Format

Send to

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

DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons.

Author information

1
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pharmacy, University of Naples "Federico II," 80131 Napoli, Italy.
5
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: sabrina.diano@yale.edu.

Abstract

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

PMID:
28190775
PMCID:
PMC5366041
DOI:
10.1016/j.cmet.2017.01.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center