The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes

The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1(-/-) mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1(-/-) mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1(-/-) mice expressed increased amounts of PGC1 alpha, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1 alpha promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1 alpha. Since STAT1(-/-) mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1(-/-) mice did not lose lipid from WAT. beta-adrenergic stimulation of glycerol release from isolated STAT1(-/-) WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1(-/-) adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1(-/-) mice.