FoxO1 ablation in hypothalamic pomc neurons reduces food intake and body weight

Insulin and leptin control food intake in part by regulating the transcription of orectic and anorectic neuropeptides in the hypothalamus. Activation of insulin receptor signaling results in nuclear exclusion of the transcription factor forkhead box-containing protein of the O subfamily (FoxO)-1, while Leptin activates the signal transducer and activator of transcription 3 (Stat3). We have previously shown that FoxO1 and Stat3 exert opposing actions on the expression of Agrp and Pomc, resulting in activation of Agrp and inhibition of Pomc transcription. We reported that hypothalamic adenoviral delivery of constitutively nuclear FoxO1 blunted leptin's effect to acutely reduce food intake and body weight. However, it remains unclear whether chronic changes in hypothalamic FoxO1 activity affect the physiological regulation of energy homeostasis by insulin and leptin. To investigate the role of hypothalamic FoxO1 signaling in a genetic system, we inactivated the Foxo1 gene specifically in Pomc neurons in vivo, using cre/loxP technology in mice. Pomc-Foxo–/– mice were born at normal Mendelian ratios and had normal appearance and body weight at birth. Starting at the age of 6–8 weeks, both female and male mutant mice exhibited significantly reduced body weights as compared to their wild type littermates. Pomc-Foxo–/– mice showed a sustained reduction of body weight by 7–10% until the end of the study period (29.0±0.50 vs. 31.0±0.52g in control males at wk.18, P≤0.05). Importantly, reduced body weight in female mutant mice was accompanied by marked reduction of body fat content (3.7±0.43 vs. 7.0±1.05% in controls at wk.14–15, P≤0.01). While food intake under steady state conditions appeared unaltered, male mice with Pomc-specific FoxO1-deficiency showed a blunted refeeding response to an overnight fast (79.7±4.6 vs. 93.9±3.5mg/g/6h in control males at wk.18, P≤0.05). These data are consistent with the hypothesis that FoxO1 is a critical player in hypothalamic Pomc neurons regulating energy homeostasis. Further physiologic analyses of Pomc-Foxo–/– mice are underway.