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Background Type 2 diabetes and obesity are often seen concurrently with skeletal muscle wasting, leading to further derangements in function and metabolism. Muscle wasting remains an unmet need for metabolic disease, and new approaches are warranted. The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin releasing factor receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance, glucose metabolism, and muscle mass. The aim of this study was to investigate the effects of modified UCN2 peptides as a pharmaceutical therapy to counteract the loss of skeletal muscle mass associated with obesity and casting immobilization. Methods High‐fat‐fed mice (C57Bl/6J; 26 weeks old) and ob/ob mice (11 weeks old) were injected daily with a PEGylated (Compound A) and non‐PEGylated (Compound B) modified human UCN2 at 0.3 mg/kg subcutaneously for 14 days. A separate group of chow‐fed C57Bl/6J mice (12 weeks old) was subjected to hindlimb cast immobilization and, after 1 week, received daily injections with Compound A. In vivo functional tests were performed to measure protein synthesis rates and skeletal muscle function. Ex vivo functional and molecular tests were performed to measure contractile force and signal transduction of catabolic and anabolic pathways in skeletal muscle. Results Skeletal muscles (extensor digitorum longus, soleus, and tibialis anterior) from high‐fat‐fed mice treated with Compound A were ~14% heavier than muscles from vehicle‐treated mice. Chronic treatment with modified UCN2 peptides altered the expression of structural genes and transcription factors in skeletal muscle in high‐fat diet‐induced obesity including down‐regulation of Trim63 and up‐regulation of Nr4a2 and Igf1 (P < 0.05 vs. vehicle). Signal transduction via both catabolic and anabolic pathways was increased in tibialis anterior muscle, with increased phosphorylation of ribosomal protein S6 at Ser235/236, FOXO1 at Ser256, and ULK1 at Ser317, suggesting that UCN2 treatment modulates protein synthesis and degradation pathways (P < 0.05 vs. vehicle). Acutely, a single injection of Compound A in drug‐naïve mice had no effect on the rate of protein synthesis in skeletal muscle, as measured via the surface sensing of translation method, while the expression of Nr4a3 and Ppargc1a4 was increased (P < 0.05 vs. vehicle). Compound A treatment prevented the loss of force production from disuse due to casting. Compound B treatment increased time to fatigue during ex vivo contractions of fast‐twitch extensor digitorum longus muscle. Compound A and B treatment increased lean mass and rates of skeletal muscle protein synthesis in ob/ob mice. Conclusions Modified human UCN2 is a pharmacological candidate for the prevention of the loss of skeletal muscle mass associated with obesity and immobilization.

GDF15 has potent anti-obesity effects, but its receptor was previously unknown. GFRAL has now been identified as the receptor for GDF15, and it mediates the effects of GDF15 via central actions in the hindbrain. Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism 1 . A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer 2 . In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters 3 , suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral −/− mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4 , 5 , 6 ). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.

The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.

Abstract Oxytocin (OXT) has been shown to suppress appetite, induce weight loss, and improve glycemic control and lipid metabolism in several species, including humans, monkeys, and rodents. However, OXT’s short half-life in circulation and lack of receptor selectivity limit its application and efficacy. In this study, we report an OXT peptide analog (OXTGly) that is potent and selective for the OXT receptor (OXTR). OXT, but not OXTGly, activated vasopressin receptors in vitro and acutely increased blood pressure in vivo when administered IP. OXT suppressed food intake in mice, whereas OXTGly had a moderate effect on food intake when administered IP or intracerebroventricularly. Both OXT (IP) and OXTGly (IP) improved glycemic control in glucose tolerance tests. Additionally, both OXT (IP) and OXTGly (IP) stimulated insulin, glucagon-like peptide 1, and glucagon secretion in mice. We generated lipid-conjugated OXT (acylated-OXT) and OXTGly (acylated-OXTGly) and demonstrated that these molecules have significantly extended half-lives in vivo. Compared with OXT, 2-week treatment of diet-induced obese mice with acylated-OXT [subcutaneous(ly) (SC)] resulted in enhanced body weight reduction, an improved lipid profile, and gene expression changes consistent with increased lipolysis and decreased gluconeogenesis. Treatment with acylated-OXTGly (SC) also resulted in a statistically significant weight loss, albeit to a lesser degree compared with acylated-OXT treatment. In conclusion, we demonstrate that selective activation of the OXTR pathway results in both acute and chronic metabolic benefits, whereas potential activation of vasopressin receptors by nonselective OXT analogs causes physiological stress that contributes to additional weight loss.

Tirzepatide (LY3298176) is a fatty-acid-modified, dual incretin receptor agonist that exhibits pharmacology similar to native GIP at the glucose-dependent insulinotropic polypeptide receptor (GIPR) but shows bias toward cyclic adenosine monophosphate signaling at the glucagon-like peptide-1 receptor (GLP-1R). In addition to GIPR signaling, the pathway bias at the GLP-1R may contribute to the efficacy of tirzepatide at improving glucose control and body weight regulation in type 2 diabetes mellitus. To investigate the structural basis for the differential signaling of tirzepatide, mechanistic pharmacology studies were allied with cryogenic electron microscopy. Here, we report high-resolution structures of tirzepatide in complex with the GIPR and GLP-1R. Similar to the native ligands, tirzepatide adopts an α-helical conformation with the N terminus reaching deep within the transmembrane core of both receptors. Analyses of the N-terminal tyrosine (Tyr1Tzp) of tirzepatide revealed a weak interaction with the GLP-1R. Molecular dynamics simulations indicated a greater propensity of intermittent hydrogen bonding between the lipid moiety of tirzepatide and the GIPR versus the GLP-1R, consistent with a more compact tirzepatide–GIPR complex. Informed by these analyses, tirzepatide was deconstructed, revealing a peptide structure–activity relationship that is influenced by acylation-dependent signal transduction. For the GIPR, Tyr1Tzp and other residues making strong interactions within the receptor core allow tirzepatide to tolerate fatty acid modification, yielding an affinity equaling that of GIP. Conversely, high-affinity binding with the extracellular domain of the GLP-1R, coupled with decreased stability from the Tyr1Tzp and the lipid moiety, foster biased signaling and reduced receptor desensitization. Together, these studies inform the structural determinants underlying the function of tirzepatide.

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino (BCAAs) and keto-acids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.

The members of the insulin superfamily are well conserved across the evolution tree. We recently showed that four viruses in the Iridoviridae family possess genes that share high similarity with human insulin and IGF-1. By chemically synthesizing single chain (sc, IGF-1 like) forms of these viral insulin/IGF-1 like peptides (VILPs), we previously showed that sc VILPs have insulin/IGF properties in vitro and in vivo. However, characteristics of double chain (dc, insulin-like) VILPs remain unknown. In this study, we characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). We showed that GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and they bind to IGF-1R with a higher affinity than human insulin. These dcVILPs stimulate receptor phosphorylation and post-receptor signaling in vitro and in vivo. LCDV-1 dcVILP stimulated a weak response in in vitro signaling experiments, although we could not determine binding competition. Both GIV and SGIV dcVILPs stimulated glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (2.5 mU/kg/min) and GIV dcVILP (125 mU/kg/min) stimulate a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulates ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This is due to increased Akt phosphorylation and glucose transporter type 4 (GLUT4) expression compared to insulin specifically in WAT. Taken together, these results show that dc GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. This observation evokes questions about their potential roles in human disease including diabetes and cancer. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action and design new analogues that specifically target the tissues.