DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

• DOI: 10.1016/j.cmet.2017.01.003
• Publication Date: 2017-02-09T16:02:45Z
• Authors: Anna Santoro; Michela Campolo; Chen Liu; Hiromi Sesaki; Rosaria Meli; Zhong-Wu Liu; Jung Dae Kim; Sabrina Diano
• Keywords: Dynamins; Leptin; 0301 basic medicine; Pro-Opiomelanocortin; Drp1; leptin; 03 medical and health sciences; Drp1; POMC neurons; counter-regulatory responses to hypoglycemia; glucose sensing; leptin; mitochondrial fission; Animals; RNA, Messenger; Potassium Channels, Inwardly Rectifying; Neurons; POMC neurons; glucose sensing; mitochondrial fission; Counter-regulatory responses to hypoglycemia, Drp1; glucose sensing, Leptin, Mitochondrial fission, POMC neurons, Animals, Dynamins, Energy Metabolism, Feeding Behavior, Gene Deletion, Glucose, Hypoglycemia, Leptin, Mice, Inbred C57BL, Mitochondria, Neurons, PPAR gamma, Potassium Channels, Inwardly Rectifying, Pro-Opiomelanocortin, RNA, Messenger, Reactive Oxygen Species; Feeding Behavior; Hypoglycemia; Mitochondria; Mice, Inbred C57BL; PPAR gamma; Glucose; counter-regulatory responses to hypoglycemia; Energy Metabolism; Reactive Oxygen Species; Gene Deletion

Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1fl/fl-POMC-cre:ERT2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1fl/fl-POMC-cre:ERT2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.