Hypoxia inducible factor 1α plays an indispensible role in maintaining the thermogenic functions of brown adipose tissue in mice

Abstract

Hypoxia in adipose tissue has been proposed as a possible mechanism for obesity-related chronic inflammation, insulin resistance and metabolic dysfunction. Hypoxia inducible factor 1α(HIF1α), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the patho-physiological role of HIF1α in obesity-related pathologies remains to be determined. To address this question, we have generated a transgenic mouse model with adipose tissue-selective expression of a dominant negative version of HIF1α under the transcriptional control of the aP2 gene promoter. The transgenic mice developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared to their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial DNA copy number and reduced expression of PGC1α and uncoupling protein-1, both of which are critically involved the biogenesis of BAT. Furthermore, impaired BAT function and reduced thermogenesis in the transgenic mice occurred prior to the development of obesity. In the transgenic mice, angiogenesis in BAT was decreased as early as four weeks after birth, but was elevated in WAT at the late stage of obesity. These findings support an indispensible role of HIF1α in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue.