Metabolic Characterization of Human FOXC2 in Adipose Tissue

Abstract

In mice, the overexpression of the nuclear transcription factor FOXC2 in adipose tissue counteracts obesity and diet-induced insulin resistance. Transgenic mice that overexpress FOXC2 in adipose tissue (FOXC2 tg mice) have the key feature of an apparent "conversion" of their intra-abdominal white adipose tissue (WAT) depot into brown adipose tissue (BAT). BAT is very different structurally and metabolically from WAT as it effectively "wastes" energy in the form of heat because of the expression of uncoupling protein-1 (UCP1). In brown adipocytes, thermogenesis is activated through sympathetic stimulation of beta3 adrenergic receptors (beta3ARs) and it is believed that FOXC2 increases the sensitivity of this pathway in adipocytes. FOXC2 tg mice show an increased energy expenditure at 24°C, and 30°C (thermoneutrality) when compared with wild type (wt) mice. However, the FOXC2 tg mice have a blunted response to the beta3AR agonist, CL-316,243 while wt mice show a normal increase in whole body O2 consumption. O2 consumption of isolated BAT and WAT from FOXC2 tg and wt mice was assessed and it was observed that "converted" FOXC2 tg WAT had a similar O2 consumption profile to that of wt BAT. Furthermore, transmission electron microscopy (TEM) of tissues demonstrated an increased multilocularity of cellular lipid droplets and increased mitochondrial content in FOXC2 tg WAT similar to that of FOXC2 tg and wt BAT. Moreover, the oxidative capacity of differentiated mouse embryonic fibroblasts (MEFs) from FOXC2 tg mice was increased compared with wt differentiated MEFs. Taken together, these findings clearly indicate important roles ofFOXC2 in adipocyte energy metabolism, affecting mitochondrial energetics, in particular.