Calcium Channel CaV2.3 Subunits Regulate Hepatic Glucose Production by Modulating Leptin-Induced Excitation of Arcuate Pro-opiomelanocortin Neurons.

Abstract

Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes.

• Authors: Mark A Smith, Loukia Katsouri, Samuel Virtue, Agharul I Choudhury, Antonio Vidal-Puig, Michael L J Ashford, Dominic J Withers
• Journal: Cell reports (Cell Rep) Vol. 25 Issue 2 Pg. 278-287.e4 (10 09 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30304668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Cacna1e protein, mouse
• Calcium Channels, R-Type
• Cation Transport Proteins
• Leptin
• Pro-Opiomelanocortin
• Glucose
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels, R-Type (genetics, metabolism)
• Cation Transport Proteins (genetics, metabolism)
• Cells, Cultured
• Glucose (metabolism)
• Homeostasis
• Humans
• Hypothalamus (drug effects, metabolism)
• Leptin (pharmacology)
• Liver (metabolism)
• Male
• Mice
• Mice, Transgenic
• Neurons (drug effects, metabolism)
• Pro-Opiomelanocortin (metabolism)