The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake

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Abstract
Insulin action in the brain is known to inhibit food intake. Now Leona Plum and her colleagues show that in hypothalamic neurons insulin inhibits FoxO1-mediated transcriptional repression of Cpe, a gene that encodes a carboxypeptidase that is required for proper processing of key anorexigenic neuropeptides. The team also found that this pathway is disturbed in states of diet-induced obesity, suggesting that obesity-induced insulin resistance may affect obesity even further. Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1−/− mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of α-melanocyte–stimulating hormone (α-Msh) and carboxy-cleaved β-endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1−/− mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc-Foxo1−/− mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications.