Background: Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose tissue (WAT) is an attractive therapeutic approach to oppose obesity, glucose intolerance and insulin resistance. Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in improving insulin resistance in adipose tissue by reducing fat mass and adipocyte hypertrophy. Forkhead box C2 (FOXC2) plays a vital role in the regulation of lipid metabolism.

Objects: Here, we investigated the effect of brown remodeling induced by the GLP-1 receptor (GLP-1R) agonist exenatide (exendin-4) in human adipose-derived stromal cells (hADSCs) isolated from omentum. We also looked at the role of FOXC2 in this process.

Methods: hADSCs were isolated, cultured and differentiated as previously described. The effect of Exendin-4 on brown remodeling during differentiation of hADSCs was examined. The knockdown by siRNA was performed to determine the roles of FOXC2 in brown remodeling during differentiation of hADSCs.

Results: In our study, oil red O test showed that Exendin-4 significantly increased the number of smaller lipid droplets, which is more similar to the morphological characteristics of brown fat. QPCR showed that Exendin-4 treatment could significantly up-regulate mRNA levels of some pro-brown adipogenic genes (UCP-1, FOXC2, PPARGC1A, PRDM16 and DIO2). Western blot also indicated that Exendin-4 could increase the protein levels of FOXC2 and UCP-1. Exendin-4-induced responses were partially blocked by GLP-1 receptor antagonist exendin9-39. The pro-brown adipogenic effects and increased expression of adipocyte specific markers caused by Exendin-4 was significantly reversed by the knockdown of FOXC2.

Conclusions: Our data highlight that a GLP-1R agonist promotes brown remodeling of WAT in a FOXC2-dependent manner, this might be one of the mechanisms underlying its effect on weight loss.


X. He: None. L. Liu: None. W. Ke: None. Y. Li: None.

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