Transcriptional and physiological roles for STAT proteins in leptin action

Warren Pan, Margaret B. Allison, Paul Sabatini, Alan Rupp, Jessica Adams, Christa Patterson, Justin C. Jones, David P. Olson, Martin G. Myers Jr.

Leptin, a peptide hormone produced by white adipose tissue in proportion to energy stores, plays a central role in the control of feeding and energy balance. Leptin acts via its receptor to activate several members of the signal transducer and activator of transcription (STAT) transcription factor family. Pan, Allison, and colleagues investigated the roles of STAT1, STAT3 and STAT5 in response to leptin. Although leptin receptor activates STAT1, STAT3, and STAT5 in cultured cells, their findings reveal no role for STAT1 or STAT5 in leptin action in vivo.

Objective: 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 (Stat3LepRbKO 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 Stat3LepRbKO mice, ablating Stat1 in LepRb neurons failed to alter energy balance (even on the Stat3LepRbKO 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.