DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

Publication date: Available online 9 February 2017
Source:Cell Metabolism
Author(s): Anna Santoro, Michela Campolo, Chen Liu, Hiromi Sesaki, Rosaria Meli, Zhong-Wu Liu, Jung Dae Kim, Sabrina Diano
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 (Drp1^fl/fl-POMC-cre:ER^T2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1^fl/fl-POMC-cre:ER^T2 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.

Graphical abstract

Teaser

Mitochondrial fission protein DRP1 is decreased in activated glucose-excited POMC neurons, resulting in increased leptin sensitivity and glucose responsiveness and enhanced hypoglycemic counter-regulatory response. Mechanistically, altered ROS levels affect PPARγ targets, such as the KATP channel Kcnj11, which affects POMC neuronal responsiveness to metabolic shifts.


http://ift.tt/2kWQyA4