Role of Hypothalamic Proopiomelanocortin Neuron Autophagy in the Control of Appetite and Leptin Response

Autophagy is a catabolic cellular process involving the degradation of the cell's own components. Although the role of autophagy of diverse tissues in body metabolism has been investigated, the importance of autophagy in hypothalamic proopiomelanocortin (POMC) neurons, key regulators of energy balance, has not been addressed. The role of autophagy in leptin sensitivity that is critical for the control of body weight and appetite has also not been investigated. Weproduced mice with specific deletion of autophagy-related 7 (Atg7), an essential autophagy gene, in hypothalamic POMC neurons (Atg7(Delta POMC) mice). Atg7 expression was deficient in the arcuate nucleus of the hypothalamus of Atg7(Delta POMC) mice. p62, a specific substrate of autophagy, accumulated in the hypothalamus of Atg7(Delta POMC) mice, which colocalized with ubiquitin. Atg7(Delta POMC) mice had increased body weight due to increased food intake and decreased energy expenditure. Atg7(Delta POMC) mice were not more prone to diet-induced obesity compared with control mice but more susceptible to hyperglycemia after high-fat diet. The ability of leptin to suppress fasting-elicited hyperphagia and weight gain during refeeding was attenuated in Atg7 Delta POMC mice. Deficient autophagy did not significantly affect POMC neuron number but impaired leptin-induced signal transducer and activation of transcription 3 activation. Our findings indicate a critical role for autophagy of POMC neurons in the control of energy homeostasis and leptin signaling. (Endocrinology 153: 1817-1826, 2012)