<p>Effect of Insulin-Regulated FOXC2 Expression in Adipocyte Differentiation and Insulin Resistance</p>

Abstract

Objective 1) To investigate the effect of FOXC2 on the differentiation of adipose-derived mesenchymal stem cells. 2) To analyze the mechanism between FOXC2 expression regulation in adipose differentiation and insulin resistance (IR). Methods We first amplified the FOXC2 promoter region-512 and cloned it into the luciferase expression vector. The reporter gene system was transfected into the adipose tissue-derived mesenchymal stem cell to study insulin-mediated FOXC2 expression. We also manipulated FOXC2 protein expression by either siRNA or overexpression and studied the differentiation capability of adipose tissue-derived mesenchymal stem cell into adipocytes, as well as the influence on several IR-related genes: GLUT4 , PPARγ , UCP1 and PAI-1 . Results 1) Insulin effectively induced the expression of FOXC2 protein in adipose tissue-derived mesenchymal stem cells under differentiation ( P <0.01). Insulin also induced FOXC2-pro-512T promoter activity significantly ( P <0.01). 2) The stem cell adipose differentiation decreased in the FOXC2 overexpression group. 3) When FOXC2 was overexpressed, the expression of GLUT4 , PAI-1 and UCP1 was higher than control groups ( p <0.001). When FOXC2 was down-regulated by siRNA, both GLUT4 and PAI-1 ’s protein expression were decreased ( p <0.001), and the protein expression of PPARγ was increased ( p <0.001). In the presence of insulin induction, overexpression of FOXC2 led to significantly higher UCP-1 expression ( p <0.001) and lower PAI-1 expression ( p <0.001). The protein expression of GLUT4 , PAI-1 ( p <0.001) and UCP-1 ( p <0.05) was decreased in cells transfected with FOXC2 siRNA. Conclusion Insulin effectively induced the expression of FOXC2 protein in adipose tissue-derived mesenchymal stem cells under differentiation, possibly through the regulation of the FOXC2-pro-512T promoter activity. The different protein expression of FOXC2 has regulatory effects on several genes related to insulin resistance. FOXC2 is an important regulatory factor in adipocyte differentiation and insulin resistance.

Effects of different ethnicities and FOXC2 gene C-512T polymorphisms on the intestinal flora: A study on healthy Dai and Han populations in Yunnan

“…Our previous research has confirmed that FOXC2 is strongly associated with glycolipid metabolism [10,11]. The polymorphism of C-512T in the 5 untranslated region of FOXC2 is significantly associated with insulin resistance (HOMA-IR) [12].…”

Micro ribonucleic acid‐363 regulates the phosphatidylinositol 3‐kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus

“…Forkhead box C2 (FOXC2) is an important member of helix/forkhead transcription factor family 19 , and plays an important role in regulating lipid metabolism and glucose metabolism 20 . Therefore, FOXC2 was considered to have the function to regulate insulin resistance 21 . More importantly, Nian et al 22 showed that FOXC2 expression in visceral adipose tissue of type 2 diabetes patients was significantly lower than those of non-diabetes patients.…”