-26), prostate-derived factor (PDF) (Paralkar VM 1998, J Biol Chem. 273:137607), and nonsteroidal anti-inflammatory drug-activated gene (NAG-1) (Baek SJ 2001, J Biol Chem. 276: 33384-92), is a secreted protein that circulates in the plasma as a ~25 kDa homodimer. GDF15 binds to the GDNF-α receptor family (GFRAL) with high affinity. GDF15-induced cell signaling is thought to require the interaction of GFRAL with the coreceptor RET. GDF15 has been linked to multiple biological activities. Elevated GDF15 levels have been shown to correlate with weight loss, and GDF15 administration has been shown to reduce food intake and body weight. Glucose-dependent insulinotropic polypeptide (GIP, formerly called gastric inhibitory polypeptide) and glucagon-like polypeptide-1 (GLP-1) are known insulinotropic factors (incretins). GIP is a single peptide of 42 amino acids, and human GIP is derived from the processing of proGIP, a 153-amino-acid precursor. GIP secretion is induced by food intake and has several physiological effects, including promoting fat storage in adipocytes and promoting pancreatic islet β-cell function and glucose-dependent insulin secretion. Intact GIP is rapidly degraded by DPPIV to an inactive form. The receptor for GIP, the receptor of MA / a / zuzi / uiur ót GIP (GIPR) is a member of the secretin-glucagon family of G protein-coupled receptors (GPCRs). Human GIPR comprises 466 amino acids. Glucagon-like peptide-1 (GLP-1) is a 31-amino-acid peptide derived from the proglucagon gene. It is secreted by intestinal L cells and released in response to food intake to induce insulin secretion from pancreatic β cells. In addition to its incretin effects, GLP-1 also reduces glucagon secretion, slows gastric emptying, and reduces caloric absorption. GLP-1 exerts its effects by activating the GLP-1 receptor (GLP-1R), which belongs to a class B G protein-coupled receptor. GLP-1 function is limited by rapid degradation by the enzyme DPP-IV. Longer-acting GLP-1R agonists, such as exenatide, liraglutide, and dulaglutide, have been developed and are used clinically to improve glycemic control in patients with type 2 diabetes.In addition, GLP-1 receptor agonists can promote weight loss, as well as reduce blood pressure and plasma cholesterol levels in patients. Therefore, there is a need for combination therapy comprising a GDF15 molecule with one or more other therapeutic agents, such as a GLP-1 receptor agonist (e.g., a GLP-1 analogue) and / or a GIPR antagonist (e.g., a GIPR antibody). This disclosure addresses this need and provides associated benefits. SUMMARY This document provides a combination therapy comprising a GDF15 molecule, including methods for treating a condition by administering a GDF15 molecule and another therapeutic agent. In one embodiment, the other therapeutic agent is a GIPR antagonist, such as a GIPR antigen-binding protein. In one embodiment, the GIPR antigen-binding protein is an antibody. In another embodiment, the other therapeutic agent is a GLP-1 receptor agonist, such as dulaglutide. Also provided herein is a method for treating a metabolic condition in a subject comprising administering a GDF15 molecule and a GIPR antagonist, wherein the administration of the GDF15 molecule and the GIPR antagonist has a synergistic effect compared to the administration of the GDF15 molecule or GIPR antagonist alone. The present description also provides a method for treating a metabolic condition in a subject comprising administering a GDF15 molecule and dulaglutide, wherein the administration of the GDF15 molecule and dulaglutide has a synergistic effect compared to the administration of the GDF15 molecule or dulaglutide alone. MA / a / zuzi / uiur ót In one embodiment, the combination therapy comprises the administration of a GDF15 molecule with a corresponding Fe molecule, as described herein and in Table 6. In one embodiment, the GDF15 molecule and the other therapeutic agent are administered simultaneously. In another embodiment, the GDF15 molecule and the other therapeutic agent are administered sequentially. Also provided herein is a pharmaceutical composition comprising a GDF15 molecule and another therapeutic agent, such as a pharmaceutical composition comprising a GDF15 molecule and a GIPR antagonist, wherein administration of the composition has a synergistic effect compared to administration of the GDF15 molecule or the GIPR antagonist alone. In some embodiments, the GIPR antagonist is an antibody. In some embodiments, the synergistic effect is a decrease in body weight. The GIPR antagonist of the composition may comprise CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively.In some embodiments, the GIPR antagonist of the composition comprises a light-chain variable region and a heavy-chain variable region comprising the amino acid sequences SEQ ID NO: 89 and 90; 91 and 92; 93 and 94; or 95 and 96, respectively. In some embodiments, the GIPR antagonist of the composition comprises a light chain and a heavy chain comprising the amino acid sequences SEQ ID NO: 97 and 98; 99 and 100; 101 and 102; 103 and 104; or 105 and 106, respectively. In some embodiments, the GDF15 molecule of the composition is a fusion protein comprising a GDF15 region linked to an Fe region. In some embodiments, the GDF15 region is linked to the Fe region by a linker. In some embodiments, the GDF15 region comprises the amino acid sequence of SEQ ID NO: 6 and at least one mutation. In some embodiments, at least one of the mutations is to aspartate at position 5.In some embodiments, the aspartate at position 5 is mutated to glutamate. In some embodiments, the GDF15 region further comprises a mutation of the asparagine at position 3. In some embodiments, the asparagine at position 3 is mutated to glutamine. In some embodiments, the linker of the GDF molecule bound to the Fe region is a (G4S)non(G4Q)n linker, where n is greater than 0 (e.g., n is 1 or 2). The Fe region may comprise a charged-pair mutation or a truncated hinge region, or both. In some embodiments, the Fe region is selected from Table 3. Still in other embodiments, the composition further comprises an Fe molecule corresponding to the GDF15 molecule, e.g., as described herein and in Table 6. iviA / a / zuz ι / ui uro / Also provided herein is a pharmaceutical composition comprising a GDF15 molecule and dulaglutide, wherein administration of the composition has a synergistic effect compared to administration of the GDF15 molecule or dulaglutide alone. In some embodiments, the synergistic effect is a decrease in body weight. In some embodiments, the GDF15 molecule of the composition is a fusion protein comprising a GDF15 region linked to an Fe region. In some embodiments, the GDF15 region is linked to the Fe region by a linker. In some embodiments, the GDF15 region comprises the amino acid sequence of SEQ ID NO: 6 and at least one mutation.In some embodiments, at least one of the mutations is of the aspartate at position 5. In some embodiments, the aspartate at position 5 is mutated to glutamate. In some embodiments, the GDF15 region further comprises a mutation of the asparagine at position 3. In some embodiments, the asparagine at position 3 is mutated to glutamine. In some embodiments, the linker of the GDF molecule bound to the Fe region is a (G4S)non(G4Q)n linker, where n is greater than 0 (e.g., n is 1 or 2). The Fe region may comprise a charged-pair mutation or a truncated hinge region, or both. In some embodiments, the Fe region is selected from Table 3. Still in other embodiments, the composition further comprises an Fe molecule corresponding to the GDF15 molecule, e.g., as described herein and in Table 6. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A shows the change in body weight in grams in mice administered vehicle weekly (Group A); dulaglutide twice a week (Group B); GIPR 2.63.1 antibody weekly and vehicle weekly, the latter on the alternate day of dulaglutide dosing (Group C); FcA10(-)-(G4S)4-GDF15 (SEQ ID NO: 39) (together with its heterodimerization component, FcA10(+,K) (SEQ ID NO: 32)) weekly and vehicle weekly, the latter on the alternate day of dulaglutide dosing (Group D); FcA10(-)-(G4S)4-GDF15) (together with its heterodimerization component, FcA10(+,K)) weekly and dulaglutide twice a week (Group E); FcA10(-)-(G4S)4-GDF15 (together with its heterodimerization component, FcA10(+,K)) weekly and GIPR 2.63.1 antibody weekly (Group F). Figure 1B shows the percentage change in body weight of the mice in the AF Groups. Figure 2A shows the percentage change in body weight of the mice in the AF Groups 2 weeks after treatment began. MA / a / zuzi / uiur ót Figure 2B shows the percentage change in body weight of mice in the AF Groups 5 weeks after treatment began. Figure 3A shows the oral glucose tolerance test (OGTT) glucose levels of mice in the AF Groups two weeks after treatment. Figure 3B shows the AUC results of glucose from the OGTT of mice in the AF Groups two weeks after treatment. Figure 4A shows the intraperitoneal glucose tolerance test (IPGTT) glucose levels of mice in the AF Groups five weeks after treatment. Figure 4B shows the IPGTT glucose AUC results from mice in the AF Groups five weeks after treatment. Figure 5A shows the fasting blood glucose levels measured two weeks and five weeks after treatment of mice in the AF Groups. Figure 5B shows the serum insulin levels measured two weeks and five weeks after treatment of mice in the AF Groups. Figure 5C shows the serum triglyceride levels measured two weeks and five weeks after treatment of mice in the AF Groups. Figure 5D shows the total serum cholesterol levels measured two weeks and five weeks after treatment of mice in the AF Groups. Figure 6 shows the daily food intake measured three consecutive days a week during the treatment of mice in the AF Groups. DETAILED DESCRIPTION This document provides a combination therapy comprising a GDF15 molecule and another therapeutic agent or molecule. In one embodiment, the other agent or molecule is a molecule that reduces body weight, food intake, and / or treats obesity and / or a related condition. Methods of preparing the molecules and methods of using the molecules are also provided herein. In some embodiments, the GDF15 molecule is a GDF15-Fc fusion protein. The fusion protein may comprise a GDF15 region linked to an Fe region. In some embodiments, the GDF15 region is linked to the Fe via a linker. In some embodiments, the GDF15 region comprises wild-type GDF15. Both human and murine GDF15 have a signal peptide and a dominant region. The nucleotide sequence for full-length human GDF15 is: atgcccgggc aagaactcag gacggtgaat ggctctcaga tgctcctggt gttgctggtg ctctcgtggc tgccgcatgg gggcgccctg tctctggccg aggcgagccg cgcaagtttc ccgggaccct cagagttgca ctccgaagac tccagattcc gagagttgcg gaaacgctac gaggacctgc taaccaggct gcgggccaac cagagctggg aagattcgaa caccgacctc gtcccggccc ctgcagtccg gatactcacg ccagaagtgc ggctgggatc cggcggccac ctgcacctgc MA / a / zuzi / uiur ót gtatctctcg ggccgccctt cccgaggggc tccccgaggc ctcccgcctt caccgggctc tgttccggct gtccccgacg gcgtcaaggt cgtgggacgt gacacgaccg ctgcggcgtc agctcagcct tgcagacccccgccgc gcgactgtcg ccgccgccgt cgcagcgga ccaactgctg gcagaatctt cgtccgcacg gccccagctg gagttgcact tgcggccgca agccgccagg gggcgccgca ggcgcgtgc gcgcaacggg gaccactgtc cgctcgcggcgcgcgct acacggtccg cgcgtcgctg gaagacctgg gctgggccga ttgggtgctg tcgccacggg aggtgcaagt gaccatgtgc atcggcgcgt gcccgagcca gttccgggcg gcaaacatgc acgcgcagat caagacgagc ctgcacccgcc tgagcccgcgc gcgtgcccgc cagctacaat cccatggtgc tcattcaaaa gaccgacacc ggggtgtcgc tccagaccta tgatgacttg ttagccaaag actgccactg catatga (SEQ ID NO: 1) The amino acid sequence for the full-length human GDF15 308 amino acids) is: MPGQELRTVNGSQMLLVLLVLSWLPHGGALSLAEASRASFPGPSELHSEDSRFRELR KRYEDLLTRLRANQSWEDSNTDLVPAPAVRILTPEVRLGSGGHLHLRISRAALPEGLPEASRL HRALFRLSPTASRSWDVTRPLRRQLSLARPQAPALHLRLSPPPSQSDQLLAESSSARPQLEL HLRPQAARGRRRARARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIG ACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDC HCI (SEQ ID NO: 2) The nucleotide sequence for human GDF15 without its signal sequence is: ctgtctctgg ccgaggcgag ccgcgcaagt ttcccgggac cctcagagtt gcactccgaa gactccagat tccgagagtt gcggaaacgc tacgaggacc tgctaaccag gctgcgggcc aaccagagct gggaagattc gaacaccgac ctcgtcccgg cccctgcagt ccggatactc acgccagaag tgcggctggg atccggcggc cacctgcacc tgcgtatctc tcgggccgcc cttcccgagg ggctccccga ggcctcccgc cttcaccggg ctctgttccg gctgtccccg acggcgtcaa ggtcgtggga cgtgacacga ccgctgcggc gtcagctcag ccttgcaaga ccccaggcgc ccgcgctgca cctgcgactg tcgccgccgc cgtcgcagtc ggaccaactg ctggcagaat cttcgtccgc acggccccag ctggagttgc acttgcggcc gcaagccgcc agggggcgcc gcagagcgcg tgcgcgcaac ggggaccact gtccgctcgg gcccgggcgt tgctgccgtc tgcacacggt ccgcgcgtcg ctggaagacc tgggctgggc cgattgggtg ctgtcgccac gggaggtgca agtgaccatg tgcatcggcg cgtgcccgag ccagttccgg gcggcaaaca tgcacgcgca gatcaagacg agcctgcacc gcctgaagcc cgacacggtg ccagcgccct gctgcgtgcc cgccagctac aatcccatgg tgctcattca aaagaccgac accggggtgt cgctccagac ctatgatgac ttgttagcca aagactgcca ctgcatatga (SEQ ID NO: 3) The amino acid sequence for human GDF15 without its signal sequence of amino acid 29 (279 amino acids) is: LSLAEASRASFPGPSELHSEDSRFRELRKRYEDLLTRLRANQSWEDSNTDLVPAPAV RILTPEVRLGSGGHLRISRAALPEGLPEASRLHRALFRLSPTASRSWDVTRPLRRQLSLARP QAPALHLLRLSPPPSQSDQLLAESSSARPQLELHLRPQAARRRNGDHCPLGRCCPL RLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSSLHRLKPDTVPAPC CVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO: 4) MA / a / juzi / uiur ot The nucleotide sequence for human GDF15 without its signal peptide or prodomain is: gcgcgcaacggggaccactgtcgctcgggcccggggttgctgcgtctgcacggcgcgcgtcgctggaagac ctgggctgggccgattgggtgctcgccacgggaggtgcaagtgaccatgcatcggcgcgtc caaacatgcacgcgcagatcaagacgagcctgcaccgcctgaagcccgacacggtgccagcgccctgcgtgcccgccagc tacaatcccatggtgctcattcaaaagaccgacaccggggtcgctccagacctatgatgacttgttagccaaagacggcgccgcgatgatgacttgttagccaaagactgccacgc a NO ID:5 The amino acid sequence for human GDF15 without its signal peptide or prodomain (the 112-amino-acid active domain of GDF15) is: ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAA NMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI (SEQ ID NO: 6) The nucleotide sequence for the full-length murine GDF15 is: atggccccgc ccgcgctcca ggcccagcct ccaggcggct ctcaactgag gttcctgctg ttcctgctgc tgttgctgct gctgctgtca tggccatcgc aggggacgc cctggcaatg cctgaacagc gaccctccgg ccctgagtcc caactcaacg ccgacgagct acggggtcgc ttccaggacc tgctgagccg gctgcatgcc aaccagagcc gagagctc gaactcagaa ccaagtcctg acccagctgt ccggatactc agtccagagg tgagattggg gtcccacggc cagctgctac tccgcgtcaa ccgggcgtcg ctgagtcagg gtctccccga agcctaccgc gtgcaccgag cgctgctcct gctgacgccg acggcccgcc cctgggacat cactaggccc ctgaagcgtg cgctcagcct ccggggaccc cgtgctcccg cattacgcct gcgcctgacg ccgcctccgg acctggctat gctgccctct ggcggcacgc agctggaact gcgcttacgg gtagccgccg gcaggggcg ccgaagcgcg catgcgcacc caagagactc gtgcccactg ggtccggggc gctgctgtca cttggagact gtgcaggcaa ctcttgaaga cttgggctgg agcgactggg tgctgtcccc gcgccagctg cagctgagca tgtgcgtggg cgagtgtccc cacctgtatc gctccggaa cacgcatgcg cagatcaaag cacgcctgca tggcctgcag cctgacaagg tgcctgcccc gtgctgtgtc ccctccagct acaccccggt ggttcttatg cacaggacag acagtggtgt gtcactgcag acttatgatg acctggtggc ccggggctg cactgcgcttga (SEQ ID NO: 7) The amino acid sequence for the full-length murine GDF15 303 amino acids) is: FOLDERQPPGGSQLRFLLFLLLLLLLLSWPSQGDALAMPEQRPSGPESQLNADEL RGRFQDLLSRLHANQSREDSNSEPSPDPAVRILSPEVRLGSHGQLLLRVNRASLSQGLPEAY RVHRALLLLTPTARPWDITRPLKRALSLRGPRAPALRLRLTPPLAMLPSGLRQLEQLEQLE GRGRRSAHAHPRDSCPLGPGRCCHLETVQATLEDLGWSDWVLSPRQLQLSMCVGECPHLY RSANTHAQIKARLHGLQPDKVPAPCCVPSSYTPWLMHRTDSGVSLQTYDDLVARGCHCA (SEQ ID NO: 8) The nucleotide sequence for murine GDF15 without its signal sequence is: tcgcagggggacgccctggcaatgcctgaaccgaccctccggcctgagtcccaactcaacgccgacgagctacg gggtcgcttccaggacctgcgcggctgcatgccaaccagagccgagactcgaactcagaaccaactctgaccctc tgtccggatactcagtccagaggtgagattggggtcccacggccagctgctactccggtcaaccgggcgtcgctgagtcagggtct MA / a / zuzi / uiur ot ccccgaagcctaccgcgtgcaccgagcgctgctcctgacgccgacggcccgccctgggacatcactaggccctgaagcg tgcgctcagcctcc cacgcagctggaactgcgcgggtagccgcggcagggcgcgcgcgcgcgcgctgctcacttggagactgtgcaggcaaccttgaagacttgggctggcgcgcggcgccgcgcg cagctgcagctgagcatgtgcgtgggcgagtgtccccacctgtatcgctcgcgaacgcatgcgcagatcaaagcacgcctgc atgcctgcagcctgacaaggtgcctgccccgtgctgtgtccccgccccggtggttcttgcac gtgtgtcactgcagacttatgatgacctggtggcccggggctgccactgcgcttga (SEQ ID NO: 9) The amino acid sequence for murine GDF15 without its 32 amino acid signal sequence (271 amino acids) is: SQGDALAMPEQRPSGPESQLNADELRGRFQDLLSRLHANQSREDSNSEPSPDPAVR ILSPEVRLGSHGQLLLRVNRASLSQGLPEAYRVHRALLLLTPTARPWDITRPLKRALSLRGPRA PALRLRLTPPPDLAMLPSGGTQLELRVAAGRGRSAHAHPRDSCPLTVGQLELR LEDLGWSDWVLSPRQLQLSMCVGECPHLYRSANTHAQIKARLHGLQPDKVPAPCCVPSSYT PWLMHRTDSGVSLQTYDDLVARGCHCA (SEQ ID NO: 10) The nucleotide sequence for murine GDF15 without its signal sequence or prodomain is: agcgcgcatgcgcacccaagagactcgtgcccactgggtccggggcgctgtcacttggagactgtgcaggcaact cttgaagacttgggctgagcgactggtgctcccgcgctgcagctgagcatgcgtgggcgagtgtccccacctgtat cgctccgcgaaccgcatgcgcagatcaaagcacgcctgcatgcctgcagcctgacaaggtgccctgccccgtgcaggacagacagtgggtgtcactgcacgacttatgatgacctggcgcggcgcgcgcgcgcgcgct NO: The amino acid sequence for the murine GDF15 without its signal peptide or prodomain (active domain of 115 amino acids) is: SAHAHPRDSCPLGPGRCCHLETVQATLEDLGWSDWVLSPRQLQLSMCVGECPHLY RSANTHAQIKARLHGLQPDKVPAPCCVPSSYTPWLMHRTDSGVSLQTYDDLVARGCHCA (SEQ ID NO: 12) In some embodiments, the GDF15 molecule comprises a GDF15 region comprising an active domain of GDF15, e.g., GDF15 without its signal peptide or prodomain. In some embodiments, the GDF15 region comprises the amino acid sequence of SEQ ID NO: 6 or 12. In some embodiments, the GDF15 region comprises a GDF15 sequence with one or more mutations, such as at least one mutation in the active domain of GDF15. In particular embodiments, the mutation or mutations do not reduce or eliminate GDF15 activity. In some embodiments, the GDF15 region comprises a mutation in the active domain of human GDF15. In one embodiment, the mutation is a deletion of the first three amino acids of the active domain, such as GDF15(A3), which is an active domain of human GDF15 in which the first three amino acids are deleted (i.e., SEQ ID NO: 13). MA / a / ZUZl / UlU / In some embodiments, the GDF15 region comprises a mutation of asparagine at position 3 (N3) of the active domain of human GDF15 (SEQ ID NO: 6). An N3 mutation may refer to a mutation of the asparagine moiety at position 3 of SEQ ID NO: 6 or a mutation of an asparagine moiety corresponding to the asparagine at position 3 of SEQ ID NO: 6 in a GDF15 amino acid sequence. In some embodiments, the asparagine at position 3 is mutated to glutamine (N3Q) or aspartate (N3D). Accordingly, in some embodiments, the GDF15 molecule comprises a GDF15 region of GDF15(N3Q) having the amino acid sequence of SEQ ID NO: 14. In other embodiments, the GDF15 molecule comprises a GDF15 region of GDF15(N3D) having the amino acid sequence of SEQ ID NO: 15. In some embodiments, the GDF15 region comprises an aspartate mutation at position 5 (D5) of the active domain of human GDF15 (SEQ ID NO: 6).A D5 mutation can refer to the mutation of the aspartate residue at position 5 of SEQ ID NO: 6 or the mutation of an aspartate residue corresponding to the aspartate at position 5 of SEQ ID NO: 6 in an amino acid sequence of GDF15. In one embodiment, the aspartate at position 5 is mutated to glutamate (D5E). Consequently, in some embodiments, the GDF15 molecule comprises a GDF15 region of GDF15(D5E) having the amino acid sequence of SEQ ID NO: 16. In other embodiments, the GDF15 region comprises a combination of mutations, such as a combination of Δ3 and D5 mutations, for example, GDF15(A3 / D5E) (SEQ ID NO: 17), or a combination of N3 and D5 mutations, for example, GDF15(N3D / D5E) or GDF15(N3Q / D5E). Within this region, the GDF15 area comprises the amino acid sequence of SEQ ID NO: 18. Table 1 provides examples of GDF15 regions that can be used in GDF15 molecules. Table 1 - Regiones de GDF15 SEQ ID NO: Designación Secuencia 6 GDF15 ARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPRE VQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPC CVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI 13 GDF15(A3) GDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQV TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI 14 GDF15(N3Q) ARQGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPRE VQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPC CVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCCHI 15 GDF15(N3D) ARNGEHCPLGPGRCCRLHTVRASLEDLGWADWVLSPRE TMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVP ASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI 18 GDF15(N3Q / D5E) ARQGEHCPLGPGRCCRLHTVRASLEDLGWADWVLSPRE VQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPC CVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI MA / a / zuzi / uiur ót In some embodiments, the GDF15 molecule is directly fused to an Fe atom. In other embodiments, the Fe atom is fused to the GDF15 molecule via a linker. In some embodiments, the linker is a G4S linker (SEQ ID NO: 19). In other embodiments, the linker is a G4Q linker (SEQ ID NO: 24). The linker can be a (G4S)n linker, where n is greater than 0. In some embodiments, n is 1 or 2. In some embodiments, the fusion protein has a linker that is a G4A linker (SEQ ID NO: 107), such as a (G4A)n linker, where n is greater than 0. In some embodiments, n is 1 or 2. In some embodiments, n is greater than 2, such as 3, 4, 5, 6, 7, or 8. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 19, 20, 21, 22, 23, 24, 25, or 107 as shown in Table 2. Table 2 - Linkers SEQ ID NO: Designation Sequence 19 G4S GGGGS 20 (G4S)2 GGGGSGGGGS 21 (G4S)4 GGGGSGGGGSGGGGSGGGGS 22 (G4S)8 GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS 23 G4 GGGG 24 G4Q GGGGQ 25 (G4Q)4 GGGGQGGGGQGGGGQGGGGQ 107 G4A GGGGA In some embodiments, the GDF15 molecule comprises an Fe region. The Fe region may comprise or be derived from the Fe domain of an antibody heavy chain. In some embodiments, the Fe region may comprise an Fe domain with a mutation, such as a charged-pair mutation, a mutation at a glycosylation site, or the inclusion of a non-natural amino acid. The Fe region may be derived from a human IgG constant domain of IgG1, IgG2, IgG3, or IgG4. In some embodiments, the Fe region comprises the constant domain of an IgA, IgD, IgE, or IgM heavy chain. In some embodiments, the Fe region comprises an Fe domain with a charged pair mutation. By introducing a mutation that results in a charged Fe region, the Fe molecule of GDF15 can dimerize with a corresponding Fe molecule that has the opposite charge. For example, an aspartate-to-lysine mutation (E356K, where 356 is the position using EU numbering, and corresponds to the positions as shown in Tables 3-5) and a glutamate-to-lysine mutation (D399K, where 399 is the position using EU numbering, and corresponds to the positions as shown in Tables 3-5) can be introduced into the Fe region that is linked to a GDF15 region, optionally via a linker, resulting in a positively charged Fe region for the GDF15 Fe molecule.The lysine-to-aspartate mutations (K392D, K409D; where 392 and 409 are the positions using EU numbering and correspond to the positions as indicated in Tables 3-5) can be introduced into an Fe domain of a separate Fe molecule, resulting in a negatively charged Fe molecule. The aspartate residues in the negatively charged Fe molecule can associate with the lysine residues of the positively charged Fe region of the GDF15 Fe molecule through an electrostatic force, facilitating the formation of Fe heterodimers between the Fe region of the GDF15 Fe molecule and the Fe molecule, while reducing or preventing the formation of Fe homodimers between the Fe regions of the GDF15 molecules or between Fe molecules. In some embodiments, one or more lysine-to-aspartate mutations (K392D, K409D) are introduced into the Fe region that is linked to a GDF15 region, optionally via a linker, and an aspartate-to-lysine mutation (E356K) and a glutamate-to-lysine mutation (D399K) are introduced into the Fe domain of another molecule. The aspartate residues in the Fe region of the GDF15 molecule can associate with the lysine residues of the Fe molecule through electrostatic forces, facilitating the formation of Fe heterodimers between the Fe region of the GDF15 molecule and the Fe molecule, and reducing or preventing the formation of Fe homodimers between the Fe regions of the GDF15 molecules or between Fe molecules. In some embodiments, the GDF15 molecule comprises an Fe region comprising an Fe domain with a mutated hinge region. In some embodiments, the Fe domain comprises a deletion in the hinge. In some embodiments, ten amino acids are deleted from the hinge, for example, FcA10. In other embodiments, they are MA / a / zuzi / uiur or sixteen amino acids are deleted from the hinge, for example, FcA16. In some embodiments, the Fe domain comprises a hinge deletion (for example, FcA10 or FcA16) and a charged pair mutation, such that the Fe domain is positively or negatively charged. For example, the Fe domain may comprise a ten-amino-acid deletion at the hinge and lysine-to-aspartate mutations (K392D, K409D), such as FcA10(-). In another embodiment, the Fe domain may comprise a ten-amino-acid deletion at the hinge and an aspartate-to-lysine mutation (E356K) and a glutamate-to-lysine mutation (D399K), such as FcA10(+). In another embodiment, the Fe domain may comprise a deletion of sixteen amino acids at the hinge and lysine to aspartate mutations (K392D, K409D), such as FcA16(-).In another embodiment, the Fe domain may comprise a deletion of sixteen amino acids at the hinge and a mutation from aspartate to lysine (E356K) and a mutation from glutamate to lysine (D399K), such as an FcA16(+). In some embodiments, an Fe molecule comprising a hinge deletion and a charged pair mutation heterodimerizes with said GDF15 molecule. For example, the Fe molecule may have a hinge deletion and a charged pair mutation that complements the hinge deletion and charged pair mutation of the Fe region of a GDF15 molecule. For example, an Fe molecule may comprise an Fe domain with a ten-amino-acid deletion at the hinge and lysine-to-aspartate mutations (K392D, K409D) such as FcA10(-), which may optionally comprise a C-terminal lysine (e.g., FcA10(-, K)).The Fe molecule can heterodimerize with a GDF15 molecule comprising an FcA10(+)-. In another embodiment, the Fe molecule can comprise a deletion of ten amino acids at the hinge and a mutation from aspartate to lysine (E356K) and a mutation from glutamate to lysine (D399K) such as an FcA10(+), which can optionally comprise a C-terminal lysine (e.g., FcA10(+, K)). The Fe molecule can heterodimerize with a GDF15 molecule comprising an FcA10(-). In another embodiment, the Fe molecule can comprise a deletion of sixteen amino acids at the hinge and mutations from lysine to aspartate (K392D, K409D), such as an FcA16(-), which can optionally comprise a C-terminal lysine (e.g., FcA16(-, K)). The Fe molecule that can heterodimerize with a GDF15 molecule comprising an FcA16(+).In another embodiment, the Fe molecule may comprise a deletion of sixteen amino acids at the hinge and a mutation from aspartate to lysine (E356K) and a mutation from glutamate to lysine (D399K) such as an FcA16(+), which may optionally comprise a C-terminal lysine (e.g., FcA16(-, K)). The Fe molecule may heterodimerize with a GDF15 molecule comprising an FcA16(-). In some embodiments, the Fe region or Fe molecule comprises an Fe domain with an L234A and / or L235A mutation, where 234 and 235 are the positions using EU numbering and correspond to the positions as indicated in Tables 3-5. The Fe domain may comprise an L234A mutation, an L235A mutation, a charged-pair mutation, a hinge deletion, or any combination thereof. In some embodiments, the Fe domain comprises both an L234A mutation and an L235A mutation. In some embodiments, the Fe domain comprises a hinge deletion, an L234A mutation, an L235A mutation, and a charged-pair mutation, such as FcA10(+, L234A / L235A), FcA10(-, L234A / L235A), FcA16(+, L234A / L235A), or FcA16(-, L234A / L235A). In some embodiments, the Fe domain comprises an optional C-terminal lysine, for example, FcA10(+,K,L234A / L235A), FcA10(-,K,L234A / L235A), FcA16(+,K,L234A / L235A), or FcA16(,K,L234A / L235A). In some embodiments, the Fe region or Fe molecule comprises an Fe domain with a cysteine ​​clamp. A cysteine ​​clamp mutation involves the introduction of a cysteine ​​into the Fe domain at a specific location through a mutation, such that when incubated with another Fe domain that also has a cysteine ​​introduced at a specific location through the mutation, a disulfide bond (cysteine ​​clamp) can form between the two Fe domains (e.g., between an FcA16(+) domain having a cysteine ​​clamp mutation and an FcA16(-) domain having a cysteine ​​clamp mutation). The cysteine ​​can be introduced into the CH3 domain of an Fe domain. In some embodiments, an Fe domain may contain one or more such cysteine ​​clamp mutations.In one embodiment, a cysteine ​​clamp is provided by introducing a serine-to-cysteine ​​mutation (S354C, where 354 is the position using EU numbering, and corresponds to the position as indicated in Tables 3-5) in a first Fe domain and a tyrosine-to-cysteine ​​mutation (Y349C, where 349 is the position using EU numbering, and corresponds to the position as indicated in Tables 3-5) in a second Fe domain. In one embodiment, a GDF15 molecule comprises an Fe region comprising an Fe domain with a cysteine ​​clamp, a negatively charged pair mutation, and a sixteen-amino-acid hinge deletion (e.g., GDF15-FcA16(-,CC)), and an Fe molecule comprising an Fe domain comprising a cysteine ​​clamp, a positively charged pair mutation, a sixteen-amino-acid hinge deletion, and an optional lysine in C-terminal (e.g., FcA16(+,K,CC)).The clamping of cysteine ​​can increase the heterodimerization of the GDF-Fc molecule with the Fe molecule. Examples of Fe regions that can be used in a GDF15 molecule are shown in Table 3. Table 3 - Iron Regions MA / a / zuzi / uiur ót SEQ ID NO: Sequence Designation 5 26 FcA10(-) APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTP PVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG The underlined and bolded remains are the K392D and K409D mutations. 10 15 27 FcA10(+) APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG The underlined and bolded remains are the E356K and D399K mutations. 20 25 28 FcA10(-,CC) APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTP PVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG The rest underlined and in italics is the Y349C mutation; the rest underlined and in bold are the K392D and K409D mutations.30 29 FcA16(-,CC) GPSVFLFPPKPKDTLMISRTPEVWWDVSHEDPEWKFNW YVDGVEVHNACTKPREEQYNSTYRWSVLTVLHQDWLNGK EYKCKVSNCALPAPIEKTISKAKGQPREPQVCTLPPSREEMT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTPPVLDS DGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPG The underlined and italicized residue is the Y349C mutation; the underlined and bold residues are the K392D and K409D mutations. 35 30 FcA16(-) GPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEWKFNW YVDGVVHNACTKPREEQYNSTYRVVSVLTVLHQDWLNGK. MA / a / juzi / uiur ot The underlined and bold remains are the K392D and K409D mutations. 31 FcA10(,L234A / L235A) APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTP PVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPG The underlined and italicized remnants are the L234A and L235A mutations; the underlined and bold remnants are the K392D and K409D mutations. Examples of Fe molecules are shown in Table 4, where the CMA / a / zuzi / uiu / ot terminal is optional. Table 4 - Fe Molecules SEQ ID NO: Designation Sequence 32 FcA10(+,K) APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPE VKFNWYVDGVEVHNACTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNCALPAPIQQPPREEQVGGTL RKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK The underlined and bold residues are the E356K and D399K mutations. 33 FcA10(-,K) APELLGGPSVFLFPPKPKDTLMISRTPEVVVDVSHEDPE VKFNWYVDGVEVHNACTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNCALPAPIEKTISKAKGQPREPQVTPPQVTPP REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYDTTP PVLDSDGSFFLYSDLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK The underlined and bold residues are the K392D and K409D mutations. 34 FcA10(+,K,CC) APELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPE VKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPC RKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLKSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK The rest underlined and in italics is the S354C mutation; the rest underlined and in bold are the E356K and D399K mutations. 35 FcA16(+,K,CC) GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRKEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK The remainder underlined and italicized is the S354C mutation; the underlined and bold residues are the E356K and D399K mutations.36 FcA16(+,K) GPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWY VDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRKEMTKN QVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLKSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK The underlined and bold residues are the E356K and D399K mutations. 37 FcA10(+,K,L23 4A / L235A) apeaaggpsvflfppkpkdtlmisrtpevtcwvdvshedpe VKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS RKEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP pvlksdgsfflyskltvdksrwqqgnvfscsvmhealhnh YTQKSLSLSPGK The underlined and italicized remnants are the L234A and L235A mutations; the underlined and bold remnants are the E356K and D399K mutations. Fe molecules can be used to dimerize with a molecule comprising a complementary Fe domain. For example, an FcA10(+,K) Fe molecule can dimerize with a molecule comprising an Fe region with a ten-amino-acid hinge deletion and a negatively charged pair mutation such as FcA10(-) (e.g., a GDF15 molecule comprising an FcA10(-) Fe region). An FcA10(+,K,CC) Fe molecule can dimerize with a molecule comprising an Fe region with a ten-amino-acid hinge deletion and a negatively charged pair mutation such as FcA10(-,CC) (e.g., a GDF15 molecule comprising an FcA10(-,CC) Fe region). An FcA16(+,K,CC) Fe molecule can dimerize with a molecule comprising an Fe region with a ten-amino-acid hinge deletion and a negatively charged pair mutation such as FcA16(-,CC) (e.g., a GDF15 molecule comprising an FcA16(-,CC) Fe region). An FcA16(+,K) Fe molecule can dimerize with a molecule comprising an Fe region comprising a ten-amino-acid hinge deletion and a negatively charged pair mutation such as FcA16(-) (e.g., a GDF15 molecule comprising an FcA16(+) Fe region).An Fe molecule of FcA10(+,K,L234A / L235A) can dimerize with a molecule comprising an Fe region comprising a ten-amino-acid hinge deletion and a negatively charged pair mutation such as FcA10(-, L234A / L235A) (e.g., a GDF15 molecule comprising an Fe region of FcA10(-, L234A / L235A)). Examples of GDF15 molecules that are GDF15-Fc fusion proteins are shown in Table 5. MA / a / ZUZl / UlU / ot Table 5 - GDF15 Molecules GDF15-Fc fusion protein GDF15-Fc fusion protein components SEQ ID NO SEQID NO. Designation Sequence Fe Region Linked r Region GDF15 38 scFc-GDF15 GGGERKSSVECPPCPAPPV AGPSVFLFPPKPKDTLMISR TPEVTCWVDVSHEDPEVQF NWYVDGVEVHNAKTKPREE QFNSTFRVVSVLTWHQDW LNGKEYKCKVSNKGLPAPIE KTISKTKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYK TTPPMLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGGGG GSGGGSGGGSGGGSGGGS GGGGSGGGSGGGSGGGSGGGSGGGSGG GGSERKSSVECPCPAPPV AGPSVFLFPPKPKDTLMISR TPEVTCVVVDVSHEDPEVQF NWYVDGVEVHNAKTKPREE QFNSTFRVVSVLTWHQDW LNGKEYKCKVSNKGLPAPIE KTISKTKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYK TTPPMLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPGSGG GGSGGGSGGGSGGGSGGGG SARNGDHCPLGPGRCCRLH TVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAAN Μ H AQIKTS LH RLKP DTVP AP CCVPASYNPMVLIQKTDTGV SLQTYDDLLAKDCHCI 39 26 21 6 MA / a / zuzi / uiur ót VMHEALHNHYTQKSLSLSP GGGGGSGGGGSGGGGSG GGGSARNGDHCPLGPGRC CRLHTVRASLEDLGWADWV LSPREVQVTMCIGACPSQFR AANMHAQIKTSLHRLKPDTV PAPCCVPASYNPMVLIQKTD TGVSLQTYDDLLAKDCCHI Los restos subrayados y en negrita son las mutaciones K392D y K409D. 40 FcA10(+)(G4)-GDF15 APELLGGPSVFLFPPKPKDT LMI SRTP E VTC WVDVS H ED PEVKFNWYVDGVEVHNAKT KPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQV YTLPPSRKEMTKNQVSLTCL VKGFYPSDIAVEWESNGQP ENNYKTTPPVLKSDGSFFLY SKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSP GGGGGARNGDHCPLGPGR CCRLHTVRASLEDLGWADW VLSPREVQVTMCIGACPSQF RAANMHAQIKTSLHRLKPDT VPAPCCVPASYNPMVLIQKT DTGVSLQTYDDLLAKDCCHI The rest of the sub-rayados and the other ones are E356K and D399K. 27 23 6 41 FcA10(-)- GDF15(A3) APELLGGPSVFLFPPKPKDT LM I SRTP E VTC WVDVS H ED PEVKFNWYVDGVEVHNAKT KPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNKAL 26 13 MA / a / 4ÍU¿l / UlU / PAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLY 5 10 15 SDLTVD KS RWQQG N VFSCS VMHEALHNHYTQKSLSLSP GGDHCPLGPGRCCRLHTVR ASLEDLGWADWVLSPREVQ VTMCIGACPSQFRAANMHA QIKTSLHRLKPDTVPAPCCV PASYNPMVLIQKTDTGVSLQ TYDDLLAKDCCHI Los restos subrayados y en negrita son las mutaciones K392D y K409D. 20 25 30 35 42 FcA10(-)- GDF15(N3D) APELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKT KPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLY S DLTVD KS RWQQG N VFSCS VMHEALHNHYTQKSLSLSP GARDGDHCPLGPGRCCRLH TVRASLEDLGWADWVLSPR EVQVTMCIGACPSQFRAAN Μ H AQIKTS LH RLKP DTVP AP CCVPASYNPMVLIQKTDTGV SLQTYDDLLAKDCCHI Los restos subrayados y en negrita son las mutaciones K392D y K409D. 26 15 43 FcA10(,CC)GDF15(A3) APELLGGPSVFLFPPKPKDT LMISRTP E VTCWVDVS H ED PEVKFNWYVDGVEVHNACT KPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKAL PAPERQPPREPQCVSQLQTCL VKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLY SDLTVD KS RWQQG N VFSCS VMHEALHNHYTQKSLSLSP GGDHCPLGPGRCCRLHTVR ASLEDLGWADWVLSPREVQ VTMCIGACPSQFRAANMHA QIKTSLKVLSPREVCLVPDVLDQTQTQ TYDDLLAKDCHCI The underlined and italicized residue is the Y349C mutation; the underlined and bold residues are the K392D and K409D mutations. 28 13 44 FcA10(- ,CC)- GDF15(N3D) APELLGGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNACT KPREEQYNSTYRVVSVLTVL HQDWLNGKEYKKVSKKKKKKKQPQQ CTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLY SDLTVD KS RWQQG N VFSCS VMHEALHNHYTQKSLSLSP GARDGDHCPLGPGRCCRLH TVRASLEDLGWADWVLSPR EVQVTMFRCCIAN 28CPSQ15 MA / a / juzi / uiur ot Μ H AQIKTS LH RLKP DTVP AP CCVPASYNPMVLIQKTDTGV SLQTYDDLLAKDCHCI The residue underlined and in 5 italics is mutation Y349C; the underlined and bold residues are the K392D and K409D mutations. 10 15 20 25 30 45 FcA16(,CC)GDF15(A3 / D 5E) GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKAL PAPER TISKAKGQPREPQVCTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNEDT TPPVLDSDGSFFLYSDLTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGGEHCP LGPGRCCRLHTVRASLEDL G WAD WVLS P RE VQVTMCIG ACPSQFRAANMHAQIKTSLH RLKPDTVPAPCCVPASYNP MVLIQKTDTGVSLQTYDDLL AKDCHCI The underlined and italicized residue is mutation Y349C; the underlined and bold residues are the K392D and K409D mutations. 29 17 35 46 FcA16(,CC)GDF15(N3Q / D5E) GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVCTLPPS 29 18 MA / a / judge / uiur ót REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTVD KSRWQQGNVFSCSVMHEAL 5 10 15 HNHYTQKSLSLSPGARQGE HCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTM CIGACPSQFRAANMHAQIKT SLHRLKPDTVPAPCCVPASY NPMVLIQKTDTGVSLQTYDD LLAKDCHCI The underlined and italicized remainder is the Y349C mutation; the underlined and bold remainders are the K392D and K409D mutations. 20 25 30 35 47 FcA16(-)- GDF15(N3Q / D5E) GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGARQGE HCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTM CIGACPSQFRAANMHAQIKT SLHRLKPDTVPAPCCVPASY NPMVLIQKTDTGVSLQTYDD LLAKDCHCI The underlined remains The K392D and K409D mutations are shown in bold. 30 18 MA / a / zuzi / uiur ót 48 FcA16(-)- (G4Q)4GDF15 GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEWKFN WYVDGVEVHNACTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKCKVSNCALPAPIEK TISKGPRQPQPQP REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPPGGGGGQ GGGGQGGGGQGGGQAR NGDHCPLGPGRCCRL VTMCIGACPSQFRAANMHA QIKTSSLHRLKPDTVPAPCCV PASYNPMVLIQKTDTGVSLQ TYDDLLAKDCHCI The underlined and bold residues are the K392D and K409D mutations. 30 25 6 49 FcA16(-)- (G4Q)4- GDF15(N3Q GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEWKFN WYVDGVVHNACTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKKPACKPAEKVSNKVS TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGGGGGQ GGGGQGGGGQGGGGGGGGGGCPLVRGR ASLEDLGWADWVLSPREVQ VTMCIGACPSQFRAANMHA 30 25 14 ΜΛ / a / zuzi / uiur ót QIKTSLHRLKPDTVPAPCCV PASYNPMVLIQKTDTGVSLQ TYDDLLAKDCHCI The residues underlined and in bold 5 are the K392D and K409D mutations. 10 15 20 25 50 FcA16(-)- (G4Q)4- GDF15(N3Q / D5E) GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEWKFN WYVDGVVHNAKTKPREEQ YNSTYRVVSVLTVLKQLQKKWKW TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGGGGGQ GGGGQGGGGQGGGGGGQPLQPLHRGVRGC ASLEDLGWADWVLSPREVQ VTMCIGACPSQFRAANMHA QIKTSLHRLKPDTVPAPCCV PASYNPMVLIQKTDTGVSLQ TYDDLLAKDCHCI The underlined and bold residues are the K392D and K409D mutations. 30 25 18 30 35 51 FcA16(-)- (G4S)2- GDF15(N3Q GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEWKFN WYVDGVVHNAKTKPREEQ YNSTYRVVSVLTVLHQLNGKKWKKKPIKVKVKVKFN TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGFFFLYSDLTTVD 30 20 14 MA / a / juzi / uiur ot KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGGGGGS GGGGSARQGDHCPLGPGR CCRLHTVRASLEDLGWADW VLSPREVQVTMCIGACPSQF RAANMHAQIKTSLHRLKPDT VPAPCCVPASYNPMVLIQKT DTGVSLQTYDDLLAKDCHCI The underlined and bold remains are the K392D and K409D mutations. 52 FcA16(-)- (G4S)2GDF15(N3Q / D5E) GPSVFLFPPKPKDTLMISRT PEVTCWVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGGGGGS GGGGSARQGEHCPLGPGR CCRLHTVRASLEDLGWADW VLSPREVQVTMCIGACPSQF RAANMHAQIKTSLHRLKPDT VPAPCCVPASYNPMVLIQKT DTGVSLQTYDDLLAKDCHCI The underlined and bold remains These are the K392D and K409D mutations. 30 20 18 53 FcA16(-)- G4SGDF15(N3Q GPSVFLFPPKPKDTLMISRT PEVTCWVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEK 30 19 14 MA / a / ZUZl / UlU / TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTTVD 5 10 15 KSRWQQGNVFSCSVMHEAL HNHYTQSLSLSPGGGGGS ARQGDHCPLHCPLGPLADWLEWLEW VQVTMCIGACPSQFRAANM HAQIKTSLHRLKPDTVPAPC CVPAS YN PM VLI QKTDTGVS LQTYDDLLAKDCHCI The underlined and bold residues are the K392D and K409D mutations. 20 25 30 35 54 FcA16(-)- G4SGDF15(N3Q / D5E) GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEWKFN WYVDGVVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWL NGKYKPIKVSKEK TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGGGGS ARQGEHCPLGPGRCCRLHT VRADVLSPRDLWLEGWLEW VQVTMCIGACPSQFRAANM HAQIKTSLHRLKPDTVPAPC CVPAS YN PM VL I QKTDTG VS LQTYDDLLAKDCHCI The underlined and bold residues are the K392D and K409D mutations. 30 19 18 MA / a / juzi / uiur ot 55 FcA16(-)- GDF15(N3Q GPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQ YNSTYRVVSVLTVLHQDWL NGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYDT TPPVLDSDGSFFLYSDLTVD KSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPGARQGD HCPLGPGRCCRLHTVRASL EDLGWADWVLSPREVQVTM CIGACPSQFRAANMHAQIKT SLHRLKPDTVPAPCCVPASY NPMVLIQKTDTGVSLQTYDD LLAKDCHCI The underlined and bolded remains are the K392D and K409D. 30 14 56 FcA10(,L234A / L235 A)-(G4Q)4- GDF15(N3Q APEA4GGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKT KPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLY S DLTVD KS RWQQG N VFSCS VMHEALHNHYTQKSLSLSP GGGGGQGGGGQGGGGQG GGGQARQGDHCPLGPGRC CRLHTVRASLEDLGWADWV LSPREVQVTMCIGACPSQFR AANMHAQIKTSLHRLKPDTV 31 25 14 PAPCCVPASYNPMVLIQKTD TGVSLQTYDDLLAKDCHCI The underlined and italicized remnants are the L234A and L235A mutations; the underlined and bold remnants are the K392D and K409D mutations. 57 FcA10(,L234A / L235 A)-(G4Q)4GDF15(N3Q / D5E) APEA4GGPSVFLFPPKPKDT LMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKT KPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCL VKGFYPSDIAVEWESNGQP ENNYDTTPPVLDSDGSFFLY S DLTVD KS RWQQG N VFSCS VMHEALHNHYTQKSLSLSP GGGGGQGGGGQGGGGQG GGGQARQGEHCPLGPGRC CRLHTVRASLEDLGWADWV LSPREVQVTMCIGACPSQFR AANMHAQIKTSLHRLKPDTV PAPCCVPASYNPMVLIQKTD TGVSLQTYDDLLAKDCHCI The underlined and italicized remnants are the L234A and L235A mutations; the underlined and bold remnants are the K392D and K409D mutations. 31 25 18 In some embodiments, the fusion protein is an scFc-GDF15 in which the GDF15 region is linked to two Fe regions. In some embodiments, the fusion protein comprises an amino acid sequence that has at least 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 38. In some embodiments, the fusion protein comprises an amino acid sequence of SEQ ID NO: 38. When calculating the percentage of sequence identity, the sequences being compared are aligned in a way that gives the greatest match between the sequences. One program that can be used to determine the percentage identity is the GCG program package, which includes GAP (Devereux et al., (1984) Nuci. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, Wis.). The GAP computer algorithm can be used to align the two polypeptides or polynucleotides for which the percentage of sequence identity is to be determined.The sequences are aligned for optimal matching of their respective amino acids or nucleotides (the matching interval, as determined by the algorithm). Along with the algorithm, a gap opening penalty (calculated as 3x the average diagonal, where the average diagonal is the average of the diagonals of the comparison matrix being used; the diagonal is the score or number assigned to each perfect amino acid match by the particular comparison matrix) and a gap extension penalty (typically 1 / 10 times the gap opening penalty) are used, as well as a comparison matrix such as PAM 250 or BLOSUM 62. In certain implementations, the algorithm also uses a standard comparison matrix (see Dayhoff et al., (1978), Atlas of Protein Sequence and Structure 5:345-352 for the PAM 250 comparison matrix; Henikoff et al., (1992) Proc. Nati. Acad. Sci. USA9:10915-10919 for the BLOSUM 62 comparison matrix). The parameters that can be used to determine the percentage of identity using the GAP program are as follows:. Algorithm: Needleman et al., 1970, J. Mol. Biol. 48:443-453; Comparison matrix: BLOSUM 62 from Henikoff et al., 1992, cited above; Penalty for gap: 12 (but no penalty for final gaps) Penalty for gap length: 4 Similarity threshold: 0 Certain alignment schemes for aligning two amino acid sequences can result in the matching of only a short region of the two sequences, and this small aligned region may have a very high sequence identity even if there is no significant relationship between the two full-length sequences. Therefore, it is possible to adjust the selected alignment method (e.g., the GAP program), if desired, to produce an alignment that extends over at least 50 contiguous amino acids of the target polypeptide. In some embodiments, the GDF15 molecule is FcA10(-)-(G4S)4-GDF15, FcA10(+)-(G4)-GDF15, FcA10(-)-GDF15(A3), FcA10(-)-GDF15(N3D), FcA10(-,CC)GDF15(A3), FcA10(-,CC)-GDF15(N3D), FcA16(-,CC)-GDF15(A3 / D5E), FcA16(-,CC)GDF15(N3Q / D5E), FcA16(-)-GDF15(N3Q / D5E), FcA16(-)-(G4Q)4-GDF15, FcA16(-)-(G4Q)4MA / a / zuzi / uiur ót GDF15(N3Q), FcA16(-)-(G4Q)4-GDF15(N3Q / D5E), FcA16(-)-(G4S)2-GDF15(N3Q), FcA16(-)(G4S)2- GDF15(N3Q / D5E), FcA16(-)-G4S-GDF15(N3Q), FcA16(-)-G4S-GDF15(N3Q / D5E), FcA16(-)-GDF15(N3Q), FcA10(-,L234A / L235A)-(G4Q)4-GDF15(N3Q), o FcA10(,L234A / L235A)-(G4Q)4-GDF15(N3Q / D5E). In some embodiments, the GDF15 molecule comprises the amino acid sequence of SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57. In some embodiments, the GDF15 molecules comprise an amino acid sequence having at least 85% sequence identity with SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57. In some embodiments, the GDF15 molecules comprise an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 or 57. In some embodiments, the GDF15 molecules comprise an amino acid sequence that has at least 95% sequence identity with the SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 or 57.In some embodiments, the GDF15 molecules comprise an amino acid sequence having at least 99% sequence identity with SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57. In some embodiments, the GDF15 molecule is a molecule of FcA10(-)-(G4S)4GDF15, FcA10(+)-(G4)-GDF15, FcA10(-)-GDF15(A3), FcA10(-)-GDF15(N3D), FcA10(-,CC)GDF15(Á3), FcA10(-,CC)-GDF15(N3D), FcA16(-,CC)-GDF15(A3 / D5E), FcA16(-,CC)GDF15(N3Q / D5E), FcA16(-)-GDF15(N3Q / D5E), FcA16(-)-(G4Q)4-GDF15, FcA16(-)-(G4Q)4GDF15(N3Q), FcA16(-)-(G4Q)4-GDF15(N3Q / D5E), FcA16(-)-(G4S)2-GDF15(N3Q), FcA16(-)(G4S)2-GDF15(N3Q / D5E), FcA16(-)-G4S-GDF15(N3Q), FcA16(-)-G4S-GDF15(N3Q / D5E), FcA16(-)-GDF15(N3Q), FcA10(-,L234A / L235A)-(G4Q)4-GDF15(N3Q), or FcA10(,L234A / L235A)-(G4Q)4-GDF15(N3Q / D5E) which has at least 85%, 90%, 95% or 99% sequence identity with its Fe region and / or GDF15 region.For example, an FcA10(-)-(G4S)4-GDF15 molecule with at least 85%, 90%, 95%, or 99% sequence identity with its Fe region and / or its GDF15 region, includes a GDF15 molecule with an Fe region having a ten-amino-acid deletion of the hinge region and having a negatively charged pair mutation and having at least 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 26 and / or a GDF15 region having at least 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 6.In another example, an FcÁ16(-)-(G4Q)4-GDF15(N3Q / D5E) molecule with at least 85%, 90%, 95%, or 99% sequence identity with its Fe region and / or a GDF15 region includes a GDF15 molecule with an Fe region having a deletion of sixteen amino acids from the hinge region and a negatively charged pair mutation having at least 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 30 and / or. MA / a / zuzi / uiur or a GDF15 region that has at least 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 18. In another example, an FcA10(-,L234A / L235A)(G4Q)4-GDF15(N3Q / D5E) molecule with at least 85%, 90%, 95%, or 99% sequence identity with its Fe region and / or a GDF15 region includes a GDF15 molecule with an Fe region having a ten-amino-acid deletion of the hinge region, a negatively charged pair mutation, and leucine-to-alanine mutations at positions 234 and 235, and has at least 85%, 90%, 95%, or 99% sequence identity with SEQ ID NO: 31 and / or a GDF15 region that has at least 85%, 90%, 95% or 99% sequence identity with SEQ ID NO: 18. Dimers and tetramers comprising a GDF15 molecule provided herein are also provided. In one embodiment, the dimer comprises a GDF15-Fc fusion comprising the amino acid sequence of any one of the SEQ ID NO: 39-57. In some embodiments, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 or 57 is dimerized with an Fe molecule comprising the amino acid sequence of SEQ ID NO: 32, 33, 34, 35, 36 or 37 (in which the C-terminal lysine is optional) as shown in Table 6. For example, in some embodiments, the dimer is FcA10(-)-(G4S)4-GDF15: FcA10(+,K). In another embodiment, the dimer is FcA10(-,L234A / L235A)-(G4Q)4-GDF15(N3Q): FcA10(+,K,L234A / L235A). In yet another embodiment, the dimer is FcA10(-,L234A / L235A)-(G4Q)4-GDF15(N3Q):FcA10(+,K,L234A / L235A). Table 6 - Dimers SEQ ID NO. of the GDF15Fc fusion Name of the GDF15-Fc fusion SEQ ID NO. of the Fe molecule Number of the corresponding Fe molecule 39 FcA10(-)-(G4S)4-GDF15 32 FcA10(+,K) 40 FcA10(+)-(G4)-GDF15 33 FcA10(-,K) 41 FcA10(-,K) FcA10(+,K) 42 FcA10(-,K)-GDF15(N3D) 32 FcA10(+,K) 43 FcA10(-,CC)-GDF15(A3) 34 FcA10(+,K,CC) 44 FcA10(-,CC)-GDF15(N3D) 34 FcA10(+,K,CC) 45 FcA16(-,CC)-GDF15(A3 / D5E) 35 FcA16(+,K,CC) 46 FcA16(-,CC)-GDF15(N3Q / D5E) 35 FcA16(+,K,CC) 47 FcA16(-)-GDF15(N3Q / D5E) 36 FcA16(+,K) 48 FcA16(-)-(G4Q)4-GDF15 36 FcA16(+,K) 49 FcA16(-)-(G4Q)4-GDF15(N3Q) 36 FcA16(+,K) 50 FcA16(-)-(G4Q)4- GDF15(N3Q / D5E) 36 FcA16(+,K) 51 FcA16(-)-(G4S)2-GDF15(N3Q) 36 FcA16(+,K) 52 FcA16(-)-(G4S)2- GDF15(N3Q / D5E) 36 FcA16(+,K) 53 FcA16(-)-G4S- GDF15(N3Q) 36 FcA16(+,K) 54 FcA16(-)-G4S-GDF15(N3Q / D5E) 36 FcA16(+,K) 55 FcA16(-)-GDF15(N3Q) 36 FcA16(+,K) 56 FcA10(-,L234A / L235A)-(G4Q)4- GDF15(N3Q) 37 FcA10(+,K,L234A / L235A) 57 FcA10(-,L234A / L235A)-(G4Q)4- GDF15(N3Q / D5E) 37 FcA10(+,K,L234A / L235A) This is real, we use GDF15-Fc que Include the amino acids MA / a / zuzi / uiur ót of SEQ ID NO: 39 dimerizes with an Fe molecule comprising SEQ ID NO: 32 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 40 dimerizes with an Fe molecule comprising SEQ ID NO: 33 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 41 dimerizes with an Fe molecule comprising SEQ ID NO: 32 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 42 dimerizes with an Fe molecule comprising SEQ ID NO: 32 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 43 dimerizes with an Fe molecule comprising SEQ ID NO: 34 (optional C-terminal lysine).In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 44 dimerizes with an Fe molecule comprising SEQ ID NO: 34 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 44 dimerizes with an Fe molecule comprising SEQ ID NO: 34 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 45 dimerizes with an Fe molecule comprising SEQ ID NO: 35 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 46 dimerizes with an Fe molecule comprising SEQ ID NO: 35 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 47 dimerizes with an Fe molecule comprising SEQ ID. NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 48 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 49 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 50 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 51 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine).In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 52 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 53 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 54 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 55 dimerizes with an Fe molecule comprising SEQ ID NO: 36 (optional C-terminal lysine). In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 56 dimerizes with an Fe molecule comprising SEQ ID NO: 37 (optional C-terminal lysine).In another embodiment, a GDF15-Fc fusion comprising the amino acid sequence of SEQ ID NO: 57 dimerizes with an Fe molecule comprising SEQ ID NO: 37 (optional C-terminal lysine). In some embodiments, dimers form tetramers. For example, the dimers in Table 6 can form tetramers. In some embodiments, tetramers are formed from the same dimers. In some embodiments, two dimers of FcA10(-)-(G4S)4GDF15:FcA10(+,K); FcA10(+)-(G4)-GDF15:FcA10(-,K); FcA10(-)-GDF15(A3):FcA10(+,K); FcA10(-)-GDF15(N3D):FcA10(+,K); FcA10(−,CC)-GDF15(A3):FcA10(+,K,CC); FcA10(-,CC)GDF15(N3D):FcA10(+,K,CC); FcA16(-,CC)-GDF15(A3 / D5E):FcA16(+,K,CC); FcA16(-,CC)GDF15(N3Q / D5E):FcA16(+,K,CC); FcA16(-)-GDF15(N3Q / D5E):FcA16(+,K); FcA16(-)-(G4Q)4GDF15:FcA16(+,K); FcA16(-)-(G4Q)4-GDF15(N3Q):FcA16(+,K); FcA16(-)-(G4Q)4GDF15(N3Q / D5E):FcA16(+,K); FcA16(-)-(G4S)2-GDF15(N3Q):FcA16(+,K); FcA16(-)-(G4S)2GDF15(N3Q / D5E):FcA16(+,K); FcA16(-)-G4S- GDF15(N3Q):FcA16(+,K); FcA16(-)-G4SGDF15(N3Q / D5E): FcA16(+,K); FcA16(-)-GDF15(N3Q): cA16(+,K); FcA10(-,L234A / L235A)(G4Q)4-GDF15(N3Q):FcA10(+,K,L234A / L235A); or FcA10(-,L234A / L235A)-(G4Q)4GDF15(N3Q / D5E):FcA10(+,K,L234A / L235A) form a tetramer, such as through dimerization of the two regions of GDF15. ινΐΛ / a / zuz ι / ui day / Also provided herein are host cells comprising the nucleic acids and vectors for producing the GDF15 and Fe molecules disclosed herein. In some embodiments, the vector or nucleic acid is integrated into the host cell genome; in other embodiments, the vector or nucleic acid is extrachromosomal. Recombinant cells, such as yeast cells, bacterial cells (e.g., E. coli), and mammalian cells (e.g., immortalized mammalian cells), are provided, comprising the nucleic acid, vector, or combinations thereof. In various embodiments, the cells comprise a non-integrated nucleic acid, such as a plasmid, cosmid, phagemid, or linear expression element comprising a sequence encoding the expression of a GDF15 molecule and / or an Fe molecule. In some embodiments, one cell comprises a nucleic acid for the production of a GDF15 molecule, and another cell comprises a nucleic acid for the production of an Fe molecule for dimerization with the GDF15 molecule (e.g., a vector for encoding a GDF15 molecule in one cell and a second vector for encoding an Fe molecule in a second cell).In other embodiments, a host cell comprises a nucleic acid for the production of a GDF15 molecule and an Fe molecule (e.g., a vector encoding both molecules). In another embodiment, a host cell comprises a nucleic acid for producing a GDF15 molecule and another nucleic acid for producing an Fe molecule (e.g., two separate vectors, one encoding a GDF15 molecule and one encoding an Fe molecule, within a single host cell). A vector comprising a nucleic acid sequence encoding a GDF15 molecule and / or an Fe molecule can be introduced into a host cell by transformation or transfection, such as by methods known in the field. A nucleic acid encoding a GDF15 molecule can be placed into and / or delivered to a host cell or animal via a viral vector. A viral vector may comprise any number of viral polynucleotides, alone or in combination with one or more viral proteins, facilitating the delivery, replication, and / or expression of the nucleic acid of the invention in a desired host cell. The viral vector may be a polynucleotide comprising all or part of a viral genome, a viral protein / nucleic acid conjugate, a virus-like particle (VLP), or an intact virus particle comprising viral nucleic acids and a nucleic acid encoding a polypeptide comprising a GDF15 region. A virus-particle vector may comprise a wild-type virus particle or a modified virus particle.The viral vector can be a vector that requires the presence of another vector or wild-type virus for replication and / or expression (for example, a viral vector can be a helper-dependent virus), such as an adenoviral vector amplicon. Viral vector particles. Suitable MA / a / zuzi / uiur vectors in this sense include, for example, adenoviral vector particles (including any virus of or derived from an Adenoviridae virus), adeno-associated viral vector particles (AAV vector particles) or other parvoviruses and parvoviral vector particles, papillomavirus vector particles, flaviviral vectors, alphaviral vectors, herpesvirus vectors, varicella-zoster virus vectors, retroviral vectors, including lentiviral vectors. A GDF15 molecule can be isolated using conventional protein purification methods. A polypeptide comprising a GDF15 region can be isolated from a cell that has been genetically engineered to express a polypeptide comprising a GDF15 region, for example, a cell that does not naturally express natural GDF15. Known protein purification methods can be employed to isolate GDF15 molecules, as well as associated materials and reagents. Purification methods for a single GDF15 molecule are also provided in the Examples section of this document. Additional purification methods that may be useful for isolating GDF15 molecules can be found in references such as Bootcov MR, 1997, Proc. Nati. Acad. Sel. USA 94:11514-9, and Fairlie WD, 2000, Gene 254: 67-76. Pharmaceutical compositions comprising a GDF15 molecule (and optionally, an Fe molecule, such as a dimer or tetramer disclosed herein) are also provided. Such polypeptide pharmaceutical compositions may comprise a therapeutically effective amount of a GDF15 molecule mixed with a pharmaceutically or physiologically acceptable formulation agent or vehicle selected for suitability with the mode of administration. The pharmaceutically or physiologically acceptable formulation agent may be one or more formulation agents suitable for achieving or enhancing the delivery of a GDF15 molecule into the human or non-human subject body. Pharmaceutically acceptable substances such as wetting or emulsifying agents, preservatives, or buffers that enhance the shelf life or efficacy of the GDF15 molecule may also act as, or form a component of, a formulation vehicle.Pharmaceutically acceptable vehicles are preferably non-toxic to the recipients at the dosages and concentrations used. The pharmaceutical composition may contain formulation agents to modify, maintain, or preserve, for example, pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption, or penetration of the composition. The effective amount of a pharmaceutical composition containing a GDF15 molecule for therapeutic use will depend, for example, on the therapeutic area and objectives. A practitioner will appreciate that the appropriate dosage levels for treatment will therefore vary depending, in part, on the specific molecule. The dosage frequency depends on the indication for which a GDF15 molecule is being used, the route of administration, and the size (body weight, body surface area, or organ size) and condition of the subject (age and general health). The dosage frequency will depend on the pharmacokinetic parameters of the GDF15 molecule in the formulation being used. The pharmaceutical composition can be administered orally; by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intra-arterial, intraportal, or intralesional injection; via sustained-release systems (which can also be injected); or via implantation devices. When desired, the compositions can be administered by bolus injection or continuously by infusion, or via an implantation device. The composition can also be administered locally by implanting a membrane, sponge, or other suitable material in which the desired molecule has been adsorbed or encapsulated.When using an implantation device, the device can be implanted in any suitable tissue or organ, and the delivery of the desired molecule can be by diffusion, programmed release bolus, or continuous delivery. A GDF15 molecule can be used to treat, diagnose, or improve a metabolic condition or disorder. In one embodiment, the metabolic disorder is diabetes, for example, type 2 diabetes. In another embodiment, the metabolic condition or disorder is obesity. In other embodiments, the metabolic condition or disorder is dyslipidemia, elevated glucose levels, elevated insulin levels, or diabetic nephropathy. For example, a metabolic condition or disorder that can be treated or improved using a GDF15 molecule includes a state in which the human subject has a fasting blood glucose level of 125 mg / dL or higher, for example, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, or more than 200 mg / dL. Blood glucose levels can be determined while fasting, after eating, or randomly.A metabolic condition or disorder may also encompass a condition in which an individual is at elevated risk of developing a metabolic disorder. For a human subject, such conditions include a fasting blood glucose level of 100 mg / dL. Conditions that can be treated using a pharmaceutical composition comprising a GDF15 molecule can also be found in American Diabetes Association Standards of Medical Care in Diabetes Care - 2011, American Diabetes Association, Diabetes Care Vol. 34, Supplement No. 1, S11-S61, 2010. Administration can be by IV injection, intraperitoneal (IP) injection, subcutaneous injection, intramuscular injection, or orally in tablet or liquid form. A therapeutically effective dose of a GDF15 molecule will depend on the administration schedule and the unit dose of agent administered. The effectiveness of GDF15 depends on whether the GDF15 molecule is administered in combination with other therapeutic agents, the recipient's immune status, and overall health. A therapeutically effective dose is an amount of GDF15 that elicits a biological or medical response in a tissue system, animal, or human, as observed by a researcher, physician, or other practitioner. This response includes relief or improvement of symptoms of the disease or disorder being treated; that is, an amount of GDF15 that ensures an observable level of one or more desired biological or medical responses, such as a reduction in blood glucose, insulin, triglyceride, or cholesterol levels; a reduction in body weight; improved glucose tolerance, energy expenditure, or insulin sensitivity; or reduced food intake. A therapeutically effective dose of GDF15 may also vary depending on the desired outcome. Also provided herein is a method comprising measuring a baseline level of one or more metabolically relevant compounds such as glucose, insulin, cholesterol, or lipid in a subject, administering a pharmaceutical composition comprising a GDF15 molecule to the subject, and after a desired period of time, measuring the level of the one or more metabolically relevant compounds (e.g., blood glucose, insulin, cholesterol, or lipid) in the subject. The two levels can then be compared to determine the relative change in the metabolically relevant compound in the subject. Based on the result of that comparison, another dose of the pharmaceutical composition can be administered to achieve a desired level of one or more metabolically relevant compounds. A GDF15 molecule (and optionally, its corresponding Fe molecule) can be administered in combination with another therapeutic agent, such as an agent that reduces blood glucose, insulin, triglyceride, or cholesterol levels; reduces body weight; reduces food intake; improves glucose tolerance, energy expenditure, or insulin sensitivity; or any combination thereof (e.g., antidiabetic agent, hypolipidemic agent, antiobesity agent, antihypertensive agent, or peroxisome proliferator-activated receptor agonist).For example, the agent may be selected from insulin, insulin derivatives and mimetics; insulin secretagogues; glyburide, amaryl; insulinotropic sulfonylurea receptor ligands; thiazolidinediones, pioglitazone, balaglitazone, rivoglitazone, netoglitazone, troglitazone, englitazone, ciglitazone, adaglitazone, darglitazone, cholesteryl ester transfer protein (CETP) inhibitors, GSK3 (glycogen synthase kinase-3) inhibitors; RXR ligands; sodium-dependent glucose cotransporter inhibitors; glycogen phosphorylase A inhibitors; biguanides; alpha-glucosidase inhibitors, GLP-1 (glucagon-like peptide-1), GLP-1 analogues, GLP-1 mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors; squalene synthase inhibitors; MA / a / zuzi / uiur ót FXR (farnesoid X receptor), LXR (hepatic X receptor) ligands; cholestyramine; fibrates; nicotinic acid, aspirin; orlistat, rimonabant; loop diuretics, furosemide, torsemide; angiotensin-converting enzyme (ACE) inhibitors; NaK-ATPase membrane pump inhibitors; neutralendopeptidase (NEP) inhibitors; ACE / NEP inhibitors; angiotensin II antagonists; renin inhibitors; β-adrenergic receptor blockers; inotropic agents, dobutamine, milrinone; calcium channel blockers; aldosterone receptor antagonists; aldosterone synthase inhibitors; fenofibrate, pioglitazone, rosiglitazone, tesaglitazar, BMS-298585 and L-796449. The agent administered with a GDF15 molecule disclosed herein may be a GLP-1R agonist or a GIPR antagonist. A GLP-1R agonist may be a compound with GLP-1R activity. The GLP-1R agonist may be an exendin, an exendin analogue, or an exendin agonist. Exendin includes naturally occurring exendin peptides (or synthetic versions of naturally occurring exendin) found in the salivary secretions of the Gila monster. Exendin may be exendin-3: HSDGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO: 58); or exendin-4: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2 (SEQ ID NO: 59). The exendine, exendine analogue, and exendine agonist described herein may optionally be amidated, in acid form, in pharmaceutically acceptable salt form, or in any other physiologically active form.Synthetic exendin-4, also known as exenatide, is commercially available as BYETTA® (Amylin Pharmaceuticals, Inc. and Eli Lilly and Company). Other examples of exendin analogues and exendin agonists that may be used in combination with a GDF15 molecule disclosed herein are described in WO 98 / 05351; WO 99 / 07404; WO 99 / 25727; WO 99 / 25728; WO 99 / 40788; WO 00 / 41546; WO 00 / 41548; WO 00 / 73331; WO 01 / 51078; WO 03 / 099314; U.S. Patent No. 6,956,026; U.S. Patent No. 6,506,724; and U.S. Patent No. 6,506,724. U.S. Patent No. 6,703,359; U.S. Patent No. 6,858,576; U.S. Patent No. 6,872,700; U.S. Patent No. 6,902,744; U.S. Patent No. 7,157,555; U.S. Patent No. 7,223,725; U.S. Patent No. 7,220,721; U.S. Publication No. 2003 / 0036504; U.S. Publication No. 2006 / 0094652; and U.S. Publication No. 2018 / 0311372, the descriptions of which are incorporated herein by reference in their entirety. In one embodiment, the GLP-1R agonist is GLP-1 or an analog thereof, such as GLP-1(7-37): HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 60) or a GLP-1(7-37) analog. A GLP-1(7-37) analog may be a peptide that elicits biological activity similar to that of GLP-1(7-37) when assessed by known measurements in the art, such as receptor-binding assays or in vivo blood glucose assays, as described, for example, by Hargrove et al., Regulatory Peptides, 141:113-119 (2007), the description of which is incorporated herein by reference. In one embodiment, an analog GLP-1(7-37) analogue refers to a peptide having an amino acid sequence with 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions, insertions, deletions, or a combination of two or more of these, when compared to the amino acid sequence of GLP-1(7-37). In one embodiment, the GLP-1(7-37) analogue is GLP-1(7-36)-NH2. GLP-1(7-37) analogues include the amidated forms, the acidic form, the pharmaceutically acceptable salt form, and any other physiologically active form of the molecule. In some embodiments a simple nomenclature is used to describe the GLP-1R agonist, for example, [Aib8]GLP-1(7-37) designates an analogue of GLP-1(7-37) in which the naturally occurring Ala at position 8 has been replaced with Aib.Other GLP-1(7-37) or GLP-1(7-37) analogues that may be used in combination with a GDF15 molecule disclosed herein include liraglutide (VICTOZA®, Novo Nordisk); albiglutide (SYNCRIA®, GlaxoSmithKline); taspoglutide (Hoffman La-Roche); dulaglutide (also known as LY2189265; Eli Lilly and Company); or LY2428757 (Eli Lilly and Company). In one embodiment the GLP-1R agonist is dulaglutide and comprises the amino acid sequence: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGSGGGGSAESKYGPPCPPCPA PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 61), Which optionally has a lysine at a C terminus. One or more of the GLP-1 analogues described in Pat. U.S. Patent No. 6,268,343; U.S. Patent Nos. 7,452,966; and U.S. Publication No.° 2018 / 0311372, which is incorporated herein by reference in its entirety, may also be used in combination with a GDF15 molecule disclosed herein. In one embodiment, a GDF15 molecule comprising the amino acid sequence of SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 or 57 is administered with a molecule comprising the amino acid sequence of SEQ ID NO: 58, 59, 60 or an amidated analogue therein. In one embodiment, a GDF15 molecule comprising the amino acid sequence of SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 or 57 is administered with dulaglutide, such as a molecule comprising the amino acid sequence of SEQ ID NO: 61. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 39 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 40 and 33 (optional C-terminal lysine), SEQ ID NO: 41 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 42 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 43 and 34 (optional C-terminal lysine), respectively; SEQ ID NO: 44 and 34 (optional C-terminal lysine), respectively; the MA / a / zuzi / uiur ót SEQ ID NO: 45 and 35 (Optional C-terminal power plant), respectively; SEQ ID NO: 46 and 35 (Optional C-terminal lysine), respectively; SEQ ID NO: 47 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 48 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 49 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 50 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 51 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 52 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 53 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 54 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 55 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 56 and 37 (optional C-terminal lysine), respectively; or SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively;It is administered with a molecule comprising the amino acid sequence of SEQ ID NO: 58, 59, 60 or an amidated analogue therein.; In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 39 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 40 and 33 (optional C-terminal lysine), SEQ ID NO: 41 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 42 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 43 and 34 (optional C-terminal lysine), respectively; SEQ ID NO: 44 and 34 (optional C-terminal lysine), respectively; SEQ ID NO: 45 and 35 (optional C-terminal lysine), respectively; SEQ ID NO: 46 and 35 (optional C-terminal lysine), respectively; SEQ ID NO: 47 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 48 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 49 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively;SEQ ID NO: 51 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 52 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 53 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 54 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 55 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 56 and 37 (optional C-terminal lysine), respectively; or SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively; is administered with dulaglutide, such as a molecule comprising the amino acid sequence of SEQ ID NO: 61. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively, are administered with a molecule comprising the amino acid sequence of SEQ ID NO: 58, 59, 60 or an amidated analogue therein. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively, are MA / a / zuzi / uiur ót is administered with dulaglutide, such as a molecule comprising the amino acid sequence of SEQ ID NO: 61. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively, are administered with a molecule comprising the amino acid sequence of SEQ ID NO: 58, 59, 60 or an amidated analogue therein. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively, are administered with dulaglutide, such as a molecule comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, a GDF15 molecule disclosed herein is administered with a GIPR antagonist, such as an antigen-binding protein that binds specifically to a human GIPR. In one embodiment, the antigen-binding protein binds specifically to a human GIPR comprising or consisting of the amino acid sequence of: MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPS GLACNGSFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHT QCENPEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFML RAAAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVYLHSLL VLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPILMTILIN FLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPLLGVHEVVFAPVTEEQARGALRFAKLGF EIFLSSFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQRQLPERAFRALPSGSGPGE VPTSRGLSSGTLPGPGNEASRELESYC (SEQ ID NO: 62); MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSV AAGFVLRQCGSDGQWGLWRDHTQCENPEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLAL LILSLFRRLHCTRNYIHINLFTSFMLRAAAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQI VTQYCVGANYTWLLVEGVYLHSLLVLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENT QCWERNEVKAIWWIIRTPILMTILINFLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPLLGV HEVVFAPVTEEQARGALRFAKLGFEIFLSSFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSL GEEQRQLPERAFRALPSGSGPGEVPTSRGLSSGTLPGPGNEASRELESYC (SEQ ID NO: 63); o MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPS GLACNGSFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHT QCENPEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFML RAAAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVYLHSLL VLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPILMTILIN FLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPLLGVHEVVFAPVTEEQARGALRFAKLGF iviA / a / zuz ι / ui uro / EIFLSSFQGFLVSVLYCFINKEVGRDPAAAPALWRRRGTAPPLSAIVSQVQSEIRRGWHHCRL RRSLGEEQRQLPERAFRALPSGSGPGEVPTSRGLSSGTLPGPGNEASRELESYC (SEQ ID NO:64). The antigen-binding protein that specifically binds to a human GIPR polypeptide can inhibit GIPR activation by the GIP ligand and / or inhibit the binding of the GIP ligand to GIPR. The antigen-binding protein may have the ability to prevent or reduce GIP binding to GIPR, where levels can be measured, for example, through methods such as fluorescence- or radioactive-labeled ligand binding studies, or by the methods described herein (e.g., cAMP assay or other functional assays). The reduction can be at least 10, 25, 50, 100% or greater with respect to the pretreatment levels of SEQ ID NO: 62, 63, or 64 under comparable conditions. In certain embodiments, the antigen-binding protein has a KD (equilibrium binding affinity) less than 25 pM, 50 pM, 100 pM, 500 pM, 1 nM, 5 nM, 10 nM, 25 nM or 50 nM. The antigen-binding protein may be a human antigen-binding protein, such as a human antibody. In another embodiment, the antigen-binding protein is an antibody, such as a monoclonal antibody. In some embodiments, the antigen-binding protein is a GIPR antibody disclosed in U.S. Publication No. 2017 / 0275370 or 2018 / 0311372, each of which is incorporated herein by reference in its entirety. In one embodiment, the GIPR antigen-binding protein, such as an antibody, comprises CDRL1, CDRL2, and CDRL3 comprising the amino acid sequence of: RASQSVSSNLA (SEQ ID NO: 65), GAATRAT (SEQ ID NO: 66), and QQYNNWPLT (SEQ ID NO: 67), respectively; SGSSSNIGSQTVN (SEQ ID NO: 68), TNNQRPS (SEQ ID NO: 69), and ATFDESLSGPV (SEQ ID NO: 70), respectively; RASQDIRDYLG (SEQ ID NO: 71), GASSLQS (SEQ ID NO: 72), and LQHNNYPFT (SEQ ID NO: 73), respectively; or RASQGLIIWL (SEQ ID NO: 74), AASSLQS (SEQ ID NO: 75) and QQTNSFPPT (SEQ ID NO: 76), respectively.In one embodiment the GIPR antigen binding protein comprises a CDRH1, CDRH2 and CDRH3 comprising the amino acid sequence of: NYGMH (SEQ ID NO: 77), AIWFDASDKYYADAVKG (SEQ ID NO: 78) and DQAIFGWPDY (SEQ ID NO: 79), respectively; GYYMH (SEQ ID NO: 80), WINPNSGGTNYAQKFQG (SEQ ID NO: 81) and GGDYVFGTYRPHYYYGMDV (SEQ ID NO: 82), respectively; YFGMH (SEQ ID NO: 83), VIWYDASNKYYADAVKG (SEQ ID NO: 84) and DGTIFGVLLGDY (SEQ ID NO: 85), respectively; or SYYWS (SEQ ID NO: 86), RIYTSGSTNYNPSLKS (SEQ ID NO: 87) and DVAVAGFDY (SEQ ID NO: 88), respectively. In one embodiment, the GIPR antigen-binding protein, such as an antibody, comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the MA / a / ZUZl / UlU / amino acid sequences of: the SEQ ID NO: 65-67 and 77-79; SEO ID NO: 68-70 and 80-82; SEO ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively. In one embodiment, the GIPR antigen-binding protein, such as an antibody, comprises a light-chain variable region and a heavy-chain variable region comprising the amino acid sequences of and QVQLVESGGGWQPGRSLRLSCAASGTFFSNYGMHWVRQAPGEGLEWVAAIWFDA SDKYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDQAIFGVVPDYWGQGTLVT VSS (SEQ ID NO: 90), respectively; QSVLTQPPSASGTPGQRVTISCSGSSSNIGSQTVNWYQHLPGTAPKLLIYTNNQRPS GVPDRFSGSKSGTSASLAISGLQSEDEADYFCATFDESLSGPVFGGGTKLTVLG (SEQ ID NO: 91)y QMQVVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPN SGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGGDYVFGTYRPHYYYGM DVWGQGTTVTVSS (SEQ ID NO: 92), respectively; DIQMTQSPSSLSASIGDRVTITCRASQDIRDYLGWYQQKPGKAPKLLIYGASSLQSGV PSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNNYPFTFGQGTKVDIKR (SEQ ID NO: 93) and QVQLVESGGGWQPGRSLRLSCAASGFTFSYFGMHWVRQAPGKGLEWVAVIWYDA SNKYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGTIFGVLLGDYWGQGTLV TVSS (SEQ ID NO: 94), respectively; o DIQMTQSPSSVSASVGDRVTITCRASQGLIIWLAWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTNSFPPTFGQGTKVEIKR (SEQ ID NO: 95) y QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPAGKGLEWIGRIYTSGSTN YNPSLKSRVTMSIDTSKNQFSLKLNSVTAADTAVYYCARDVAVAGFDYWGQGTLVTVSS (SEQ ID NO: 96), respectivamente. This realizaion, the anti-GIPR protein, also comes as an anti-inflammatory, including the following and the other types of amino acids that contain it. EIVMTQSPATLSVSPGERATLLSCRASQSVSSNLAWYQQKPGQAPRLLIYGAATRATGI PARVSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPLTFGGGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 97) y QVQLVESGGGWQPGRSLRLSCAASGFTFSNYGMHWVRQAPGEGLEWVAAIWFDA SDKYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDQAIFGVVPDYWGQGTLVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYR MA / a / zuzi / uiur ót CVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 98), respectivamente; QSVLTQPPSASGTPGQRVTISCSGSSSNIGSQTVNWYQHLPGTAPKLLIYTNNQRPS GVPDRFSGSKSGTSASLAISGLQSEDEADYFCATFDESLSGPVFGGGTKLTVLGQPKAAPSV TLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 99) y QMQVVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPN SGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARGGDYVFGTYRPHYYYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTK PCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 100), respectivamente; DIQMTQSPSSLSASIGDRVTITCRASQDIRDYLGWYQQKPGKAPKLLIYGASSLQSGV PSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNNYPFTFGQGTKVDIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 101) y QVQLVESGGGWQPGRSLRLSCAASGFTFSYFGMHWVRQAPGKGLEWVAVIWYDA SNKYYADAVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGTIFGVLLGDYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTY RCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFS CSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 102), respectivamente; DIQMTQSPSSVSASVGDRVTITCRASQGLIIWLAWYQQKPGKAPKLLIYAASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTNSFPPTFGQGTKVEIKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKA DYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 103) y QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPAGKGLEWIGRIYTSGSTN YNPSLKSRVTMSIDTSKNQFSLKLNSVTAADTAVYYCARDVAVAGFDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLT VLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVK MA / a / zuzi / uiur ót GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK (SEQ ID NO: 104), respectivamente; o MKLPVRLLVLMFWIPASSSDVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGDTYLH WYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAADLGVYFCSQSTHVPPF TFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVL NSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC (SEQ ID NO: 105) y MGWSYIILFLVATATDVHSQVQLQQPGAELVKPGASVKLSCRASGYTFTSNWMHWV KQRPRQGLEWIGEINPSNGRSNYNEKFKTKATLTVDKSSSTAYMQLSSLTSEDSAVYYCARF YYGTSWFAYWGQGTLVAVSAAKTTPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTW NSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGC ​​KPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVWDISKDDPEVQFSWFVDDVEVHTAQTQP REEQFASTFRSVSELPIMHQDWLNGKEFKCRVNSAAFAPIEKTISKTKGRPKAPQVYTIPPPK EQMAKDKVSLTCMITDFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSN WEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID NO: 106), respectively. In one embodiment, a GDF15 molecule comprising the amino acid sequence of SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 or 57 is administered with a GIPR antigen-binding protein, such as an antibody, comprising CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 39 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 40 and 33 (optional C-terminal lysine), SEQ ID NO: 41 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 42 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 43 and 34 (optional C-terminal lysine), respectively; SEQ ID NO: 44 and 34 (optional C-terminal lysine), respectively; SEQ ID NO: 45 and 35 (optional C-terminal lysine), respectively; SEQ ID NO: 46 and 35 (optional C-terminal lysine), respectively; SEQ ID NO: 47 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 48 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 49 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively;SEQ ID NO: 51 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 52 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 53 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 54 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 55 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 56 and 37 (optional C-terminal lysine), respectively; or SEQ ID NO: 57 and 37 (C-terminal lysine; MA / a / zuzi / uiur or optional), respectively; is administered with a GIPR antigen-binding protein, such as an antibody, comprising a CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively, are administered with a GIPR antigen-binding protein, such as an antibody, comprising CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively. In one embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequence of SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively; It is administered with an antibody comprising CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively, are administered with a GIPR antigen-binding protein, such as an antibody, comprising CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively; It is administered with an antibody comprising CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79. In one embodiment, a GDF15 molecule comprising the amino acid sequence of SEQ ID NO: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 or 57 is administered with a GIPR antigen-binding protein, such as an antibody, comprising a light chain variable region and a heavy chain variable region comprising the amino acid sequences of SEQ ID NO: 89 and 90, SEQ ID NO: 91 and 92, SEQ ID NO: 93 and 94, or SEQ ID NO: 95 and 96, respectively. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 39 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 40 and 33 (optional C-terminal lysine), SEQ ID NO: 41 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 42 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 43 and 34 (optional C-terminal lysine), MA / a / zuzi / uiur ót respectively; SEQ ID NO: 44 and 34 (Optional C-terminal lysine), respectively; SEQ ID NO: 45 and 35 (Optional C-terminal lysine), respectively; SEQ ID NO: 46 and 35 (Optional C-terminal lysine), respectively; SEQ ID NO: 47 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 48 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 49 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 50 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 51 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 52 and 36 (Optional C-terminal lysine), respectively; SEQ ID NO: 53 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 54 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 55 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 56 and 37 (optional C-terminal lysine), respectively;or SEQ ID NO: 57 and 37 (Optional C-terminal Unit), respectively; are administered with a GIPR antigen-binding protein, such as an antibody, comprising a light chain variable region and a heavy chain variable region comprising the amino acid sequences of SEQ ID NO: 89 and 90, SEQ ID NO: 91 and 92, SEQ ID NO: 93 and 94, or SEQ ID NO: 95 and 96, respectively.; In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively, are administered with a GIPR antigen-binding protein, such as an antibody, comprising a light-chain variable region and a heavy-chain variable region comprising the amino acid sequences of SEQ ID NO: 89 and 90, SEQ ID NO: 91 and 92, SEQ ID NO: 93 and 94, or SEQ ID NO: 95 and 96, respectively. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively, are administered with a GIPR antigen-binding protein, such as an antibody, comprising a light-chain variable region and a heavy-chain variable region comprising the amino acid sequences of SEQ ID NO: 89 and 90, SEQ ID NO: 91 and 92, SEQ ID NO: 93 and 94, or SEQ ID NO: 95 and 96, respectively. MA / a / zuzi / uiur ót In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively, are administered with a GIPR antigen-binding protein, such as an antibody, comprising a light chain and a heavy chain comprising the amino acid sequences of SEQ ID NO: 97 and 98, SEQ ID NO: 99 and 100, SEQ ID NO: 101 and 102, SEQ ID NO: 103 and 104, or SEQ ID NO: 105 and 106, respectively. In some embodiments, a GDF15 molecule disclosed herein is administered with a GIPR antibody conjugated to a GLP-1R agonist, as disclosed in U.S. Publication No. 2018 / 0311372, which is incorporated herein by reference in its entirety. Other examples of agents that may be used in combination with a GDF15 molecule disclosed herein include rosiglitizine, pioglitizine, repaglinide, nateglitinide, metformin, exenatide, stiagliptin, pramlintide, glipizide, glimeprirideacarbose, orlistat, lorcasermeine, fenterideacarbose, orlistatol, lorcasermemin, notropidiontopiramatob, lixisenatide, canagliflozin, LIK-066, SAR-425899, Tt-401, FGFR4Rx, HDV-biotin, and miglitol. A GDF15 molecule administered with another therapeutic agent may include the concurrent administration of a therapeutically effective amount of the GDF15 molecule (and optionally, its corresponding Fe molecule) and a therapeutically effective amount of the other therapeutic agent.A GDF15 molecule administered with another therapeutic agent may include the subsequent administration of a therapeutically effective amount of the GDF15 molecule (and optionally, its corresponding Fe molecule) and a therapeutically effective amount of the other therapeutic agent, for example, the administration of a therapeutically effective amount of the GDF15 molecule (and optionally, its corresponding Fe molecule) followed by a therapeutically effective amount of the other therapeutic agent or the administration of a therapeutically effective amount of the other therapeutic agent followed by the administration of a therapeutically effective amount of the GDF15 molecule (and, optionally, its corresponding Fe molecule).The administration of a therapeutically effective amount of the GDF15 molecule (and optionally, its corresponding Fe molecule) may be at least 1, 2, 3, 4, 5, 6, or 7 days after the administration of a therapeutically effective amount of the other therapeutic agent. In another embodiment, the administration of a therapeutically effective amount of the other therapeutic agent may be at least 1, 2, 3, 4, 5, 6, or 7 days after the administration of an amount. MA / a / zuzi / uiur ót therapeutically effective of the GDF15 molecule (and optionally, its corresponding Fe molecule). A GDF15 molecule administered concurrently with another therapeutic agent may comprise the administration of a composition comprising both the GDF15 molecule (and optionally, its corresponding Fe molecule) and the other therapeutic agent; for example, a therapeutically effective amount of the GDF15 molecule (and optionally, its corresponding Fe molecule) is combined with a therapeutically effective amount of the other agent prior to administration. In another embodiment, the concurrent administration of the GDF15 molecule (and optionally, its corresponding Fe molecule) and another therapeutic agent may comprise the concurrent administration of a first composition comprising the GDF15 molecule and a second composition comprising the other therapeutic agent. In some embodiments, administering a GDF15 molecule with another therapeutic agent has a synergistic effect. In one embodiment, the effect is greater than that of the GDF15 molecule (and optionally its corresponding Fe molecule) alone or the other agent. In another embodiment, the effect is greater than the additive effect of both agents (the GDF15 molecule and, optionally, its corresponding Fe molecule plus the other agent). In one embodiment, combination therapy (i.e., the administration of one molecule of GDF15, optionally with its corresponding Fe molecule, with another therapeutic agent) has a greater effect than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that monotherapy with GDF15 (administration of the GDF15 molecule, and optionally its corresponding Fe molecule).In another embodiment, combination therapy (i.e., the administration of a GDF15 molecule, optionally with its corresponding Fe molecule, with another therapeutic agent) has a greater effect than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that of monotherapy with the other agent. The effect may be the amount of body weight loss (e.g., reduction in total mass or percentage of body change); reduction in blood glucose, insulin, triglyceride, or cholesterol levels; improvement in glucose tolerance, energy expenditure, or insulin sensitivity; or reduction in food intake. The synergistic effect may occur approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 49, 56, 63, or 70 days after administration. In one embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 39 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 40 and 33 (optional C-terminal lysine), SEQ ID NO: 41 and 32 (optional C-terminal lysine), respectively; SEQ ID NO: 42 and 32 (optional C-terminal lysine) MA / a / zuzi / uiur ót optional C-terminal), respectively; SEQ ID NO: 43 and 34 (optional C-terminal lysine), respectively; SEQ ID NO: 44 and 34 (optional C-terminal lysine), respectively; SEQ ID NO: 45 and 35 (optional C-terminal lysine), respectively; SEQ ID NO: 46 and 35 (optional C-terminal lysine), respectively; SEQ ID NO: 47 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 48 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 49 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 51 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 52 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 53 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 54 and 36 (optional C-terminal lysine), respectively; SEQ ID NO: 55 and 36 (optional C-terminal lysine), respectively;SEQ ID NO: 56 and 37 (optional C-terminal lysine), respectively; or SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively; administered with a GLP-1R agonist or a GIPR antagonist has an effect greater than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that of GDF15 monotherapy; an effect greater than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that of monotherapy with the GLP-1R agonist or GIPR antagonist (i.e., administration of agonist of GLP-1R alone or GIPR antagonist alone);or both, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 49, 56, 63, or 70 days after administration of the agent(s).; In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively, administered with a GLP-1R agonist (e.g., dulaglutide) has a greater effect than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that of monotherapy with GDF15; an effect greater than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that monotherapy with the GLP-1R agonist (e.g., dulaglutide); or both, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 49, 56, 63, or 70 days after administration of the GDF15 molecule and corresponding Fe molecule and / or dulaglutide. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively, administered with a GLP-1 agonist (e.g., dulaglutide) has a greater effect than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, MA / a / zuzi / uiur ót 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that monotherapy with GDF15; an effect greater than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that of monotherapy with the GLP-1 agonist R (e.g., dulaglutide); or both, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 49, 56, 63, or 70 days after administration of the GDF15 molecule and corresponding Fe molecule and / or dulaglutide. In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 50 and 36 (optional C-terminal lysine), respectively, administered with a GIPR antigen-binding protein (e.g., an antibody comprising CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively; or an antibody comprising a light-chain variable region and a heavy-chain variable region comprising the amino acid sequences of SEQ ID NO: 89 and 90, SEQ ID NO: 91 and 92, SEQ ID NO: 93 and 94, or SEQ ID NO: 95 and 96, respectively;or an antibody, comprising a light chain and a heavy chain comprising the amino acid sequences of SEQ ID NO: 97 and 98, SEQ ID NO: 99 and 100, SEQ ID NO: 101 and 102, SEQ ID NO: 103 and 104, or SEQ ID NO: 105 and 106, respectively) has a greater effect than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that monotherapy with GDF15; an effect greater than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that of GIPR antigen-binding protein monotherapy;or both, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 49, 56, 63, or 70 days after administration of the GDF15 molecule and the corresponding Fe molecule and / or the GIPR antigen-binding protein.; In another embodiment, a GDF15 molecule and the corresponding Fe molecule comprising the amino acid sequences of SEQ ID NO: 57 and 37 (optional C-terminal lysine), respectively, administered with a GIPR antigen-binding protein (e.g., an antibody comprising CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of: SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively; or an antibody comprising a light-chain variable region and a heavy-chain variable region comprising the amino acid sequences of SEQ ID NO: 89 and 90, SEQ ID NO: 91 and 92, SEQ ID NO: 93 and 94, or SEQ ID NO: 95 and 96, respectively; or an antibody, comprising a light chain and a heavy chain comprising the sequences MA / a / zuzi / uiur amino acid ot of SEQ ID NO: 97 and 98, SEQ ID NO: 99 and 100, SEQ ID NO: 101 and 102, SEQ ID NO: 103 and 104, or SEQ ID NO: 105 and 106, respectively) has a greater effect than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that monotherapy with GDF15; an effect greater than 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 times that of GIPR antigen-binding protein monotherapy; or both, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 35, 42, 49, 56, 63, or 70 days after administration of the GDF15 molecule and the corresponding Fe molecule and / or the GIPR antigen-binding protein. In one embodiment, the molar ratio of the GDF15 molecule to the GLP-1R agonist or GIPR antagonist is from approximately 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, or 1:1 to 1:5. In one embodiment, the molar ratio of the GDF15 molecule to the GLP-1R agonist or GIPR antagonist is approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 1:10, approximately 1:20, approximately 1:30, approximately 1:40, or approximately 1:50.In one embodiment, the molar ratio of the GDF15 molecule to the GLP-1R agonist (e.g., dulaglutide) is from approximately 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, or 1:1 to 1:5; or approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 1:10, approximately 1:20, approximately 1:30, approximately 1:40, or approximately 1:50.In another embodiment, the molar ratio of the GDF15 molecule with respect to the GIPR antagonist (e.g., GIPR antibody) is from approximately 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, or 1:1 to 1:5; or approximately 1:1 to 1:110, 1:1 to 1:100, 1:1 to 1:75, 1:1 to 1:50, 1:1 to 1:25, 1:1 to 1:10, or 1:1 to 1:5, or is approximately 1:1, approximately 1:2, approximately 1:3, approximately 1:4, approximately 1:5, approximately 1:10, approximately 1:20, approximately 1:30, approximately 1:33, approximately 1:40, or approximately 1:50. In one embodiment, the GDF15 molecule and the GLP-1R agonist or GIPR antagonist are present in doses that are at least approximately 1.1 to 1.4, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times lower than the doses of each compound alone required to have a therapeutic effect (e.g., treating a condition and / or disease; decreasing body weight loss; decreasing blood glucose, insulin, triglyceride, or cholesterol levels; improving glucose tolerance, energy expenditure, or insulin sensitivity; or reducing food intake). MA / a / zuzi / uiur ót The detailed description and the following examples illustrate the present invention and should not be interpreted as limiting it. Those skilled in the art may make various changes and modifications based on the description of the invention, and such changes and modifications are also included in the present invention. EXAMPLES The following examples, including the experiments carried out and the results achieved, are provided for illustrative purposes only and should not be interpreted as limiting the present invention. Example 1: Production of GDF15 molecules FcA10(-)-(G4S)4-GDF15 (SEQ ID NO: 39) was stably expressed in a serum-free, suspension-adapted CHO-K1 cell line. It was cloned into a stable expression vector containing puromycin resistance, while the Fe chain to form a heterodimer with FcA10(-)-(G4S)4-GDF15, FcA10(+,K) (SEQ ID NO: 32), was cloned into an expression vector containing hygromycin (Selexis, Inc.). Plasmids were transfected at a 1:1 ratio using lipofectamine LTX, and cells were selected 2 days post-transfection in a proprietary growth medium containing 10 µg / ml puromycin and 600 µg / ml hygromycin. The medium was changed twice weekly during selection. When the cells reached approximately 90% viability, the seeding rate was increased proportionally for batch production. The cells were seeded at 2 x 10⁶ / ml in production medium.The conditioned medium (CM) produced by the cells was collected on day 7 and cleared. Endpoint viability was typically above 90%. FcA10(-)-(G4S)4-GDF15 (SEQ ID NO: 39) (and any paired Fe) was clarified. The conditioned medium was purified using a two-stage chromatographic procedure. Approximately 5 liters of CM were applied directly to a GE MabSelect SuRe column that had been previously equilibrated with Dulbecco's phosphate-buffered saline (PBS). The bound protein underwent three washes: first, 3 column volumes (CVs) of PBS; then, 1 CV of 20 mM Tris, 100 mM sodium chloride at pH 7.4; and finally, 3 CVs of 500 mM L-arginine at pH 7.5. These washes removed unbound or loosely bound medium components and host cell impurities. The column was then re-equilibrated with 20 mM Tris 5 VC and 100 mM sodium chloride at pH 7.4, which returned the UV absorbance to the initial level. The desired protein was eluted with 100 mM acetic acid at pH 3.6 and collected in bulk.The protein pool was rapidly titrated over a pH range of 5.0 to 5.5 with 1 M Tris-HCl to pH 9.2. The pH-adjusted protein pool was then loaded onto a GE SP Sepharose HP column that had been previously equilibrated with 20 mM MES at pH 6.0. The bound protein was then washed with 5 VC of equilibration buffer and finally eluted in a linear gradient of 0 to 50% sodium chloride (0 to 400 mM) in 20 mM MES at pH 6.0. The fractions were collected during elution and analyzed by size exclusion analytical chromatography (Superdex 200) to determine the appropriate fractions to be combined for a homogeneous product. SP HP chromatography removed impurities associated with the product, such as free Fe, truncated species, and Fc-GDF15 multimers. The SP HP pool was exchanged in 10 mM sodium acetate, 5% proline buffer at pH 5.2 by dialysis. It was concentrated to approximately 15 mg / mL using a Sartorius Vivaspin 20 centrifuge with a 10 kcal molecular weight threshold. Finally, it was sterilized by filtration, and the resulting solution containing the purified FcGDF15 molecules was stored at 5 °C.The identity and purity of the final products were evaluated using mass spectrometry analysis, sodium dodecyl sulfate polyacrylamide electrophoresis, and size exclusion high-performance liquid chromatography. Example 2: Administration of GDF15 Antibodies, Dulaglutide, and / or GIPR. Male C57BI / 6 DIO mice, 19-20 weeks old (13-14 weeks on a high-fat diet) at the start of dosing, were placed into the following treatment groups: Group A: vehicle, in which the animals were administered vehicle weekly; Group B: Dulaglutide, in which the animals were administered 0.1 mg / kg (2 nmol / kg) of dulaglutide twice a week; Group C - GIPR Ab, in which the animals were administered 5 mg / kg (33 nmol / kg) of antibody 2.63.1 (having a light and heavy chain sequence of SEQ ID NO: 105 and 106, respectively) weekly and with vehicle weekly (the latter on the alternate day of dulaglutide dosing); Group D - GDF15, in which the animals were administered 0.125 mg / kg (1 nmol / kg) of FcA10(-)-(G4S)4-GDF15 (SEQ ID NO: 39) (together with its heterodimerization component, FcA10(+,K) (SEQ ID NO: 32)) weekly and with vehicle weekly (the latter on the alternate day of dulaglutide dosing); Group E - GDF15 + Dulaglutide, in which the animals were administered 0.125 mg / kg (1 nmol / kg) of FcA10(-)-(G4S)4-GDF15 (together with its heterodimerization component, FcA10(+,K)) weekly and 0.1 mg / kg (2 nmol / kg) of dulaglutide twice a week; Group F - GDF15 + GIPR Ab, in which animals were administered 0.125 mg / kg (1 nmol / kg) of FcA10(-)-(G4S)4-GDF15 (together with its heterodimerization component, FcA10(+,K)) weekly and 5 mg / kg (33 nmol / kg) of antibody 2.63.1 weekly. Animals were dosed for 5 weeks via subcutaneous injection. Body weight was measured twice a week. Figure 1 shows the change in body weight (Figure 1A in grams, Figure 1B as a percentage change in body weight). The significance of the change in body weight is shown in Table 7. Table 7 - Importance of Body Weight Change MA / a / zuzi / uiur ót Group D-4 DO D3 D7 D10 D14 D17 D21 D31 D35 A — — — — — — — — — B ns ns ns ns ** *** C ns ns ns ns ns ns ns ns ns ns D ns ns ns ** **** **** *** *** E ns ns ** **** **** **** **** **** F ns ns ns **** **** ns: not significant; *p<0.05, **p<0.005, ***p<0.001, ****p<0.0001 by two-way ANOVA with Dunnett's analysis in Graphpad prism. Figure 2 shows the percentage change in body weight 2 weeks (Figure 2A) and 5 weeks (Figure 2B) after the start of treatment. The data show that the combination treatment of GDF15 with either dulaglutide or GIPR ab was synergistic. Two weeks after treatment, mice in Group D (GDF15) had a -9.33% change in body weight, while mice in Group B (dulaglutide) or Group C (GIPR ab) had a -4.40% and -0.91% change in body weight, respectively. However, mice in Group E (GDF15 + dulaglutide) had a -18.28% change in body weight, greater than the additive effect of -13.73%. This decrease was more than three times that observed with dulaglutide alone and almost twice the decrease seen with GDF15 alone. Group F mice (GDF15+ GIPR Ab) had a -13.65% change in body weight, greater than an additive effect of -14.56%.The decrease was more than thirteen times compared to treatment with GIPR Ab alone and almost 1.5 times the decrease observed in treatment with GDF15 alone. Five weeks after treatment, mice in Group D (GDF15) experienced a -14.62% change in body weight, while mice in Group B (Dulaglutide) or Group C (GIPR Ab) experienced changes of -1.96% and 2.24% in body weight, respectively. However, mice in Group E (GDF15 + Dulaglutide) experienced a -33.56% change in body weight, greater than the additive effect of -15.58%. This decrease was more than fifteen times greater than that observed with Dulaglutide alone and more than twice the decrease seen with GDF15 alone. Mice in Group F (GDF15 + GIPR Ab) experienced a -22.62% change in body weight, greater than the additive effect of -12.38%. The decrease was more than twenty times compared to treatment with GIPR Ab alone and more than 1.5 times the decrease observed in treatment with GDF15 alone. An oral glucose tolerance test (OGTT) was performed 2 weeks after the first treatment, and Figure 3 shows the glucose levels (Figure 3A) and glucose AUC (Figure 3B) during the oral glucose tolerance test 2 weeks after treatment initiation, with the AUC differences between the treatment and vehicle groups labeled at the top of each bar in Figure 3B. Combination therapy did not have a greater effect than GDF15 monotherapy (Groups E and F having AUCs of -40.0% and -33.1%, respectively, compared to Group D having an AUC of -39.0%). Similarly, combination therapy did not have a greater effect than GDF15 monotherapy in an intraperitoneal glucose tolerance test (IPGTT). An IPGTT was performed 5 weeks after the first treatment, and Figure 4 shows the glucose levels (Figure 4A) and glucose AUC (Figure 4B) from the IPGTT 5 weeks after treatment initiation, with the AUC differences between the treatment and vehicle groups labeled at the top of each bar in Figure 4B. The combination therapy groups, Groups E and F, had an AUC of -42.4% and AUC of 40.4%, respectively, compared to the GDF15 monotherapy group, Group D, with an AUC of -38.0%. Fasting blood glucose, serum insulin, serum triglycerides, and total serum cholesterol levels were measured 2 weeks and 5 weeks after the first treatment (Figures 5A-5D, respectively). Combination therapy (Groups E and F) did not have a greater effect on reducing fasting blood glucose or triglyceride levels than GDF15 monotherapy (Group D) (Figures 5A and 5C, respectively). However, at two weeks, combination therapy had a greater effect than GDF15 monotherapy on reducing serum insulin levels, and at five weeks, the GDF15+Dulaglutide combination had a greater effect on reducing serum insulin levels than GDF15 monotherapy (Figure 5B). The GDF15+Dulaglutide combination also had a greater effect than GDF15 monotherapy on reducing total cholesterol levels (Figure 5D). Food intake was measured three consecutive days per week and the results are shown in Figure 6. The significance of the data is shown in Table 8. Table 8 - Importance of the Food Intake Trial Group D2 D8 D9 D10 D15 D16 D17 D22 D23 D24 D29 D30 D31 A — ___ — — — — — — ___ — — — — B ns ns ns ns ns ns * **** ns ns ns ns ns C ns ns ns ns ns ns ns * ns ns ns ns ns D ns * ns ns ns ns ns ** ns * ns ns E * * * ns ** •kk ns ** * * ** ns *** ns ns F ns * ns ns ns ns ns **** * ** ns ** ns ns ns: not significant; *p<0.05, **p<0.005, ***p<0.001, ****p<0.0001 by two-way ANOVA with Dunnett's analysis in Graphpad prism. Although the present invention has been described in terms of several embodiments, it is understood that those skilled in the art will consider variations and improvements. Therefore, the appended claims are intended to cover all equivalent variations that fall within the scope of the invention as claimed. Furthermore, the section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All references cited in this application are expressly incorporated by reference in this document for any purpose.

Claims

Having described the present invention as above, the following claims are considered novel and therefore claimed as property: CLAIMS 1. A method for treating a metabolic condition in a subject comprising administering a GDF15 molecule and a GIPR antagonist, wherein the administration of the GDF15 molecule and the GIPR antagonist has a synergistic effect compared to the administration of the GDF15 molecule or GIPR antagonist alone.

2. The method according to claim 1, wherein the GDF15 molecule and the GIPR antagonist are administered simultaneously.

3. The method according to claim 1, wherein the GDF15 molecule and the GIPR antagonist are administered sequentially.

4. The method according to claim 1, wherein the GIPR antagonist is an antibody.

5. The method according to claim 1, wherein the GIPR antagonist comprises CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, wherein the CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3 comprise the amino acid sequences of SEQ ID NO: 65-67 and 77-79; SEQ ID NO: 68-70 and 80-82; SEQ ID NO: 71-73 and 83-85; or SEQ ID NO: 74-76 and 86-88; respectively.

6. The method according to claim 5, wherein the GIPR antagonist comprises a light chain variable region and a heavy chain variable region comprising the amino acid sequences SEQ ID NO: 89 and 90; 91 and 92; 93 and 94; or 95 and 96, respectively.

7. The method according to claim 5, wherein the GIPR antagonist comprises a light chain and a heavy chain comprising the amino acid sequences of SEQ ID NO: 97 and 98; 99 and 100; 101 and 102; 103 and 104, or 105 and 106, respectively.

8. A method for treating a metabolic condition in a subject comprising administering a GDF15 molecule and dulaglutide, wherein the administration of the GDF15 molecule and dulaglutide has a synergistic effect compared to the administration of the GDF15 molecule or dulaglutide alone.

9. The method according to claim 8, wherein the GDF15 molecule and dulaglutide are administered simultaneously.

10. The method according to claim 8, wherein the GDF15 molecule and dulaglutide are administered sequentially.

11. The method according to any one of claims 1-10, wherein the synergistic effect is a decrease in body weight. MA / a / zuzi / uiur ót 12. The method according to any one of claims 1-11, wherein the GDF15 molecule is a fusion protein comprising a GDF15 region bound to an Fe region.

13. The method according to claim 12, wherein the GDF15 region is joined to the Fe region through a linker.

14. The method according to claim 12 or 13, wherein the GDF15 region comprises the amino acid sequence of SEQ ID NO: 6 and at least one mutation.

15. The method according to claim 14, wherein at least one of the mutations is of the aspartate at position 5.

16. The method according to claim 15, wherein the aspartate at position 5 is mutated to glutamate.

17. The method according to claim 15 or 16, wherein the GDF15 region further comprises a mutation of the asparagine at position 3.

18. The method according to claim 17, wherein the asparagine at position 3 is mutated to glutamine.

19. The method according to any one of claims 13-18, wherein the linker is a (G4S)no (G4Q)n linker, wherein n is greater than 0.

20. The method according to claim 19, wherein n is 1 or 2.

21. The method according to any one of claims 12-20, wherein the Fe region comprises a charged pair mutation.

22. The method according to any one of claims 12-21, wherein the Fe region comprises a truncated hinge region.

23. The method according to any one of claims 12-22, wherein the Fe region is selected from Table 3.

24. A pharmaceutical composition comprising a GDF15 molecule and a GIPR antagonist, wherein administration of the composition has a synergistic effect compared to administration of the GDF15 molecule or GIPR antagonist alone.

25. A pharmaceutical composition comprising a GDF15 molecule and dulaglutide, wherein administration of the composition has a synergistic effect compared to administration of the GDF15 molecule or dulaglutide alone.

26. The composition according to claim 24 or 25, wherein the synergistic effect is the reduction of body weight.