Transcriptional and physiological roles for STAT proteins in leptin action.

Abstract Objectives Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression. Methods Because STAT3 is crucial for physiologic leptin action, we used TRAP-seq to examine gene expression in LepRb neurons of mice ablated for Stat3 in LepRb neurons (Stat3^LepRbKO mice), revealing the STAT3-dependent transcriptional targets of leptin. To understand roles for STAT proteins in leptin action, we also ablated STAT1 or STAT5 from LepRb neurons and expressed a constitutively-active STAT3 (CASTAT3) in LepRb neurons. Results While we also found increased Stat1 expression and STAT1-mediated transcription of leptin-regulated genes in Stat3^LepRbKO mice, ablating Stat1 in LepRb neurons failed to alter energy balance (even on the Stat3^LepRbKO background); ablating Stat5 in LepRb neurons also failed to alter energy balance. Importantly, expression of a constitutively-active STAT3 (CASTAT3) in LepRb neurons decreased food intake and body weight and improved metabolic parameters in leptin-deficient (ob/ob) mice, as well as in wild-type animals. Conclusions Thus, STAT3 represents the unique STAT protein required for leptin action and STAT3 suffices to mediate important components of leptin action in the absence of other LepRb signals. Highlights • We used TRAP-seq to define the STAT3-dependent and independent control of gene expression in LepRb neurons. • We deleted multiple STAT proteins from LepRb neurons, revealing the unique role for STAT3 in leptin action. • Constitutively-active STAT3 in LepRb neurons controlled body weight and glucose in ob/ob and wild-type mice. • STAT3 represents the only STAT protein required for leptin action and suffices to mediate components of leptin action. [ABSTRACT FROM AUTHOR]