AbstractObjectiveThe ventromedial nucleus of the hypothalamus (VMH) is a critical component of the forebrain pathways that regulate energy homeostasis. It also plays an important role in the metabolic response to fasting. However, the mechanisms contributing to these physiological processes remain elusive. Autophagy is an evolutionarily conserved mechanism that maintains cellular homeostasis by turning over cellular components and providing nutrients to the cells during starvation. Here we investigated the importance of the autophagy-related geneAtg7inSf1-expressing neurons of the VMH in control and fasted conditions.MethodsWe generatedSf1-Cre;Atg7loxP/loxPmice and examined their metabolic and cellular response to fasting.ResultsFasting induces autophagy in the VMH, and mice lackingAtg7inSf1-expressing neurons display altered regulation in glucose and leptin homeostasis and impaired energy expenditure regulation in response to fasting. Moreover, loss ofAtg7inSf1neurons causes alterations in the central response to fasting. Furthermore, alterations in mitochondria morphology and activity are observed in mutant mice.ConclusionTogether, these data show that autophagy is nutritionally regulated in VMH neurons and that VMH autophagy participates in the control of energy homeostasis during fasting.