Introduction and Objective: GCGR agonism stimulates energy expenditure (EE) and weight loss in rodents. Moreover, when combined with the antidiabetic actions of incretins (GLP1, GIP), GCGR-agonists lack hyperglycemic side effects. We also identified anti-obesity effects of GCGR agonism for 50d after treatment cessation. Thus, we hypothesized that a GLP-1/GIP/GCGR triple agonist (GGG) will increase EE during treatment and prolong weight loss after cessation.Methods: Diet-induced obese mice were treated for 14d with vehicle, GGG, glucagon specific agonism (IUB288), Semaglutide (Sema), or GIP specific agonism (GIP-FA 085). We used indirect calorimetry to assess energy balance and multiomics (RNAseq, lipidomic, and metabolomics at treatment d4 and 14) to interrogate molecular mechanisms.Results: IUB288 increased, and Sema reduced EE, compared to vehicle-treated mice. Increased EE in GGG as compared to Sema-treated mice, suggests that the triple agonist possesses properties of both GLP1 and GCGR activity. All treatments reduced respiratory quotient (RQ) as compared to vehicle-treated mice. Multiomic analyses identified increased liver fatty acid oxidation (FAOx) including profound increases in liver and plasma ketones, mRNA expression of FAOx genes, and liver acyl-carnitines in IUB288- and GGG-treated mice. Liver steatosis was reduded in IUB288- as compared to Sema-treated DIO mice, suggesting weight-independent regulation. IUB288 and GGG treatments likewise reduced mRNA of redox stress, inflammation, and fibrosis genes. Subsequent analyses showed these IUB288-associated reductions in fibrosis are independent of its anti-steatosis activity. At study end, Sema mice gained significantly more weight than IUB288 or GGG mice, despite similar food intake during rebound.Conclusion: These results suggest that GGG exhibits both GLP1R and GCGR agonism, with respect to EE and liver steatosis effects.
T. Kim: None. K. Seck: None. R. DiMarchi: Research Support; MBX Biosciences. K.M. Habegger: Consultant; Abvance Therapeutics, Glyscend Therapeutics. Stock/Shareholder; Glyscend Therapeutics. Research Support; Eli Lilly and Company. Consultant; Merck & Co., Inc.
The project described was supported by the NIH grants 1R01DK112934 (KMH), 1R01DK137506 (KMH), P30 DK-079626, and T32 AI007051 (SRN); and the Lilly Research Award Program (WR and KMH)
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