FOXC2 : a regulator of adipocyte metabolism

Abstract

Obesity, hyperlipidemia and insulin resistance are common forerunners of type 2 diabetes, a serious and increasingly prevalent disease in both the industrialised part of the world as well as in third world countries. We have identified the human transcription factor gene FOXC2 as a key regulator of adipocyte metabolism. Increased FOXC2 expression, in white (WAT) and brown adipose tissue (BAT), has a pleiotropic effect on gene expression. Which leads to protection against diet induced insulin resistance and a decrease in: total body lipid content, serum triglycerides, plasma levels of free fatty acids, glucose and insulin. It also increases the sensitivity of the b-adrenergic/cAMP/protein kinase A signaling pathway in adipocytes. The glucose disposal after intravenous glucose challenge is significantly enhanced as a sign of increased insulin sensitivity. Insulin and TNFa strongly induces Foxc2 mRNA and Foxc2 protein levels in murine 3T3-L1 adipocytes via PI3K and ERK1/2-dependent pathways. Foxc2 mRNA is also upregulated by the PKA and PKC-signaling pathways. The expression of FOXC2 in human adipose tissue and skeletal muscle correlates with whole body insulin sensitivity. A common 5'UTR C/T polymorphism is associated with features of the metabolic syndrome such as insulin resistance and dyslipidemia.To our knowledge FOXC2 is the only known gene that, in a concerted action, can counteract most, if not all, of the symptoms associated with obesity, including hypertriglyceridemia and diet induced insulin resistance - a likely consequence hereof would be protection against type 2 diabetes.