Adipose HIF-1α causes obesity by suppressing brown adipose tissue thermogenesis

Hypoxia-inducible factor-1 alpha (HIF-1 alpha) in adipose tissue is known to promote obesity. We hypothesized that HIF-1 alpha interferes with brown fat thermogenesis, thus decreasing energy expenditure. To test this hypothesis, we compared transgenic mice constitutively expressing HIF-1 alpha in adipose tissues (HIF-1 alpha++) at usual temperature (22 A degrees C), where brown fat is somewhat active, or at thermoneutrality (30 A degrees C), where brown fat is minimally active. HIF-1 alpha++ mice or control litter mates were separated into room temperature (22 A degrees C) or thermoneutrality (30 A degrees C) groups. We assessed weight gain, food intake, calorimetry, activity, and oxygen consumption and transcriptional changes in isolated white and brown adipocytes. At 22 A degrees C, HIF-1 alpha++ mice exhibited accelerated weight gain, cold and glucose intolerance, hyperglycemia, and decreased energy expenditure without changes in food intake or activity. These changes were absent or minimal at thermoneutrality. In brown adipocytes of HIF-1 alpha++ mice, oxygen consumption decreased similar to 50 % in association with reduced mitochondrial content, uncoupling protein 2, and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1 alpha). In conclusion, adipose HIF-1 alpha overexpression inhibits thermogenesis and cellular respiration in brown adipose tissue, promoting obesity in the setting of reduced ambient temperature.