UCP2 mediates mitochondrial dynamics to induce AgRP neuronal activity

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The hypothalamic agouti-related protein (AgRP)- expressing neurons regulate feeding and whole-body energy homeostasis. A growing body of evidence indicates that changes in mitochondrial dynamics, such as fission and fusion, play a crucial role in regulating AgRP neuronal activity. However, the mechanisms underlying this process remain to be elucidated. Here, we showed a role of mitochondrial UCP2-mediated mitochondrial dynamics in AgRP neurons in regulating AgRP neuronal activity and fasting-induced feeding behavior. We analyzed mitochondrial morphology, expression of activated dynamin-related protein 1 (DRP1), and mRNA expression levels of uncoupling protein 2 ( Ucp2 ) in AgRP neurons of mice that were either in fed or fasted states. We then generated a mouse model in which Ucp2 was selectively deleted from adult AgRP neurons to assess the role of this mitochondrial protein in feeding behavior and whole-body energy metabolism. We show fasting-induced AgRP neuronal activation is associated with UCP2-mediated mitochondrial fission and mitochondrial fatty acid utilization in AgRP neurons. In line with this, mice lacking UCP2 in AgRP neurons ( Ucp2 AgRP KO) show attenuated fasting- or ghrelin-induced AgRP neuronal activation and feeding behaviors and exhibited a significant decrease in body weight and fat mass accompanied by a significant increase in energy expenditure. Altogether, our data revealed that UCP2-mediated mitochondrial dynamics and fatty acids oxidation in the hypothalamic AgRP neurons is necessary for AgRP neuronal function and fasting-induced food intake. • UCP2 in AgRP neurons mediates mitochondrial dynamics and function. • UCP2 deletion in AgRP neurons regulates fasting- and ghrelin-mediated AgRP neuronal activation and feeding responses. • UCP2 deletion in AgRP neurons regulates body weight and energy metabolism.

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