Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Steroid receptor coactivator (SRC)-1 mediates nuclear hormone receptors and transcription factor-dependent transcription (1), and interacts with STAT3 (2) an important mediator of leptin-induced POMC expression and hence satiety (3). Src-1 knockout mice are obese (4), however, the underlying mechanism is unclear. In a compelling line of evidence, these authors suggest that SRC-1 deficiency might impair leptin action via reduced STAT3 activation. They show that SRC-1 deficient mice have lower leptin-stimulated pSTAT3 binding to Pomc promoters and lower Pomc mRNA, become more obese on high fat diets and are resistant to the anorectic effect of leptin. In addition, 14 of 15 rare SRC−1 variants found in individuals with severe, early-onset obesity showed reduced SRC-1-STAT3 interaction, reduced POMC-neuron activation, and reduced POMC expression in in-vitro models; only 4 rare variants were identified in normal weight controls.