Endocrine Abstracts

Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical regulators of appetite, energy expenditure and glucose metabolism. POMC neurons are able to sense circulating hormones and nutrients informing about the energy status of the organism. However, the molecular mechanisms underlying nutrient-sensing in POMC neurons remain incompletely understood. Mitochondria are key organelles implicated in cellular nutrient/energy management and are able to bioenergetically adjust to different metabolic situations. A remarkable feature of mitochondria is their capacity to change their morphology through coordinated fusion and fission events, a mechanism that links nutrient availability with bioenergetic adaptations. Mitochondrial fusion is a process that requires the GTPases mitofusin (Mfn) 1, Mfn2 and OPA1. We hypothesized that mitochondrial fusion in hypothalamic POMC neurons may represent primary nutrient/energy-sensing processes implicated in the hypothalamic regulation of energy balance and metabolism. To test this hypothesis, we have generated mice lacking the main fusogenic proteins specifically in POMC neurons and conducted detailed phenotyping and molecular studies. Our data demonstrate divergent metabolic outcomes depending on the deleted fusion protein, which are mediated by different tissues and molecular processes. These results suggest that mitochondrial dynamics in POMC neurons is a critical mechanism implicated in the maintenance of systemic energy balance and glucose homeostasis.