1938-P: GLP-1 Receptor Agonist Ameliorates Intramyocellular Lipid Deposition Without Weight Loss by Activating AMPK

Objective: Ectopic deposition of lipids is closely related with type 2 diabetes (T2D). Whether and how GLP-1 receptor agonists (GLP-1 RAs) ameliorate lipid deposition in skeletal muscle remain unknown. Here, we investigate the effect of GLP-1 RA exenatide on intramyocellular lipid deposition of skeletal muscle in T2D models and whether this process depends on weight loss. Methods: ob/ob mice and diet-induced obese (DIO) mice were treated with exenatide, leptin or saline control i.p. for four weeks. Systemic phenotypic evaluations were carried out during and after the intervention. An in vitro model used palmitate-treated myoblast C2C12 cells. The expression of key enzymes involved in lipid metabolism was assessed in skeletal muscle of ob/ob mice and DIO mice. Results: In ob/ob mice, body weight and fat mass were not improved by four-week exenatide treatment. However, intramyocellular lipid deposition and lipid profiles were still modestly ameliorated by exenatide. In DIO mice, body weight, lipid profiles and intramyocellular lipid were all remarkably alleviated by exenatide but not by leptin. In skeletal muscle of these two models, activated AMPK signaling pathway, stimulated lipid oxidative enzymes and improved insulin signaling pathway were observed by exenatide treatment. In vitro, exendin-4 activated AMPK signaling pathway and promoted lipid metabolism to improve lipid accumulation in palmitate-treated myoblast C2C12 cells, and inhibiting AMPK abolished this effect. Conclusion: Exenatide ameliorates intramyocellular lipid deposition before the weight loss effect appears in ob/ob mice. While both body weight and intramyocellular lipid are alleviated remarkably at the same time by exenatide in DIO mice. Thus, the effect of exenatide on ameliorating intramyocellular lipid deposition could be independent on weight loss by activating AMPK signaling pathway. Disclosure F. Xu: None. H. Cao: None. Z. Chen: None. H. Gu: None. W. Guo: None. B. Lin: None. J. Weng: None.