Abstract
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 PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. 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. β-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.
Highlights
The classic JAK/STAT pathway controls cellular responses to cytokines and growth factors by regulating the expression of nuclear-encoded early response genes [1]
Unphosphorylated STAT1 regulates the expression of caspases [4], as well as proteins involved in glycolysis/gluconeogenesis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation [5]
STAT1-/- mice displayed no changes in food intake, they showed increased body fat percentage and decreased lean mass weight (Fig 1B)
Summary
The classic JAK/STAT pathway controls cellular responses to cytokines and growth factors by regulating the expression of nuclear-encoded early response genes [1]. Cytokines binding to their cell surface receptors trigger the activation of one or several JAK tyrosine kinases, which phosphorylate the cytoplasmic domains of the receptor. The later studies were performed using squamous carcinoma cells where the expression of STAT1 was ablated using STAT1 shRNA [5] Transcriptional profiling of these transformed cells in the absence and presence of STAT1 expression suggested that there were modest changes in levels of RNAs involved in glycolysis/gluconeogenesis and oxidative phosphorylation. The physiological consequences in these metabolic shifs was not examined
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