UC San Diego

Factor Inhibiting HIF-1[alpha] (FIH) is an asparaginyl hydroxylase. Hydroxylation of HIF-[alpha] proteins by FIH blocks association of HIFs with the transcriptional co- activators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene, and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, improved glucose and lipid homeostasis, and are resistant to high fat diet-induced weight gain and hepatic steatosis. Neuron -specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, enhanced insulin sensitivity, and are also protected against high fat diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism