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Acetyl-coenzyme A carboxylase 2 as a target in the regulation of fat and insulin action

A technology of acetyl coenzyme A carboxylase, applied in the treatment of diabetic patients, regulating fatty acid accumulation and oxidation, in the field of acetyl coenzyme A carboxylase ACC2 isoform, can solve problems such as deficiency

Inactive Publication Date: 2006-07-26
RES DEVMENT FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Likewise, prior art lacks methods to generate transgenic knockout mice lacking ACC2 and to use these transgenic mice

Method used

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  • Acetyl-coenzyme A carboxylase 2 as a target in the regulation of fat and insulin action
  • Acetyl-coenzyme A carboxylase 2 as a target in the regulation of fat and insulin action
  • Acetyl-coenzyme A carboxylase 2 as a target in the regulation of fat and insulin action

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Acc2 - / - Generation of transgenic mice

[0055] Mouse Acc2 genomic clones were isolated using the Acc2 cDNA probe. Based on the homology between human and mouse ACC2 genes (Abu-Elheiga, L., Almaraz-Ortega, D.B., Baldini, A. and Wakil, S.J., J Biol Chem.272, 10669-10677, 1997), from Bio Two oligonucleotides in the binding region of the protein were designed based on the human ACC2 cDNA sequence: forward primer (5'-CTGAATGATGGGGGGCTCCTGCTCT-3'; nucleotides 2551-2575) (SEQ ID No.1) and reverse primer (5' - TTCAGCCGGGTGGACTTTAGCAAGG-3'; nucleotides 2890-2913) (SEQ ID No. 2). These primers were used to amplify cDNA from the Quick-Clone mouse heart cDNA library (Clontech) template.

[0056] The obtained cDNA fragments were sequenced and used to screen the 129 / SvEv mouse genome library to isolate a 16-kbp lambda genome clone. The 16-kbp lambda genomic clone was digested with different restriction enzymes to establish a restriction map and construct a gene targeting vec...

Embodiment 2

[0059] in Acc2 - / - Acc2 expression in transgenic mice

[0060] Northern blot analysis of total RNA from skeletal muscle tissue excised from wild-type, heterozygous, and homozygous-null animals showed no detectable Acc2 mRNA in homozygous-null animals and, as expected, Acc2 mRNA in heterozygous animals. Acc2 mRNA level was half of the wild type ( Figure 1C ). Probing of biotin-containing Acc2 with avidin peroxidase / - Western blot analysis of heart, skeletal muscle, and liver tissues from mutant mice showed no expression of ACC2 protein ( Figure 1D ). ACC2 protein levels (280 kDa) were higher than ACC1 protein levels (265 kDa) in heart and skeletal muscle tissues of wild-type mice, although ACC1 proteins were more predominant in their liver tissues.

[0061] Acc2 - / - The absence of ACC2 protein in mutant mice was further confirmed by confocal immunofluorescence microscopy analysis using an affinity-purified anti-ACC2-specific antibody (Abu-Elheiga, L., W.R. Brinkley...

Embodiment 3

[0063] in Acc2 - / - Malonyl-CoA levels in transgenic mice

[0064] Since malonyl-CoA levels in animal tissues are due to the activity of ACC1 and ACC2, the consequences of the absence of ACC2 in malonyl-CoA levels in these tissues and whether ACC1 can be compensated to determine malonyl-CoA levels in these tissues improvement. Comparing wild type and Acc2 - / - There was no significant difference in malonyl-CoA levels and overall ACC activity in the liver tissues of mutant mice, indicating that almost all malonyl-CoA in the liver is provided by ACC1 ( figure 2 ).

[0065] On the other hand, comparing the skeletal muscle and heart tissues of the same two groups of mice, it was found that Acc2 - / - Malonyl-CoA levels in these tissues were approximately 30-fold and 10-fold lower in mutant mice than in wild-type mice, respectively. This suggests that ACC2 is the major provider of malonyl-CoA in skeletal muscle and heart ( figure 2 ).

[0066] During fasting, wild-type and...

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Abstract

The present invention highlights the role of acetyl-CoA carboxylase through its product malonyl-CoA in regulating fatty acid oxidation and synthesis, glucose metabolism and energy homeostasis. It discloses transgenic mice with inactivating mutations in the endogenous gene for the acetyl-CoA carboxylase 2 isoform of acetyl-CoA caboxylase. Inactivation of acetyl-CoA caroxylase 2 results in mice exhibiting a phenotype of reduced malonyl-CoA levels in skeletal muscle and heart, unrestricted fat oxidation, and reduced fat accumulation in the liver and fat storage cells. As a result, the mice consume more food but accumulate less fat and remain leaner than wild-type mice fed the same diet. These results demonstrate that inhibition of ACC2 acetyl-CoA carboxylase could be used to regulate fat oxidation and accumulation for purposes of weight control. The instant invention provides a useful animal model to regulate malonyl-CoA production by ACC2 in the regulation of fatty acid oxidation by muscle, heart, liver and other tissues. They also identify potential inhibitors for studying the mechanisms of fat metabolism and weight control.

Description

Background of the invention [0001] federal funds [0002] This invention was made in part with Federal Government funding under N.I.H.G.M. 19091. Accordingly, the Federal Government has certain rights in this invention. [0003] field of invention [0004] The present invention generally relates to fat metabolism and weight control. More specifically, the present invention relates to the role of acetyl-CoA carboxylase ACC2 isoforms in regulating fatty acid accumulation and oxidation. [0005] Description of related technologies [0006] Acetyl-CoA carboxylase (ACC), a biotinidinase, catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, an intermediate metabolite that plays a key role in regulating fatty acid metabolism. Malonyl-CoA has been found to be a pot regulator of carnitine palmitoyltransferase I (CPTI), a component of the fatty acid shuttle system involved in mitochondrial oxidation of long-chain fatty acids. This finding provides 2 opposing pathways...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/00C12Q1/00A61K49/00A61K39/395A61K38/43A01K67/027A61K45/00A61P3/04A61P3/10A61P43/00C12N5/10C12N9/00C12N9/99C12N15/09C12Q1/02C12Q1/25C12Q1/68G01N33/15G01N33/50
CPCA01K2217/075G01N33/502C12N9/93G01N33/5088G01N33/5067A01K2227/10G01N33/5061A01K2267/03G01N33/5008A01K67/0275A61P3/00A61P3/04A61P3/06A61P43/00A61P5/50A61P3/10
Inventor S·J·瓦基勒M·M·马楚克L·阿布-埃尔海格
Owner RES DEVMENT FOUND
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