Phytoecdysones and / or 20-hydroxyecdysone derivatives in combination with a GLP-1 agonist for use thereof in the treatment of obesity and excess weight

Abstract

The invention relates to the use of at least one phytoecdysone and / or at least one semi-synthetic 20-hydroxyecdysone derivative, and at least one active ingredient having the ability to activate the GLP-1 receptor, in the treatment of obesity, sarcopenic obesity or excess weight in mammals.

Description

Phytoecdysones and / or 20-hydroxyecdysone derivatives in combination with a GLP-1 agonist for use in the treatment of obesity and overweight Technical field of the invention

[0001] The invention relates to the use of phytoecdysones and / or semisynthetic derivatives of 20-hydroxyecdysone, in combination with an active ingredient having the capacity to activate the GLP-1 receptor, such as a GLP-1 receptor agonist, for their use in preventing loss of muscle function and / or mobility, or improving muscle function and / or mobility, as well as improving insulin sensitivity, in obese, sarcopenic obese or overweight mammals.The invention also relates to a composition comprising a phytoecdysone and / or a semi-synthetic derivative of 20-hydroxyecdysone, and an active ingredient having the capacity to activate the GLP-1 receptor, as well as the use of such a composition for the prevention of loss of muscle function and / or mobility, or the improvement of loss of muscle function and / or mobility, as well as in the improvement of insulin sensitivity, in obese, sarcopenic obese or overweight mammals. Prior art

[0002] Among metabolic diseases, obesity is a chronic disease whose number of cases has almost tripled since 1975. In 2016, more than 1.9 billion people aged 18 and over were overweight (39%), of which more than 650 million were obese (13%) (Aune et al., 2016). Overweight (Body Mass Index [BMI] between 25 and 29.9 kg / m 2 ) or obesity (BMI>30 kg / m 2) increases the risk of type 2 diabetes, fatty liver disease, kidney disease, and other health problems.

[0003] The concept of sarcopenic obesity was introduced a few years ago to describe, in the elderly, the concomitant excess fat mass and a reduction in lean mass and / or muscle function. The pathophysiology of sarcopenic obesity is complex, but an inter-relationship between adipose tissue and muscle, in the form of a vicious circle, is clearly documented (Cauley et al., 2015). Advancing age leads to a decrease in physical activity and basal energy expenditure, thus promoting weight gain. In response to the accumulation of this adiposity, a state of chronic inflammation appears, mediated largely by leptin but also by pro-inflammatory cytokines, inhibiting muscle anabolism (Kalinkovich et al., 2017). In addition, with aging, adipose tissue loses its capacity for lipid accumulation and expansion, which induces an increase in lipid infiltration of the muscle, causing a loss of strength as well as a decrease in protein synthesis. One of the consequences, particularly in obese elderly people, is a loss of mobility (Vincent et al. 2010). Interventions must therefore prioritize low-fat dietary intake and promote physical activity, with a view to stimulating muscle anabolism.

[0004] Incretins are hormones secreted by endocrine intestinal cells following food intake. Two physiological incretins exist: Glucose-dependent insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1), both of polypeptide nature. Incretins (mainly GLP-1) regulate glucose homeostasis by different mechanisms such as (i) stimulation of glucose-dependent insulin secretion by cells [3 and inhibition of postprandial glucagon secretion by α-cells at the pancreatic level; (ii) reduction of hepatic gluconeogenesis; (iii) increase of insulin sensitivity and increase of glucagon uptake at the muscle level.They also slow down gastric emptying and gastric acid secretion, which has the effect of reducing the postprandial glycemic peak, causing a feeling of satiety or reducing appetite, and therefore limiting food intake and weight gain (Müller et al., 2019).

[0005] GLP-1 receptor agonist (GLP-1 RA) treatments that have obtained marketing authorization are mostly peptide analogues of GLP-1, administered by subcutaneous injection and are commonly used for the treatment of type 2 diabetes, such as Dulaglutide (Trulicity®), Exenatide (Byetta®, Bydureon®), Liraglutide (Victoza®), Lixisenatide (Adlyxin®), semaglutide (Ozempic®, Wegovy®), Albiglutide (Eperzan®, Tanzeum®), Noiiglutide. The Food and Drug Administration in the United States recently authorized an oral formulation of semaglutide (Rybelsus®). Finally, the Tirzepatide (Mounjaro®) is a dual activator of GLP-1 and GIP receptors. Two GLP-1 RAs (liraglutide and semaglutide in injectable form), given their high efficacy in weight loss in obese patients, have obtained Marketing Authorization in Europe in recent years for weight loss in certain non-diabetic obese patients, in addition to lifestyle and dietary measures (Alruwaili et al., 2021; Pi-Sunyer ef al., 2015; Wilding et al., 2021). More recently, an international trial demonstrated promising effects for orforgl ipron, an orally active non-peptide GLP-1 analog, in this indication (Wharton et al., 2023).

[0006] Some results obtained following the intake of these molecules (GLP-1 RA) raise questions. At the preclinical level, in animals, a recent study showed that semaglutide maintained muscle mass, highlighting a protective effect against muscle wasting by suppressing muscle atrophy factors and stimulating myogenic factors (Xiang et al., 2023). Moreover, in humans, in the STEP 1 and SUSTAIN 8 clinical trials, the proportion of lean mass to total body mass increased overall, indicating an overall improvement in body composition. Nevertheless, a growing body of data highlights a link between GLP-1 RA and the reduction of lean body mass, particularly muscle mass. In these same clinical trials (STEP 1 and SUSTAIN 8) on semaglutide, it was shown that 39 to 40% of the weight lost with this GLP-1 RA was lean mass (Wilding et al., 2021; Lingway et al., 2019). A 2021 meta-analysis of 18 randomized controlled trials showed that GLP-1 RA drugs, including oral and subcutaneous semaglutide as well as older GLP-1 RA drugs such as lixisenatide, exenatide, and liraglutide, resulted in a significant decrease in lean mass (Uneda et al., 2021). Data from the SURMOUNT-1 study of tirzepatide (a dual GLP-1 and GIP receptor activator) led to more positive findings: fat mass decreased by 33–36% and lean mass by 10–11%, depending on the age group (Jastreboff et al., 2022). In other words, about a quarter of the weight lost in this study was lean mass. Finally, another meta-analysis concluded that semaglutide and other GLP-1 receptor agonists significantly decreased lean mass compared to placebo (Ida et al., 2021).

[0007] This muscle loss is problematic because muscle is necessary for metabolism, strength, motor function, and therefore mobility. According to the Centers for Disease Control and Prevention, 41.5% of older American adults are obese and could benefit from a weight-loss drug. Up to 34.4% of these patients over the age of 60 suffer from sarcopenic obesity, meaning the patients are overweight or obese and also have age-related low muscle mass. These sarcopenic obese patients are potentially at greatest risk of losing muscle mass if treated for obesity with a GLP-1 RA-based molecule.Patients with extremely low muscle mass may experience muscle weakness leading to poor balance, decreased walking speed, inability to ambulate, loss of mobility and independence, falls, bone fractures, and increased mortality.

[0008] Furthermore, regarding the use of GLP-1 analogues for weight loss purposes, authorities have recently called for caution, recalling that the weight losses observed are transient, with a recovery upon stopping treatment, and that no effect on obesity-related morbidity and mortality has currently been demonstrated, while the adverse effects linked to their use are potentially serious (acute pancreatitis, severe constipation, etc.).

[0009] The above evidence indicates that in individuals with a BMI>30, although GLP-1 agonist therapies have demonstrated significant effects on weight loss in treated individuals, there remains a need to find complementary therapeutic approaches that would both further protect muscle mass and function and potentiate the effects on fat mass in individuals receiving GLP-1 receptor agonist therapy.

[0010] Phytoecdysones represent a large family of polyhydroxylated phytosterols. These molecules are produced by various plant species (ferns, gymnosperms, angiosperms) and contribute to their defense against insect pests. The major phytoecdysone in the plant kingdom is 20-hydroxyecdysone.

[0011] 20-Hydroxyecdysone (20E) is pharmacologically active in mammals. It activates the MAS receptor (MASR), a receptor of the protective arm of the Renin Angiotensin system (Lafont et al., 2021) which induces a number of beneficial effects on the muscle that have been described in preclinical studies in physiological and pathological contexts. The ingestion of 20-hydroxyecdysone (20E) by obese mammals subjected to a hypocaloric diet makes it possible to reduce adipocyte diameter and improve insulin sensitivity WO2013068704 (Lafont et al., 2013).

[0012] BIO101 is a 20E preparation with a purity greater than or equal to 97%. Its preparation process is disclosed in international patent application WO201 8197731 (Lafont et al., 2018). BIO101 demonstrates anabolic properties via activation of the AKT / mTOR pathway as well as MASR activation-dependent beneficial effects on myogenic differentiation (related to increased MyoD and myogenin expression). Chronic oral BIO101 treatment induced AKT / mTOR activation and anabolic effects accompanied by improvements in physical performance in adult and aged animals (Serova et al. 2023).

[0013] B 10101 is a new drug candidate clinically developed for the treatment of sarcopenia, Duchenne muscular dystrophy and COVID-19. These therapeutic applications are notably the subject of international patent applications WO2013088084 (Veillet et al., 2012), WO201 8197708 (Dilda et al., 2018) and WO2021198588 (Dilda et al., 2021). Document WO 2013 / 088084 describes a positive effect of phytoecdysones, including 20E, on muscle quality in obese and / or sarcopenic mammals.

[0014] Semi-synthetic derivatives of 20E have also been developed, as disclosed in international patent application WO2015177469 (Lafont et al., 2015), and are used for such therapeutic applications, including improving muscle quality in obese and / or sarcopenic mammals. Presentation of the invention

[0015] According to a first aspect, it is proposed according to the present invention to use, for the prevention of loss, or improvement, of muscle function and / or mobility in obese, sarcopenic obese or overweight mammals, at least one active ingredient having the capacity to activate the GLP-1 receptor and at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone. of general formula (I): in which: R 1 is chosen from: a (Ci-C6)W(Ci-Ce) group; a (Ci-Ce)W(Ci- Ce)W(Ci-C6) group; a (Ci-C6)W(Ci-C6)CO2(Ci-Ce) group; a (Ci- Ce)A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, CH2-CH2-OH, (Ci-Ce), NH(Ci-C6), N(Ci-C6)2, CO2(Ci-C6) type; a CH2Br group; W being chosen from O, S, NH and NR where R represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms.

[0016] More particularly, the at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), and the at least one active ingredient having the capacity to activate the GLP-1 receptor, can be used together for the treatment or prevention of loss of muscle strength (muscle function "in toto") in obese, sarcopenic obese or overweight mammals. In particular, the present inventors have discovered a synergistic effect of these compounds, phytoecdysone or semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), such as 20-hydroxyecdysone, on the one hand, and active ingredient having the capacity to activate the GLP-1 receptor, such as a GPL-1 agonist, for example semaglutide, on the other hand, on reducing the loss of grip strength for mammals with induced obesity.

[0017] The at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), and the at least one active ingredient having the capacity to activate the GLP-1 receptor, can also be used together for the treatment or prevention of the degradation of the contractile properties of the muscles ("in situ" muscle function) in obese mammals, sarcopenic obese or overweight. In this regard, it has been discovered by the present inventors that, surprisingly, the administration of semaglutide to mammals with induced obesity causes a degradation of their muscle contractile properties. Such a degradation was in no way predictable from the prior art, which is concerned with nothing other than the effect of semaglutide, and GLP-1 receptor activators in general, on muscle mass, but not on muscle quality, in particular contractile properties.The combined administration of a phytoecdysone or semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), such as 20-hydroxyecdysone, with an active ingredient having the capacity to activate the GLP-1 receptor, such as a GLP-1 agonist, for example semaglutide, advantageously makes it possible not only to remedy this degradation of the muscular contractile properties of the mammals concerned, but also to improve these properties compared to untreated controls.

[0018] It has further been discovered by the present inventors that the synergistic effect between at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, is also exerted on the mobility level in subjects suffering from obesity, sarcopenic obesity or overweight: their combined administration to mammals with induced obesity significantly increases both the distance traveled and the activity time of these mammals, largely beyond the sum of the activities of these compounds tested individually.

[0019] More generally, the present invention relates to a novel therapy in which a MAS receptor (MASR) activator, more specifically a phytoecdysone (e.g., 20-hydroxyecdysone) or semi-synthetic derivatives of 20-hydroxyecdysone, and an activator of the glucagon-like peptide-1 (GLP-1) signaling pathway are used together for the treatment of obesity, sarcopenic obesity / overweight, or weight management in a mammal. In the context of the present invention, weight management encompasses not only overall weight loss, but also improvements in body composition, e.g., an increase in lean (muscle) mass relative to fat (adipose) mass or at least protection against loss of lean mass relative to fat mass, protection against weight regain, maintaining or increasing muscle strength, particularly in relation to mobility, and finally improving insulin sensitivity. Combination therapies, which we will call "combinations" of active ingredients, as well as complementary / adjunctive therapies are considered here.

[0020] The present invention aims to limit as much as possible the loss of muscle mass and strength, in particular at the appendicular level, in mammals treated with a GLP-1 receptor activator. Without being bound by a particular theory, it is envisaged here that a concomitant activation of the ACE2 / Ang-1-7 / MASR axis can prevent a loss of muscle mass and strength resulting from the chronic administration of the active ingredient having the capacity to activate the GLP-1 receptor.

[0021] To this end, the present invention relates to at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone, for its / their use in mammals treated with at least one active ingredient having the capacity to activate the GLP-1 receptor.

[0022] In particular embodiments, the invention further meets the following characteristics, implemented separately or in each of their technically operative combinations.

[0023] Some obese, sarcopenic obese, or overweight mammals that do not respond optimally to a GLP-1 pathway activator, or those that tolerate a GLP-1 pathway activator poorly, may benefit from phytoecdysones / 20-hydroxyecdysone derivatives used in conjunction with a GLP-1 pathway activator. Thus, patients who respond poorly to GLP-1 activator therapy may benefit from phytoecdysones / 20-hydroxyecdysone derivatives in combination, either as combination therapy or as adjunctive therapy.

[0024] Thus, the present invention relates to the combination of at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use in the treatment of obesity, sarcopenic obesity or overweight in mammals.

[0025] The present invention further relates to the combination of at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use in the treatment or prevention of loss of muscle mass and / or muscle strength in obese, sarcopenic obese or overweight mammals.

[0026] The present invention further relates to the combination of at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone, and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use in the treatment or prevention of loss of mobility in obese, sarcopenic obese or overweight mammals.

[0027] Without being bound by any particular theory, it is envisaged here that concomitant activation of the ACE2 / Ang-1-7 / MASR axis may enhance the effect of GLP-1 pathway activation and improve a therapeutic outcome or allow a therapeutic outcome, in terms of fat mass losses, at a lower dose or less frequent administration of the GLP-1 pathway activating drug.

[0028] According to a particular embodiment, the invention relates to the combination which is the subject of the present invention, for its use in the potentiation of the loss of fat mass in obese, sarcopenic obese or overweight mammals treated with the active ingredient having the capacity to activate the GLP-1 receptor.

[0029] The use of phytoecdysones / 20-hydroxyecdysone derivatives allows for the maintenance of weight loss in an obese or overweight subject. While not intended to be bound by theory, it is contemplated that MASR activation may lead to the avoidance of certain metabolic changes associated with weight loss in a subject that would otherwise promote weight regain. Such metabolic changes include, but are not limited to, decreased energy expenditure, decreased lean muscle mass, decreased skeletal muscle function, decreased insulin sensitivity relative to the level(s) observed in the subject prior to treatment, i.e., in the absence of a MASR activator. Thus, in certain embodiments, the present invention encompasses the use of a MASR activator to reverse metabolic changes associated with weight loss in an obese or overweight subject.Effects of such use may include increased energy expenditure, increased lean muscle mass, increased overall skeletal muscle function, increased. insulin sensitivity (Foucault et al., 2014) compared to the baseline value, i.e. in the absence of a MASR activator.

[0030] According to a particular embodiment, the invention relates to the combination which is the subject of the present invention, for its use in maintaining weight loss or protecting against weight regain, in obese, overweight or sarcopenic obese mammals, treated with the active ingredient having the capacity to activate the GLP-1 receptor.

[0031] Without being bound by any particular theory, it is envisaged here that concomitant activation of the ACE2 / Ang-1-7 / MASR axis may enhance the effect of GLP-1 pathway activation and improve insulin sensitivity, at a lower dose or less frequent administration of the active ingredient with the ability to activate the GLP-1 receptor.

[0032] According to a particular embodiment, the invention relates to the combination which is the subject of the present invention, for its use in improving insulin sensitivity in obese, sarcopenic obese or overweight mammals treated with the active ingredient having the capacity to activate the GLP-1 receptor.

[0033] Another aspect of the invention thus relates to the use of at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I) as defined above, and of at least one active ingredient having the capacity to activate the GLP-1 receptor, for improving insulin sensitivity in obese, sarcopenic obese or overweight mammals.

[0034] In this regard, it has been discovered by the present inventors a synergistic effect of phytoecdysones and / or semi-synthetic derivatives of 20-hydroxyecdysone of general formula (I), such as 20-hydroxyecdysone, on the one hand, and active ingredients having the ability to activate the GLP-1 receptor, such as a GLP-1 agonist, for example semaglutide, on the other hand, on the decrease in gene expression of the osteopontin gene by adipocyte cells. Osteopontin (OPN), encoded by the Spp1 gene, plays an important role in the development of obesity-related complications (De Fusco et al., 2017). Osteopontin expression significantly increases in the adipose tissue of obese individuals and impairs the differentiation and insulin sensitivity of primary adipocytes. OPN deficiency has been shown to improve insulin sensitivity: obese mice lacking osteopontin exhibit a improved insulin sensitivity (Nomiyama et al. 2007; Zeyda et al. 2011). These studies demonstrate that decreased osteopontin gene expression in adipocytes leads to reduced inflammation, decreased macrophage infiltration, and improved adipocyte function, all of which contribute to increased insulin sensitivity and reduced insulin resistance.

[0035] In some embodiments, the treatment comprising the active ingredient having the ability to activate the GLP-1 receptor further comprises a calorie restriction diet and / or a physical exercise regimen as part of the treatment.

[0036] Thus, the therapeutic methods described herein may be useful for chronic weight management aimed at treating excess adiposity and metabolic disorders in obese, sarcopenic obese or overweight subjects while maintaining or improving their health status, their body composition (for example, lean mass / fat mass ratios) and their muscular function, in particular appendicular and more broadly their motor function and mobility.

[0037] In the context of the present application, the term "combination therapy" or "combination" means the co-administration of at least two biologically active agents. In the case of the present invention, a first active agent is selected from phytoecdysones or semi-synthetic derivatives of 20-hydroxyecdysone or is a composition comprising at least one phytoecdysones and / or at least one semi-synthetic derivative of 20-hydroxyecdysone, at least a second active agent being the active ingredient having the ability to activate the GLP-1 receptor. The combination therapy may comprise a single formulation or several formulations. The co-administration may be carried out simultaneously or sequentially. The co-administration may be carried out by the same route of administration or by different routes of administration.It is considered a combination therapy as long as the effects of the two (or more) agents overlap in the subject to achieve additional, additive, or synergistic clinical effects.

[0038] In particular embodiments, said at least one phytoecdysone and / or said at least one semi-synthetic derivative of 20-hydroxyecdysone, and said at least one active ingredient having the capacity to activate the GLP-1 receptor are co-administered.

[0039] In particular embodiments, said at least one phytoecdysone and / or said at least one semi-synthetic derivative of 20-hydroxyecdysone, and said at least one active ingredient having the capacity to activate the GLP-1 receptor are co-administered within the same composition.

[0040] In particular embodiments, said at least one phytoecdysone and / or said at least one semi-synthetic derivative of 20-hydroxyecdysone are administered orally or systemically or intranasally to the mammal, and said at least one active ingredient having the capacity to activate the GLP-1 receptor is administered to the mammal subcutaneously and / or orally.

[0041] For oral administrations, said at least one phytoecdysone and / or said at least one semi-synthetic derivative of 20-hydroxyecdysone and / or the active ingredient having the capacity to activate the GLP-1 receptor, is preferably incorporated into an acceptable pharmaceutical formulation capable of being administered orally.

[0042] Modifications can be introduced into the peptide hormone to generate GLP-1 analogs to prolong or stabilize its activity.

[0043] Active ingredients having the capacity to activate the GLP-1 receptor, also called GLP1 receptor agonists, are well known to those skilled in the art, who are perfectly able to easily and quickly identify, for each given compound, whether or not it meets this definition. In particular, a compound is considered to have the capacity to activate the GLP-1 receptor if its effective concentration ECso, an effective dose allowing the receptor to be activated to 50% of its maximum activity, is between 0.05 and 20 nM. A method for measuring this ECso is for example described in the publication by Longwell et al., 2021. Schematically, such a method can implement mammalian cells constitutively expressing the GLP-1 receptor and a luciferase-type activation reporter.Luminescence resulting from GLP-1 receptor activation in response to increasing concentrations of a compound whose agonist properties are to be evaluated is measured using a luminometer. The compound concentration at which 50% of maximal receptor activation, ECso, can then be observed can be determined on an activation (luminescence) vs. Log 10 representation of agonist concentration. GLP-1 receptor agonists are widely described in the literature, including the review by Lupianez-Merly et al., 2023.

[0044] As indicated above, a synergistic effect of semaglutide with 20-hydroxyecdysone has been demonstrated by the present inventors, on the prevention, and even the improvement in certain aspects, of muscle function and mobility, as well as on the reduction of insulin resistance. To the extent that, in the body, semaglutide acts selectively on the GLP-1 receptor, and does not exhibit any other activity, it can reasonably be thought that its effect obtained in combination with phytoecdysones and semi-synthetic derivatives of 20-hydroxyecdysone of general formula (I), is indeed attributable to its property of activating the GLP-1 receptor. It can reasonably be deduced that the advantageous synergistic effect observed for semaglutide is therefore also exerted in the same way for other agonists of the GLP-1 receptor.

[0045] Preferably, said at least one active ingredient having the capacity to activate the GLP-1 receptor used according to the present invention is a GLP-1 analogue.

[0046] In embodiments, the active ingredient having the ability to activate the GLP-1 receptor is a peptide analog of GLP-1 selected from dulaglutide (Trulicity®), exenatide (Byetta®, Bydureon®), liraglutide (Victoza®), lixisenatide (Adlyxin®), semaglutide (Ozempic®, Wegovy®, Rybelsus®), albiglutide (Eperzan®, Tanzeum®), and noiiglutide.

[0047] The active ingredient with the ability to activate the GLP-1 receptor may be an agonist of only the GLP-1 receptor. Alternatively, it may be a multiple agonist, in that it exerts agonist activity on the GLP-1 receptor, but also on one or more other receptors.

[0048] For example, in particular embodiments of the invention, the active ingredient having the ability to activate the GLP-1 receptor is a peptide analog of GLP-1 also having the ability to activate the GIP receptor and / or the glucagon receptor. Examples of such active ingredients are tirzepatide (Mounjaro®), retatrutide (LY3437943) and HM15211.

[0049] In certain embodiments, the active ingredient having the capacity to activate the GLP-1 receptor is non-peptidic in nature. By non-peptidic is meant that the active ingredient having the capacity to activate the GLP-1 receptor is a molecule that is not peptidic, i.e. that is not a polymer of amino acids, modified or not, linked together by peptide bonds. It is thus not an analog of GLP-1. Thus, in embodiments particulars of the invention, said at least one active ingredient having the capacity to activate the GLP-1 receptor is a non-peptide compound. Non-limiting examples of non-peptide active ingredient having the capacity to activate the GLP-1 receptor include orforglipron, danuglipron, LY3502970 and OWL833.

[0050] In particular embodiments of the present invention, the active ingredient having the capacity to activate the GLP-1 receptor is a molecule of size less than or equal to 0.8 kDa.

[0051] In particular embodiments of the present invention, the active ingredient having the ability to activate the GLP-1 receptor is a peptide-type GLP-1 analog.

[0052] In particular embodiments of the present invention, the active ingredient having the ability to activate the GLP-1 receptor is GLP-1.

[0053] In particular embodiments of the present invention, the active ingredient having the capacity to activate the GLP-1 receptor is administered subcutaneously at a dose of between 0.25 and 50 mg in humans. Preferably this dose is administered once a week.

[0054] In particular embodiments of the present invention, the active ingredient having the capacity to activate the GLP-1 receptor is administered subcutaneously at a dose of between 10 and 400 pg per day in humans.

[0055] In particular embodiments of the present invention, the active ingredient having the capacity to activate the GLP-1 receptor is administered orally at a dose of between 3 and 250 mg in humans. Preferably, this dose is administered daily in one or more doses.

[0056] A phytoecdysone that can be used according to the invention is, for example, 20-hydroxyecdysone (20E).

[0057] Semi-synthetic derivatives of 20-hydroxyecdysone are understood to mean in particular the known compounds which are the subject of patent application WO 2015 / 177469 in which their production by semi-synthesis is described.

[0058] Phytoecdysones and semi-synthetic derivatives of 20-hydroxyecdysone are advantageously purified to pharmaceutical grade.

[0059] In particular embodiments of the present invention, said at least one phytoecdysone and / or said at least one semi-synthetic derivative of 20-hydroxyecdysone are in the form of a composition comprising said at least one phytoecdysone and / or said at least one semi-synthetic derivative of 20- hydroxyecdysone. According to a preferred embodiment, this composition comprises 20-hydroxyecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone.

[0060] The 20-hydroxyecdysone used is preferably in the form of a plant extract rich in 20-hydroxyecdysone or a composition comprising 20-hydroxyecdysone as the active agent. Plant extracts rich in 20-hydroxyecdysone are, for example, extracts of Stemmacantha carthamoides (also called Leuzea carthamoides or Rhaponticum carthamoides), Cyanotis arachnoidea, Cyanotis vaga, Pfaffia glomerata and Pfaffia paniculata.

[0061] The extracts obtained are preferably purified to pharmaceutical grade.

[0062] In embodiments of the invention, the 20-hydroxyecdysone is in the form included in an extract, in particular alcoholic or hydroalcoholic, of a plant or a part of a plant, said plant preferably being chosen from plants containing at least 0.5% of 20-hydroxyecdysone by dry weight of said plant. Said extract preferably comprises at least 95%, and preferably at least 97%, of 20-hydroxyecdysone. Said extract thus represents 20-hydroxyecdysone purified to pharmaceutical grade. It is preferably free of impurities whose individual content is greater than 0.5% by dry weight of the extract. Thus, preferably, the extract only comprises, as impurities, that is to say compounds other than 20-hydroxyecdysone, impurities whose individual proportions are between 0 and 0.5% by dry weight of the extract.

[0063] Preferably, the extract is an extract of the roots of the plant, in particular an extract of the root of Stemmacantha carthamoides (also called Leuzea carthamoides or Rhaponticum carthamoides), Cyanotis arachnoidea, Cyanotis vaga, Pfaffia glomerata or Pfaffia paniculata.

[0064] Any conventional extraction process in itself can be implemented to obtain, from the plant or part of the plant concerned, the extract rich in 20-hydroxyecdysone targeted. It is within the skills of the person skilled in the art to determine the exact operating parameters depending on the particular plant used. For example, the extraction process may comprise, after optional steps of drying and / or grinding the plant and / or the part of the plant, steps of: - extraction of 20-hydroxyecdysone from plant tissues, using a suitable solvent, such as ethanol or a mixture of ethanol and water, this extraction which can be carried out by maceration, percolation or ultrasonic extraction, - filtration, so as to remove solid matter from the liquid solution containing 20-hydroxyecdysone, - optionally, concentration and purification, - and optionally, recrystallization of the 20-hydroxyecdysone obtained, the implementation of these steps falling within the skills of a person skilled in the art.

[0065] Said extract comprising at least 95%, and preferably at least 97%, of 20-hydroxyecdysone, and the 20-hydroxyecdysone purified to pharmaceutical grade, are hereinafter referred to as BIO101. BIO101 remarkably comprises, as impurities, only impurities, such as minor ecdysteroids, in individual proportions of between 0 and 0.5% by dry weight of BIO101.

[0066] In particular embodiments, the phytoecdysones are administered at a dose of between 0.1 and 15 milligrams per kilogram per day in humans. Phytoecdysones are understood here to mean both phytoecdysones in general and 20-hydroxyecdysone (particularly in extract form) and its semi-synthetic derivatives.

[0067] Preferably, the phytoecdysones are administered at a dose of 5 to 1000 mg / day, in one or more doses, in an adult human, and at a dose of 0.2 to 350 mg / day, in one or more doses, in a human child or infant. Phytoecdysone is understood here to mean both phytoecdysones in general and 20-hydroxyecdysone (particularly in extract form) and its semi-synthetic derivatives.

[0068] In particular embodiments of the present invention, said at least one semi-synthetic derivative of 20-hydroxyecdysone is a compound of formula (II):

[0069] In the context of the present invention, the term "(Ci-Ce)" means any alkyl group of 1 to 6 carbon atoms, linear or branched, in particular, the methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl groups. Advantageously, it is a methyl, ethyl, iso-propyl or t-butyl group, in particular a methyl or ethyl group, more particularly a methyl group.

[0070] In the context of the present invention, the term heterocycle preferably means a cycle comprising 5 or 6 atoms including one or two heteroatoms (O, S or N), the remaining atoms being carbon atoms.

[0071] In a preferred embodiment of the present invention, in general formula (I): R 1is chosen from: a (Ci-C6)W(Ci-Ce) group; a (Ci-Ce)W(Ci- Ce)W(Ci-C6) group; a (Ci-C6)W(Ci-C6)CO2(Ci-Ce) group; a (Ci- Ce)A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, CH2-CH2-OH, (Ci-Ce), NH(Ci-C6), N(Ci-C6)2, andCO2(Ci-C6) type; W being a heteroatom chosen from O and S, and preferably S.

[0072] In particular embodiments of the present invention, said at least one semi-synthetic derivative of 20-hydroxyecdysone is a compound selected from the following compounds: No. 1: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-10,13-dimethyl-17-(2-morpholinoacetyl)-2,3,4,5,9, 11,12,15,16, 17-decahydro-1 H-cyclopenta[a]phenanthren-6-one, No. 2: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(3-hydroxypyrrolidin-1 - yl)acetyl]-10, 13-dimethyl-2,3,4,5,9, 11,12,15,16, 17-decahydro-1 H-cyclopenta[a]phenanthren-6-one, 4, 5, 9 , 11 ,12,15,16,17-decahydro-1 H- cyclopenta[a]phenanthren-6-one; No. 3: (2S,3R,5R,10R,13R,14S,17S)-2,3, 14-trihydroxy-17-[2-(4-hydroxy-1 - piperidyl)acetyl]-10, 13-dimethyl-2, 3, 4, 5, 9, 11 , 12, 15, 16, 17-decahydro-1 H- cyclopenta[a]phenanthren-6-one; No. 4: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-[4-(2-hydroxyethyl)-1 - piperidyl]acety l]-10, 13-dimethyl I-2,3,4,5,9,11,12,15,16,17-decahydro-1 H-cyclopenta[a]phenanthren-6-one;No. 5: (2S,3R,5R,10R,13R,14S,17S)-17-[2-(3-dimethylaminopropyl; (methyl)amino)acetyl]-2,3, 14-trihydroxy-10, 13-d im ethyl I-2 , 3, 4, 5, 9, 11 ,12,15,16,17- decahydro-1 H-cyclopenta[a]phenanthren-6-one; No. 6: 2-[2-oxo-2-[(2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-10,13-dimethyl- 6-OXO-2,3,4,5,9, 11,12,15,16, 17-decahydro-1 H-cyclopenta[a]phenanthren-17- yl]ethyl]sulfanylacetate; No. 7: (2S,3R,5R,10R,13R,14S,17S)-17-(2-ethylsulfanylacetyl)-2,3,14-trihydroxy- 10, 13-dim ethyl I-2,3,4,5,9,11,12,15,16,17-decahydro-1 H-cyclopenta[a]phenanthren- 6-one; No. 8: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(2-hydroxyethylsulfanyl)acetyl]-10, 13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1H cyclopenta[a]phenanthren-6-one.

[0073] According to another aspect, the present invention relates to a composition comprising: - at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I): in which: R 1 is chosen from: a (Ci-C6)W(Ci-Ce) group; a (Ci-Ce)W(Ci- Ce)W(Ci-C6) group; a (Ci-C6)W(Ci-C6)CO2(Ci-Ce) group; a (Ci- Ce)A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, CH2-CH2-OH, (Ci-C6), NH(Ci-C6), N(Ci-C6)2, CO2(Ci-C6) type; a CH2Br group; W being chosen from O, S, NH and NR where R represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms; and - at least one active ingredient having the capacity to activate the GLP-1 receptor.

[0074] Each of these constituents of the composition according to the invention can meet one or more of the characteristics described above with reference to the use according to the invention of at least one phytoecdysone and / or at least one derivative semi-synthetic 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, as far as it is concerned.

[0075] The present invention relates in particular to such a composition for its use in preventing the loss, or improving, muscle function and / or mobility in obese, sarcopenic obese or overweight mammals.

[0076] According to the invention, the composition can in particular be used for the treatment or prevention of loss of muscle strength in obese, sarcopenic obese or overweight mammals, and / or for the treatment or prevention of degradation of the contractile properties of muscles in obese, sarcopenic obese or overweight mammals.

[0077] More generally, the present invention relates to such a composition for its use in the treatment of obesity, sarcopenic obesity or overweight in mammals. Such a composition can in particular be used in the treatment or prevention of loss of muscle mass and strength, in particular loss of mobility, in obese, sarcopenic obese or overweight mammals. It can also be used in the potentiation of loss of fat mass in obese, sarcopenic obese or overweight mammals, and in the maintenance of weight loss in obese or overweight or sarcopenic obese mammals. Finally, this composition can be used to improve insulin sensitivity in obese, sarcopenic obese or overweight mammals.

[0078] This composition for the uses cited may meet one or more of the characteristics described above with reference to the use in combination of said at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone, and said at least one active ingredient having the capacity to activate the GLP-1 receptor.

[0079] In particular embodiments of the invention, the composition is incorporated into a pharmaceutically acceptable formulation which can be administered orally or intranasally or subcutaneously or systemically.

[0080] In the context of the present invention, the term "pharmaceutical acceptable" means that which is useful in the preparation of a pharmaceutical composition, which is generally safe, non-toxic and is acceptable for veterinary as well as human pharmaceutical use.

[0081] The present invention is also expressed in terms of a method for preventing loss of, or improving, muscle function and / or mobility in obese, sarcopenically obese or overweight mammals, which method comprises administering, in a therapeutically effective amount, to a subject in need thereof: - at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), - and at least one active ingredient having the capacity to activate the GLP-1 receptor.

[0082] The present invention is also expressed in terms of a method for improving insulin sensitivity in obese, sarcopenically obese or overweight mammals, this method comprising administering, in a therapeutically effective amount, to a subject in need thereof: - at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), - and at least one active ingredient having the capacity to activate the GLP-1 receptor.

[0083] These methods may meet one or more of the characteristics described above with reference to the use according to the invention of at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor. It may in particular comprise the administration in a therapeutically effective amount, to a subject in need thereof, of a composition according to the invention as defined above, or of a medicament comprising it or comprising at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor. Brief description of the figures

[0084] The invention will be better understood by reading the following description, given as a non-limiting example, and made with reference to the figures which represent:

[0085] Figure 1 represents a schematic illustrating the scientific rationale for ACE2 / Ang1-7 / Mas axis activation concomitantly with activation of the GLP-1 receptor pathway resulting in a reduction of muscle atrophy, stimulation of muscle differentiation and improvement of insulin sensitivity.

[0086] Figure 2 shows a graph representing the level of expression of the Osteopontin gene (Spp1) by untreated 3T3 L1 adipocytes, or treated with 1000nM semaglutide, or with 10pM BIO101, or with a combination of 1000nM semaglutide and 10pM BIO101 (“Combo”). Values ​​are presented as mean ± sem (n=3). With ACt = Ct gene - Ct endogenous control and AACt = ACt sample - ACt calibrator, where Ct stands for “Cycle Threshold”.

[0087] Figure 3 shows a diagram representing the percentage loss of grip strength by grip strength test for the 4 legs of the animal (between the grip strength test performed before treatment and the grip strength test performed after 4 weeks of treatment), for groups of C57BL6 DIO mice respectively: untreated (“B6 DIO untreated”), treated with BIO101 (“B6 DIO BIO101”), treated with semaglutide (“B6 DIO Semaglutide”), and treated with BIO101 and semaglutide (“B6 DIO COMBO”). *: p<0.01 compared to the untreated group; §: p<0.05 and §§: p<0.01 compared to the group treated with BIO101. The number “n” of each group is mentioned in parentheses after the group name. Values ​​are presented as mean ± sem.

[0088] Figure 4 shows graphs resulting from the analysis of the contractile properties of the Edi muscle during twitch-type contractile responses (single electrical stimulation), more specifically, in A, the absolute twitch amplitude (expressed in g), in B, the relative twitch amplitude (expressed in g / mg of muscle), in C, the contraction velocity (expressed in g / s), and in D, the relaxation velocity (expressed in g / s), after 4 weeks of treatment of groups of C57BL6 DIO mice respectively: untreated (“B6 DIO untreated”), treated with BIO101 (“B6 DIO BIO101”), treated with semaglutide (“B6 DIO Semaglutide”), and treated with BIO101 and semaglutide (“B6 DIO COMBO”). *: p<0.05 compared to the untreated group and n: p<0.05 compared to the group treated with semaglutide alone. The size "n" of each group is indicated in parentheses after the group name. Values ​​are presented as mean ± sem.

[0089] Figure 5 shows representative diagrams, in A, of the total distance traveled (expressed in cm), and in B, of the activity time (expressed in %), evaluated during an actimetry test after 4 weeks of treatment of groups of C57BL6 DIO mice respectively: untreated (“B6 DIO untreated”), treated with BIO101 (“B6 DIO BIO101”), treated with semaglutide (“B6 DIO Semaglutide”), and treated with BIO101 and semaglutide (“B6 DIO COMBO”). *: p<0.05 compared to the untreated group. Description of the embodiments

[0090] In all the experiments below, the phytoecdysone used is 20-hydroxyecdysone, in the form of the BIO101 product containing it in a content greater than or equal to 97%. BIO101 is prepared from 20-hydroxyecdysone pure to the order of 90%, extracted from a plant or part of a plant containing at least 0.5% of 20-hydroxyecdysone by dry weight of said plant, according to the following steps: i) hot dissolution of 20-hydroxyecdysone pure to the order of 90% in methanol, filtration by means of a 0.2 pm particle filter and partial concentration, preferably by vacuum distillation, for example at a temperature of the order of 50°C and preferably in the presence of methanol MeOH, ii) addition of 3 volumes of acetone, iii) cooling to a temperature between 0 and 5°C, with stirring, iv) filtration of the precipitate obtained, v) successive rinsing with acetone and water, and vi) drying, preferably under vacuum at a temperature of the order of 50°C.B IO101 contains impurities, such as minor ecdysteroids, in individual proportions between 0 and 0.5%.

[0091] The active ingredients with the ability to activate the GLP-1 receptor used for the experiments are agonists of this receptor (GLP-1 RA), such as semaglutide.

[0092] I. Tests carried out on myoblast cultures

[0093] a. Culture conditions, treatments and gene expression analysis

[0094] The mouse myoblast cell line used is C2C12 (ATCC CRL 1772; Yaffe and Saxel, 1977). For proliferation of C2C12 cells were maintained in a DMEM / F-12 mixture (for "Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12" in English terminology) in a 50 / 50 ratio containing 2.5 g / L of glucose supplemented with 15% fetal bovine serum (FBS). To induce C2C12 differentiation, the medium was replaced by a DMEM / F-12 mixture supplemented with 2% horse serum.

[0095] Myotubes were then treated with 1.0 mM Palmitic Acid (PA) for 24 hours to simulate obesity in vitro and induce myotube atrophy. The cells were divided into five groups: control group, PA-only group, PA + GLP-1 RA group, PA + BIO101 group, and PA + GLP-1 RA + BIO101 group.

[0096] Multi-gene expression analysis was performed using the following primers: - the forward or “forward” primer in Anglo-Saxon terminology (F) 5 - CTTCTCGACTGCCATCCTGGAT-3' (SEQ ID No: 1) and antisense primer or "reverse" in English terminology (R) 5'- TCTTTTGGGCGATGCCACTCAG-3' (SEQ ID No: 2) for the gene coding for the Atrogin 1 protein (Identification number 67731 for the primer pair of the Origene® brand); - primer (F) 5 -TACCAAGCCTGTGGTCATCCTG-3' (SEQ ID No: 3) and primer (R) 5'-ACGGAAACGACCTCCAGACATG-3' (SEQ ID No: 4) for the gene coding for the MURF1 protein (Identification number 433766 for the primer pair of the Origene® brand); - the primer (F) 5'-AGCACTACAGTGGCGACTCAGAT-3' (SEQ ID No: 5) and the primer (R) 5'-TAGTAGGCGGTGTCGTAGCCAT-3' (SEQ ID No: 6) for the gene coding for the protein MyoD (Identification number 17927, from the brand Origene®); - primer (F) 5 -CCATCCAGTACATTGAGCGCCT-3' (SEQ ID No: 7) and primer (R) 5'-CTGTGGGAGTTGCATTCACTGG-3' (SEQ ID No: 8) for the MyoG gene coding for the Myogenin protein (Identification number 17928 for the primer pair of the Origene® brand); - the primer (F) 5'-GGAGCAGATTAGTAAGCGGCTTG-3' (SEQ ID No: 9) and the primer (R) 5'-GTTACTGCCACAGGAACTAGAGG-3' (SEQ ID No: 10) for the SIRT1 gene coding for the Sirtuin 1 protein (Identification number 93759 for the primer pair of the Origene® brand); - the primer (F) 5'-GGTGTGGTCAATACGGTCTTCAC-3' (SEQ ID No: 11) and the primer (R) 5'-AGCAGAGCCACGGTCATCAAGA-3' (SEQ ID No: 12) for the gene coding for the GLUT4 protein (Identification number 20528 for the primer pair of the Origene® brand); - primer (F) 5 -CATCACTGCCACCCAGAAGACTG-3' (SEQ ID No: 13) and primer (R) 5 -ATGCCAGTGAGCTTCCCGTTCAG-3' (SEQ ID No: 14) for the gene coding for the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Identification number 14433 for the primer pair of the Origene® brand); - the primer (F) 5'-GCAGTGCCTATCCAGAAAGTCC-3' (SEQ ID No: 15) and the primer (R) 5'-GGAATGAAGTCCAAGCCAGTGAC-3' (SEQ ID No: 16) for the gene coding for the protein Leptin (Identification number 16846 for the primer pair of the Origene® brand).

[0097] b. Preparation of cell lysates and western blots

[0098] C2C12 cell cultures under various conditions were harvested directly into ice-cold radioimmunoprecipitation assay (RIPA) buffer. For Western blots, cell lysates were electrophoresed on 5-15% gradient sodium dodecyl sulfate-polyacrylamide (or SDS-polyacrylamide) gels, transferred to a nitrocellulose membrane, and incubated with primary antibodies diluted 1:1000 overnight at 4°C (anti-SIRT1, anti-GLUT4, anti-Atrogin, anti-Myogenin, anti-GAPDH). The membrane was then incubated with a secondary antibody at 37°C for 1 hour.

[0099] II. Tests carried out on adipocyte cultures

[0100] In a first experiment, 3T3-L1 cells were cultured into pre-adipocytes in an adequate cellular medium. For adipocyte differentiation, 3T3-L1 cells that reached ~90% confluence were cultured in adipocyte induction medium for 3 days. The cells were treated during the differentiation phase with different concentrations of GLP-1 A alone, or with BIQ101 alone, or in combination (BIQ101 + GLP1 -RA).

[0101] An assessment of adipocyte proliferation was performed using Ki67 labeling. Lipid droplet production (using Oil Red O labeling) was determined, as well as adipocyte differentiation capacities using RTqPCR analysis of the expression of genes coding for proteins. C / EBPa and PPARy. The primer pairs used are as follows: - primer (F) 5'-GCAAAGCCAAGAAGTCGGTGGA-3' (SEQ ID No: 17) and primer (R) 5'-CCTTCTGTTGCGTCTCCACGTT-3' (SEQ ID No: 18) for the gene coding for the C / EBPa protein (Identification number 12606 for the primer pair of the Origene® brand); - primer (F) 5'-GTACTGTCGGTTTCAGAAGTGCC-3' (SEQ ID No: 19) and primer (R) 5'-ATCTCCGCCAACAGCTTCTCCT-3' (SEQ ID No: 20) for the gene coding for the PPARy protein (Identification number 19016 for the primer pair of the Origene® brand).

[0102] In a second experiment, osteopontin expression was assessed in cultures of these 3T3-L1 adipocyte cells. As indicated above, the expression of osteopontin (OPN), encoded by the Spp1 gene, significantly increases in the adipose tissue of obese individuals and alters the differentiation and insulin sensitivity of primary adipocytes.

[0103] 3T3-L1 cells were cultured into pre-adipocytes in an appropriate cell medium. For adipocyte differentiation, 3T3-L1 cells that reached 100% confluence were cultured in adipocyte induction medium for 3 days and then in maintenance medium for 2 days. The cells were treated during the differentiation phase with GLP-1 RA alone (1000 nM semaglutide), or with BIQ101 alone (10 pM), or in combination with 10 pM BIQ101 and 1000 nM semaglutide (“Combo”).

[0104] The evaluation of gene expression of the osteopontin gene (Spp1) was carried out by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RNAs were extracted in Trizol™ reagent, then assayed and converted into cDNA by reverse transcription. Quantitative PCR reactions were carried out in SYBR Green for 40 cycles at an annealing temperature of 60°C. The primer pairs used are as follows: - the sense primer (F) 5'-CAAGGTAAGCCTGCAGTGGC-3' (SEQ ID No: 21) and the antisense primer (R) 5'-ACTGCCAATCTCATGGTCGT-3' (SEQ ID No: 22) for the gene coding for the Spp1 gene (identification numbers 36505097 and 36505098 for the primers of the Eurofins Genomics® brand); - the sense primer (F) 5'-CTCTAGACTTCGAGCAGGAG-3' (SEQ ID No: 23) and the antisense primer (R) 5'-GGTACCACCAGACAGCACT-3' (SEQ ID No: 24) for the gene encoding the Actb gene (calibrator) (identification numbers 36505101 and 36505102 for Eurofins Genomics® brand primers).

[0105] The results obtained are shown in Figure 2. It is observed that differentiated adipocyte cells treated with semaglutide alone exhibit Spp1 expression similar to untreated cells, showing that this compound has no effect in itself on Spp1 gene expression. Treatment with BIO101 at 10 pM reduces Spp1 expression in 3T3-L1 cells by 40.2%, compared to untreated cells. Quite unexpectedly and advantageously, treatment in combination with BIO101 with semaglutide reduces Spp1 expression even more significantly. Indeed, in the “Combo” group, expression is reduced by -57.3% compared to the untreated group.

[0106] These results strongly suggest that the implementation of semaglutide in conjunction with BIO101 thus leads to a significant reduction in insulin resistance of adipocytes.

[0107] 111. Tests carried out on rodents

[0108] Animal models mimicking obesity have been used, such as the obese rat or mouse model induced by the consumption of a high-fat diet ("High fat diet" in Anglo-Saxon terminology).

[0109] A / General protocols

[0110] a. Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT).

[0111] After 16 hours of fasting, mice received an intraperitoneal injection of 20% glucose at a dose of 2.0 g / kg body weight. Blood glucose levels were then determined at 0, 15, 30, 60, and 120 minutes post-injection. One week after the glucose tolerance test, mice were fasted for 4 hours and then received an intraperitoneal injection of insulin at 0.5 U / kg body weight (Unit per kg). Blood glucose levels were then determined at 0, 15, 30, 45, 60, and 90 minutes post-injection.

[0112] b. Assessment of body weight and lower limb muscle weight and biochemical markers

[0113] Mice body weight was determined weekly, during and after cessation of GLP-1 and / or BIO101 treatment. After anesthesia and sacrifice of the animals, the lower limb muscles were separated, removed, and weighed. The muscles in question are the gastrocnemius muscle, the tibialis anterior muscle, the soleus muscle and the quadriceps femoris muscle.

[0114] A longitudinal analysis of biomarkers related to lipid homeostasis was carried out using plasma assays of adipokines (adiponectin, leptin), triglycerides, and cholesterol.

[0115] c. Tissue preparation and histological analysis

[0116] The muscles collected and mentioned above were frozen in a suitable compound to preserve the cellular ultrastructure which is OCT ("Optimal Cutting Temperature" in English terminology) then cut into 7 pm sections in order to be stained with hematoxylin-eosin, or with Oil Red O, in order to be able to respectively determine the average diameter of the muscle fibers and quantify the fatty infiltration in the muscle (positive area for Oil Red O).

[0117] d. Grip strength test

[0118] The grip strength of mice is measured using an electronic grip meter. The mouse grasps the metal grid with its limbs, then progressive traction is applied to the tail backwards and parallel to the table until it releases the grid. The maximum force developed is recorded and corresponds to the grip strength of the mouse. This operation is repeated three times per animal.

[0119] e. Suspension test

[0120] Each mouse is placed inverted under a grid that it grasps with the claws of all four limbs. The suspension time is measured. This operation is repeated three times per animal and the maximum suspension time is determined.

[0121] f. Physical activity in toto on treadmill

[0122] Mice were subjected to a running tolerance test on a horizontal motorized treadmill. Their maximum running speed (Vmax) and maximum running distance were recorded at the end of the experiment. The treadmill speed increased to 20 cm / s over 2 minutes. The speed was then increased by 5 cm / s every 5 minutes until the mice were exhausted.

[0123] g. In situ evaluation of the strength and contractile properties of isolated muscles

[0124] This approach was used at the end of treatment to analyze the overall strength and contractile characteristics of the extensor digitorum longus (Edi, fast muscle) and soleus (slow muscle) in anesthetized animals. Mechanical responses such as twitch and tetanus, developed in response to electrical stimulation of increasing intensity and frequency, were analyzed. This approach also allows the analysis of sensitivity to the muscle fatigue process as well as the capacity for post-fatigue recovery (Auda-Boucher et al., 2007).

[0125] All these experiments were performed blindly.

[0126] Mice were anesthetized with sodium pentobarbital ip (85 mg / kg). The tibialis anterior was freed from the distal tendon, and then a suture (Flexocrin 6 / 0) was passed under the Edl tendons. The muscle was then ligated, and the tendons were cut below this ligature. The muscle was hooked to the tension transducer. Stimulating electrodes were placed under the muscle perfused with HEPES-buffered Ringer's.

[0127] B / In vivo study in mice with diet-induced obesity of the effect of a combined treatment of semaqlutide and B IO101

[0128] B.1 / Duration of the study and method of administering treatments

[0129] C57BL / 6J mice were previously fed a high-fat diet (Formula D12492, Research Diets, Inc.) for 16 weeks. 48 male C57BL / 6J “Diet-Induced Obesity” (B6 DIO) mice (Janvier Labs, 22 weeks old at the start of the study), were divided into 4 groups: - control mice (untreated B6 DIO; n=12), - mice treated with BIO101 at 50 mg / kg / day per os (PO) (B6 DIO BIO101; n=12), - mice treated with semaglutide by subcutaneous (SC) injection at 0.120 mg / kg (B6 DIO Semaglutide; n=12), - mice treated in combination with B 10101 at 50 mg / kg / day per os and semaglutide by subcutaneous injection at 0.120 mg / kg (B6 DIO COMBO; n=12).

[0130] BIO101 was administered in the drinking water 7 days a week. The drinking water containing BIO101 was replaced five times a week for the duration of the study (4 weeks), until the animals were sacrificed (at 22 weeks of age) and adjusted according to food and water consumption and body weight of the mice, determined twice a week. The mean exposure value of the mice is 52±1 mg / kg / day for the group treated with BIO101 alone (B6 DIO BIO101), and 68±3 mg / kg / day for the group treated in combination with semaglutide and BIO101 (B6 DIO COMBO). The fatty diet was maintained ad libitum for the duration of the study. Semaglutide was injected SC, 5 days on 7. The animals were treated for 4 weeks of treatment, i.e. from 22 to 26 weeks of age of the mice.

[0131] B.2 / Analysis of gripping force: Grip test

[0132] The grip test (grip strength test) assesses the grip strength of animals. For this, the mouse is placed on a grid (10 x 10 cm) connected to a tension sensor (Panlab-Bioseb) so that it clings to the grid by all four paws. The animal is then pulled horizontally backward by the tail until the grid is released. The tension sensor records the maximum resistance developed in each test. A total of 5 measurements separated by 30 seconds of rest are taken. The results are expressed as the average of the 3 median values ​​obtained, in absolute values ​​(g) and normalized to the animal's weight (g / g).

[0133] The results obtained are shown in Figure 3. After 4 weeks of study, a decrease in grip strength of the 4 paws of untreated control animals was observed (-16.8%±3.1) compared to the test carried out at the beginning of the study. In mice treated with BIO101 alone (B6 DIO B 10101), a decrease in grip strength of the animals was also observed (-20.5%±4.3), without significant difference compared to the untreated group. In the group of animals treated with semaglutide alone (B6 DIO Semaglutide), a less significant decrease in performance was observed (-7%±3.7), without significant difference compared to the untreated group. Surprisingly and advantageously, a synergy operates between BIO101 and semaglutide during the combined treatment. Indeed, the treatment in combination of semaglutide and BIO101 (B6 DIO COMBO) significantly reduced the loss of grip performance in mice, compared to the untreated group (-1%±2.6; *p<0.05).The effect of the two products combined is significantly greater than the effect of each product taken separately.

[0134] B.3 / In situ exploration of muscle function - analysis of the contractile properties of a muscle of interest: Edi

[0135] In situ exploration of contractile function allows the analysis of the overall strength and contractile characteristics of the Extensor digitorum longus (Edi, fast muscle) in non-vigilant animals, by analyzing twitch-type mechanical responses (single electrical stimulation).

[0136] Briefly, the animal is anesthetized with a subcutaneous injection of a mixture of ketamine (150 mg / kg) and xylazine (30 mg / kg). The Tibialis Anterior (TA) is freed, then a suture is passed under the distal tendons of the Edl. The muscle is then ligated, the tendons are cut under this ligature, then the suture is connected to a force sensor. The stimulation electrodes are placed around the muscle which is continuously perfused with Ringer's solution (Na + 140 mM, K + 6 mM, Ca 2+ 3 mM, Mg 2+ 2mM, Cl' 156 mM, pH 7.4) buffered with N-2-hydroxyethylenepiperazine N'-2-ethanesulfonic acid (HEPES).

[0137] The stimulation protocol includes the analysis of twitch-type contractile responses: 3 stimulations of 10 V lasting 0.5 ms are applied. For each response, the voltage, the rise time to peak and the half-relaxation time are measured and then averaged.

[0138] This in situ study of the Edi muscle allows the analysis of the contractile properties of skeletal muscle. The results are shown in Figure 4. Unexpectedly, treatment of animals with semaglutide for 4 weeks induced a decrease in twitch-type contractile properties. Indeed, the “B6 DIO Semaglutide” group showed a loss of the absolute amplitude of contraction (3.36 g±0.19), compared to the untreated group (3.68 g±0.18; a loss of -8.7%). Interestingly, treatment in combination with BIO101 and semaglutide improved the amplitude of muscle contraction (3.9 g±0.3) and allowed an improvement compared to untreated animals (+6%), as well as an improvement of +16.1% compared to animals treated with semaglutide alone (in A in Figure 4).

[0139] In order to analyze the specific force of Edl, the same analysis was performed by relating the contraction amplitude to muscle mass. As can be seen in B in Figure 4, the “B6 DIO Semaglutide” group shows a loss of the specific contraction amplitude (0.23 g / mg±0.01), in comparison with the untreated group (0.26 g / mg±0.01; a loss of -11.5%). Interestingly, treatment in combination with BIO101 and semaglutide improves the muscle specific force (0.28 g / mg±0.02) and allows an improvement compared to the untreated animals (+7.7%), as well as an improvement of +21.7% compared to the animals treated with semaglutide alone.

[0140] As shown in C in Figure 4, the muscle contraction velocity of Edl is also impaired upon treatment with semaglutide compared to untreated animals (respectively 143.9 ± 7.2 g / s versus 131.7 ± 7.2 g / s in the “B6 DIO Semaglutide” and “untreated B6 DIO” groups), i.e. a loss of -8.5% in contraction speed. Treatment in combination with BIO101 and semaglutide increases muscle contraction speed (151.6 ± 11.7 g / s). This improvement is +5.4% compared to the untreated mouse groups, and +15.1% compared to the group of mice treated with semaglutide alone.

[0141] Finally, as observed in D in Figure 4, the Edl relaxation rate is significantly decreased compared to the untreated control group (121.6±5.9 g / s versus 148.5±8 g / s in the “B6 DIO Semaglutide” and “untreated B6 DIO” groups respectively), a significant loss of -18.8% (p<0.05). Treatment in combination with BIO101 and semaglutide induces a significant improvement in muscle relaxation rate (157.7±10.1 g / s). This improvement is +6.2% compared to the untreated mouse groups, and +29.7% (p<0.05) compared to the group of mice treated with semaglutide alone.

[0142] B.4 / Analysis of spontaneous movement activity

[0143] At the end of the 4-week study, the spontaneous motor activity of the animals was measured using an infrared actimeter (Letica LE881 1, BIOSEB). Each animal was placed for 5 min in a transparent arena surrounded by 32 infrared sensors located at different heights (adjustable according to the size of the animal) thus allowing horizontal and vertical movements to be measured. Different parameters were analyzed using Actitrack software, namely the total distance traveled and the activity time.

[0144] The results obtained concerning the total distance traveled are shown in A in Figure 5. It is observed in mice treated with BIO101 (“DIO BIO101”) that the total distance traveled (561.4 cm) is not increased compared to the untreated control mice (559.6 cm or +0.3%; p=ns). In the group of animals treated with semaglutide (“B6 DIO Semaglutide”; total distance traveled = 688 cm), although not significant, an increase in the spontaneous activity of the animals of +23% is observed compared to the untreated group. Surprisingly and advantageously, a synergy operates between B IO101 and semaglutide during the combined treatment (total distance traveled = 768.1 cm). Indeed, the treatment in combination of semaglutide and BIO101 (“B6 DIO COMBO”) makes it possible to improve the mobility of the animals with an increase of +37.3% in the total distance traveled compared to the untreated group (p=0.06).

[0145] The results obtained concerning the activity time are shown in B in Figure 5. It is observed that the activity time of the mice treated with BIO101 increases slightly compared to the untreated group (46.5% versus 44.8% respectively, i.e. +3.8%; p=ns). In the group of animals treated with semaglutide (“B6 DIO Semaglutide”; activity time = 51.6%), although not significant, an increase in the percentage of the animals’ activity time of +15.3% is observed compared to the untreated group. Surprisingly and advantageously, a synergy operates between BIO101 and semaglutide during the combined treatment (activity time = 57.7%). Indeed, the treatment in combination of semaglutide and BIO101 (“B6 DIO COMBO”) allows to significantly improve the animals’ activity time with an increase of +28.9% (p<0.05) compared to the untreated group.

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Claims

Claims Claim 1. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use for the prevention of loss, or improvement, of muscle function and / or mobility in obese, sarcopenic obese or overweight mammals: in which: R 1 is chosen from: a (Ci-C6)W(Ci-Ce) group; a (Ci- Ce)W(Ci-C6)W(Ci-C6) group; a (Ci-C6)W(Ci-C6)CO2(Ci-Ce) group; a (Ci-Ce)A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, CH2-CH2-OH, (Ci-Ce), NH(Ci-Ce), N(Ci- Ce)2, CO2(Ci-Ce) type; a CH2Br group; W being chosen from O, S, NH and NR where R represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms. Claim 2. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to claim 1, for the treatment or prevention of loss of muscle strength in obese, sarcopenic obese or overweight mammals. Claim 3. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use for improving insulin sensitivity in mammals obese, sarcopenic obese or overweight: in which: R 1is chosen from: a (Ci-C6)W(Ci-Ce) group; a (Ci- Ce)W(Ci-C6)W(Ci-C6) group; a (Ci-C6)W(Ci-C6)CO2(Ci-Ce) group; a (Ci-Ce)A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, CH2-CH2-OH, (Ci-Ce), NH(Ci-Ce), N(Ci- Ce)2, CO2(Ci-Ce) type; a CH2Br group; W being chosen from O, S, NH and NR where R represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms. Claim 4. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to any one of claims 1 to 3, in which the active ingredient having the capacity to activate the GLP-1 receptor is a GLP-1 analogue. Claim 5. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to any one of claims 1 to 4, in which the active ingredient having the capacity to activate the GLP-1 receptor is chosen from dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, albiglutide, noiiglutide and tirzepatide. Claim 6. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to any one of claims 1 to 5, wherein the active ingredient having the capacity to activate the GLP-1 receptor is a non-peptide compound. Claim 7. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to any one of claims 1 to 6, in which said at least one phytoecdysone is 20-hydroxyecdysone. Claim 8. At least one phytoecdysone and / or at least one semisynthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to claim 7, in which the 20-hydroxyecdysone is in the form of a plant extract or a part of a plant, said extract comprising at least 95%, and preferably at least 97%, of 20-hydroxyecdysone. Claim 9. At least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to any one of claims 1 to 8, wherein said at least one semi-synthetic derivative of 20-hydroxyecdysone is a compound of formula (H): Claim 10. At least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I), and at least one active ingredient having the capacity to activate the GLP-1 receptor, for their use according to one of claims 1 to 9, in which at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I) is chosen from: No. 1: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-10,13-dimethyl-17-(2- morpholinoacetyl)-2,3,4,5,9,11 , 12,15,16,17-decahydro-1 H- cyclopenta[a]phenanthren-6-one, No. 2: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(3- hydroxypyrrolidin-1 -y I )acety l]-10, 13-dim éthy I-2 , 3, 4, 5, 9, 11 , 12,15, 16,17- decahydro-1 H-cyclopenta[a]phenanthren-6-one; No. 3: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(4-hydroxy-1- piperidyl)acety l]-10, 13-dimethyl-2,3,4,5,9,11,12,15,16,17-decahydro-1 H-cyclopenta[a]phenanthren-6-one; No. 4: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-[4-(2- hydroxyethyl)-1 -pi peridyl]acety I]- 10, 13-dim ethy I-2 , 3 , 4 , 5 , 9 , 11 ,12,15,16,17- decahydro-1 H-cyclopenta[a]phenanthren-6-one; No. 5: (2S,3R,5R,10R,13R,14S,17S)-17-[2-(3-dimethylaminopropyl (methyl)amino)acetyl]-2,3, 14-trihydroxy-10, 13-dimethyl- 2,3,4,5,9,11, 12,15, 16,17 -decahydro-1 H-cyclopenta[a]phenanthren-6-one; No. 6: 2-[2-oxo-2-[(2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-10,13- dimethyl-6-oxo-2,3,4,5,9, 1 1 ,12,15,16,17-decahydro-1 H-cyclopenta[a]phenanthren-17-yl]ethyl]sulfanylacetate; No. 7: (2S,3R,5R,10R,13R,14S,17S)-17-(2-ethylsulfanylacetyl)-2,3,14- trihydroxy-10, 13-d im ethyl I-2, 3 , 4, 5, 9, 11 , 12, 15, 16, 17-decahydro-1 H- cyclopenta[a]phenanthrene-6-one; No. 8: (2S,3R,5R,10R,13R,14S,17S)-2,3,14-trihydroxy-17-[2-(2-hydroxyethyl sulfanyl)acetyl]-10, 13-d im ethyl I-2, 3, 4, 5, 9, 11 , 12, 15, 16, 17-decahydro-1 H cyclopenta[a]phenanthren-6-one. Claim 11. Composition comprising: - at least one phytoecdysone and / or at least one semi-synthetic derivative of 20-hydroxyecdysone of general formula (I): in which: R 1is chosen from: a (Ci-C6)W(Ci-Ce) group; a (Ci- Ce)W(Ci-C6)W(Ci-C6) group; a (Ci-C6)W(Ci-C6)CO2(Ci-Ce) group; a (Ci-Ce)A group, A representing a heterocycle optionally substituted by a group of the OH, OMe, CH2-CH2-OH, (Ci-Ce), NH(Ci-Ce), N(Ci- Ce)2, CO2(Ci-Ce) type; a CH2Br group; W being chosen from O, S, NH and NR where R represents a linear or branched alkyl group comprising from 1 to 6 carbon atoms; and - at least one active ingredient having the capacity to activate the GLP-1 receptor. Claim 12. Composition according to claim 11, for its use for the prevention of loss, or the improvement, of muscle function and / or mobility in obese, sarcopenic obese or overweight mammals. Claim 13. Composition for use according to claim 12, for the treatment or prevention of loss of muscle strength in obese, sarcopenic obese or overweight mammals. Claim 14. Composition according to claim 11, for its use for improving insulin sensitivity in obese, sarcopenic obese or overweight mammals.

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