Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control

Abstract

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release.

Mild Impairment of Mitochondrial OXPHOS Promotes Fatty Acid Utilization in POMC Neurons and Improves Glucose Homeostasis in Obesity

“…These findings are in line with previous reports by Padilla et al revealing that POMCCre mice efficiently mark POMC neurons, but also a subpopulation of AgRP neurons, which during development temporarily express POMC (Padilla et al, 2010). Thus, since POMC-Cre-mediated recombination inherent to the use of this widely applied POMC-Cre mouse model (Ramirez et al, 2017; Santoro et al, 2017; Schneeberger et al, 2013) also occurs in a subpopulation of hypothalamic neurons, which only transiently express POMC during development, we cannot exclude an additional effect of removing AIFm1 from these cells.…”

“…Since ROS derived from mitochondrial OXPHOS can activate POMC neurons, we investigated whether improved glucose metabolism, as observed upon AIF deletion in POMC neurons in obesity, might be linked to enhanced ROS generation. To this end, obese AIF ΔPOMC and control mice were centrally applied with either vehicle or the ROS scavenger honokiol (Diano et al, 2011; Ramirez et al, 2017; Schneeberger et al, 2013). While acute i.c.v.…”

An energetic view of stress: Focus on mitochondria

“…Based mostly on evidence from in vitro systems and animal models, chronic inhibition of mitochondrial fusion leading to persistent fragmentation of mitochondria might contribute to the adverse and pro-aging effects of metabolic stress (Picard and Turnbull, 2013). In physiological conditions, changes in mitochondrial shape enable neurons of the hypothalamus to sense glucose (Ramirez et al, 2017) and lipid (Schneeberger et al, 2013; Benani et al, 2007), triggering satiety and regulating insulin and energy balance. Thus, dynamic mitochondrial responses to circulating energy levels may be involved in regulating allostasis systemically.…”

Short‐term tamoxifen treatment has long‐term effects on metabolism in high‐fat diet‐fed mice with involvement of Nmnat2 in POMC neurons

“…POMC (Proopiomelanocortin) neurons have an important role in regulating lipid and glucose metabolism . SIRT1, a nicotinamide adenine dinucleotide (NAD + )‐dependent protein deacetylase, plays an essential role in regulating lipid and glucose metabolism , and mice with POMC neuron‐specific deletion of SIRT1 displayed a striking hypersensitivity to HFD‐induced obesity .…”