247 : Stat1 inhibits mitochondrial biogenesis

Abstract

Stat1 plays a central role in orchestrating responses to a variety of pathogens by activating the transcription of nuclear encoded genes that mediate the antiviral, antigrowth, and the immune surveillance effects of interferons. Previous studies have indicated that Stat3 plays a role in energy metabolism. Since Stat1 and Stat3 often have antagonist actions, we performed metabolic cage analysis. These studies indicate that Stat1−/− mice display increased energy expenditure compared to Stat1+/+ mice. Furthermore, nuclear magnetic resonance show increased fat storage in Stat1−/− mice. Consistent with elevated energy expenditure, Stat1−/− mice show increased mitochondrial biogenesis in the liver which is a primary response to fasting. Interestingly, Stat1 protein levels are decreased in the livers of fasted mice. RNA levels of PGC1α, a master regulator of mitochondrial biogenesis is increased in fed Stat1−/− mice compared with Stat1+/+ mice. No further changes in PGC1α levels are observed in livers from fasted Stat1−/− animals while fasted wild type mice have increased levels of PGC1α. These results suggest that Stat1 represses the expression of PGC1a. To explore this possibility, we performed chromatin immunoprecipitation assays to examine the binding of Stat1 to the promoter of PGC1α in fed mice and fasted animals. Stat1 binding to the PGC1α promoter was observed in fed mice, and binding was lost in fasted animals. These results identify a previously unknown role of Stat1 in regulation of energy metabolism.