Background: Accumulating evidence indicates that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lower glucose mainly by enhancing glucose-dependent stimulation of insulin secretion. However, the underlying mechanisms remain to be further investigated.

Methods: C57BL6/J mice fed with 12-week high-fat diet (HFD) were treated with exenatide (a GLP-1 RA, 24nmol/kg/d), GW501516 (a PPARΔ agonist, 2mg/kg/d) or saline injection as control for 8 weeks. Phenotypic evaluations were performed during and after the intervention. Tolerance tests and insulin measurement were performed after 8-week treatment. The mouse pancreatic β-cell line MIN6 was used as an in vitro model. The MIN6 cells were treated with GW501516 (10uM), exendin-4 (a GLP-1 RA, 20nM) combined with GSK0660 (a PPARΔ antagonist, 10uM) or not. Furthermore, mediums containing various concentrations of exendin-4 (1, 20 and 100 nM) or GW501516 (0.1, 1, 10 and 100uM) were applied. And the cells were incubated for 24 hours. PPARΔ and uncoupling protein-2 (UCP-2) protein expression were detected.

Results: Compared with the control group, exenatide and GW501516 treatment led to decreased body weight and improved insulin sensitivity in HFD mice. The mice in control group had higher serum insulin levels during the tolerant tests, but their early-phase insulin secretion was lacking, indicating the impaired insulin sensitivity and β-cell function. Both exenatide and GW501516 decreased the serum insulin levels in the HFD mice. Importantly, the lacking early-phase insulin secretion were recovered by both exenatide and GW501516. The protein expression of PPAR Δ was promoted while that of UCP-2 was decreased by exendin-4 in a dose-dependent manner. Similar results were found in cells treated with GW501516. However, these salient effects were partly reversed by GSK0660.

Conclusions: The effect of the GLP-1 RA exenatide on promoting β-cell function might be related to the activation of PPARΔ/UCP-2 pathway.


Y. Su: None. W. Xu: None. B. Lin: None. Z. Liu: None. Y. Chen: None. Z. Ye: None. L. Gan: None. B. Yao: None.


National Natural Science Foundation of China (81770821 to W.X.)

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