Obesity Disrupts CtBP2 ‐Mediated Maintenance of Transcriptional Equilibrium in Hypothalamic Feeding Circuitry

Feeding behavior, which is crucial for all mammals, is regulated by a delicate equilibrium between the orexigenic and anorexigenic activities of hypothalamic neurons. This exquisite control of the neuropeptides that govern the feeding behavior could be a focal point in the pathogenesis of obesity. We reported that inactivation of C-terminal binding protein 2 (CtBP2), a transcriptional corepressor with metabolite-sensing capabilities, contributes to the pathogenesis of obesity in liver tissues and pancreatic β-cells. Here, we describe a transcriptional system regulated by CtBP2 in the hypothalamus. Our global mapping of CtBP2 binding sites using ChIP-seq combined with functional analyses revealed that CtBP2 functions as a corepressor for orexigenic neuropeptide promoters. In response to the metabolic abnormalities associated with obesity, CtBP2 undergoes allosteric inactivation and dissociates from these promoters, thereby resulting in the derepression of orexigenic neuropeptide expression. Consistently, the loss of CtBP2 in hypothalamic neurons in mice increases the expression of orexigenic neuropeptides, thus leading to increased feeding behavior. These findings highlight how obesity disrupts homeostatic mechanisms that normally maintain body weight within a healthy range.