Short-term GLP-1 receptor agonist exenatide ameliorates intramyocellular lipid deposition without weight loss in ob/ob mice

• Published in: International Journal of Obesity Vol. 44; no. 4; pp. 937 - 947
• Main Authors: Xu, Fen, Cao, Huanyi, Chen, Zonglan, Gu, Huimin, Guo, Wanrong, Lin, Beisi, Weng, Jianping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2020; Nature Publishing Group
• Subjects: 13/105; 13/51; 14/63; 64/60; 692/163/2743/137/773; 692/699/2743/393; 82/1; Accumulation; Agonists; AMP; AMP-activated protein kinase; Animal models; Antidiabetics; Body fat; Body weight; Body weight loss; Deposition; Diabetes mellitus (non-insulin dependent); Dosage and administration; Drug therapy; Enzymes; Epidemiology; Exenatide; Fatty liver; Health aspects; Health Promotion and Disease Prevention; Insulin; Internal Medicine; Kinases; Leptin; Lipid metabolism; Lipid peroxidation; Lipids; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Muscles; Musculoskeletal system; Myoblasts; Obesity; Oxidation; Palmitic acid; Physiological aspects; Public Health; Receptors; Signal transduction; Signaling; Skeletal muscle; Steatosis; Type 2 diabetes; Weight loss; Weight reduction; China
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/s41366-019-0513-y

Objective
Ectopic lipid deposition is closely associated with type 2 diabetes (T2D). Accumulating evidence shows that GLP-1 receptor agonists (GLP-1 RAs) improve obesity and liver steatosis. However, it remains unknown whether and how they ameliorate lipid deposition in skeletal muscle. This study aimed to investigate the effect of exenatide (a GLP-1 RA) on intramyocellular lipid deposition in the skeletal muscle of T2D models and its dependence on weight loss.
Methods
Ob/ob mice and diet-induced obese (DIO) mice were treated with exenatide (24 nmol/kg), leptin (1 mg/kg), or saline control intraperitoneally once daily for 4 weeks. Phenotypic evaluations were performed during and after the intervention. PA-induced myoblast C2C12 cells were used as an in vitro model. The expression of key enzymes involved in lipid metabolism was assessed in the skeletal muscle of ob/ob mice and DIO mice.
Results
In ob/ob mice, 4-week exenatide treatment did not improve the body weight and fat mass, but modestly ameliorated intramyocellular lipid deposition and lipid profiles. In DIO mice, it remarkably alleviated the body weight, lipid profiles, and intramyocellular lipid deposition. In the skeletal muscle of these two models, exenatide treatment activated the AMP-activated protein kinase (AMPK) signaling pathway, stimulated lipid oxidation enzymes, and upregulated the insulin signaling pathway. In vitro, exendin-4 activated the AMPK signaling pathway and stimulated lipid metabolism to improve lipid accumulation in palmitate-induced myoblast C2C12 cells.
Conclusions
Exenatide ameliorated intramyocellular lipid deposition without body weight reduction in ob/ob mice, but alleviated body weight and intramyocellular lipid deposition in DIO mice. The underlying mechanism included the activation of AMPK signaling pathway and improvement in insulin sensitivity, independent of weight loss in ob/ob mice.