Hypothalamic extended synaptotagmin-3 contributes to the development of dietary obesity and related metabolic disorders

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Significance The epidemic of obesity has reached an alarming level worldwide. Understanding the etiology of obesity is important for identifying a new approach of prevention or treatment. Accumulating evidence demonstrates that the central nervous system plays a critical role in animal’s energy homeostasis. Here, we show that extended synaptotagmin (E-Syt3) is expressed in the hypothalamus and contributes to diet-induced obesity development. Whole-body or proopiomelanocortin neuron-specific deletion of E-Syt3 significantly protects mice against DIO and related metabolic disorders. Mechanistically, we show that inhibition of E-Syt3 can lead to increased hypothalamic content of α-melanocyte-stimulating hormone. Thus, our current work suggests that E-Syt3 might be a relevant target for treating obesity.