Protective role of adipocyte hypoxia-inducible factor-2 in diet-induced obesity in mice

In obesity excessive accumulation of lipids in the fat depots is accompanied by fast growth of adipocytes which results in relative tissue hypoxia within the adipose tissue. Hypoxia inducible factors (HIFs) are transcription factors which represent the main response elements to hypoxia in cells, leading to a coordinate cellular program including switch to anaerobic metabolism or activation of angiogenesis. Although previous studies have analysed the role of HIF-1 in obesity, little is known about the possible involvement of HIF-2. In our study, we focused in a diet-induced obesity model in mice deficient for HIF-2 specifically in white and brown adipocytes. Mice lacking this protein gained more weight upon diet-induced obesity and became more insulin resistant and glucose intolerant compared to HIF2-proficient mice. This was accompanied by enhanced fibrosis and macrophage presence in the white adipose tissue. Brown adipose tissue was also affected, showing enhanced adipocyte size and reduced uncoupling protein (UCP)-1 content suggesting impaired thermogenic function of brown adipose tissue. In addition, adipocyte-specific HIF-2-deficient mice were prone to lipid accumulation in the liver. The reduced number of endothelial cells and enhanced hypoxia presence found in the white adipose tissue from HIF-2 deficient mice suggest that the lack of HIF-2-induced angiogenesis could be responsible for the phenotype seen in the adipose-specific HIF-2 knockout mice.