DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

Cell Metab. 2017 Mar 7;25(3):647-660. doi: 10.1016/j.cmet.2017.01.003. Epub 2017 Feb 9.


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.

Keywords: Drp1; POMC neurons; counter-regulatory responses to hypoglycemia; glucose sensing; leptin; mitochondrial fission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dynamins / metabolism*
  • Energy Metabolism
  • Feeding Behavior
  • Gene Deletion
  • Glucose / metabolism*
  • Hypoglycemia / metabolism
  • Hypoglycemia / pathology
  • Leptin / metabolism*
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Neurons / metabolism*
  • PPAR gamma / metabolism
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Pro-Opiomelanocortin / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism


  • Kir6.2 channel
  • Leptin
  • PPAR gamma
  • Potassium Channels, Inwardly Rectifying
  • RNA, Messenger
  • Reactive Oxygen Species
  • Pro-Opiomelanocortin
  • Dnm1l protein, mouse
  • Dynamins
  • Glucose