Short-term GLP-1 receptor agonist exenatide ameliorates intramyocellular lipid deposition without weight loss in ob/ob mice
Abstract
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.
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Few studies of anti-obesity drug treatment directly evaluate intramyocellular lipids in humans or animals, and none were conducted in aged humans or animals; all involved models of obesity and/or Type 2 diabetes.
“There are few studies of anti-obesity drug treatment that directly evaluate IMCLs in either humans or animals [153–156], which report either decreases or no change in IMCL. However, none of these studies were conducted in aged humans or animals, and all involved models of obesity and/or Type 2 diabetes.”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [154]
In a rodent model of obesity, GLP-1 receptor agonist exenatide at a dose that improved serum glucose and insulin sensitivity, but not body or fat mass, reduced intramyocellular lipids.
“a recent study using a rodent model of obesity found that GLP-1 receptor agonist (exenatide) treatment at a dose that improved serum glucose and insulin sensitivity, but not body or fat mass, reduced IMCL [154].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [154]
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- Authors
- Xu, F., Cao, H., Chen, Z., Gu, H., Guo, W., Lin, B., & Weng, J.
- Affiliations
- Key Laboratory of Guangdong Province (CN)
- Central South University (CN)
- Corresponding author
- Weng, Jianping
- Venue
- International Journal of Obesity
- Published
- 2020-01-07
- Volume
- 44
- Issue
- 4
- Pages
- 937-947
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- OpenAlex
- W2999774672
- Cited by
- 31
- References
- 38
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 3
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- exenatide, GLP-1 receptor agonists, skeletal muscle lipid metabolism, type 2 diabetes, obesity, AMPK, insulin signaling, exendin-4, leptin, diet-induced obesity, ob/ob mice, lipid oxidation, insulin sensitivity
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Glucagon-Like Peptide-1 Receptor Agonists, Animals, Body Weight, Cells, Cultured, Male, Mice, Obese, Signal Transduction, Weight Loss, Lipid Metabolism, Mice, AMP-Activated Protein Kinases
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