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

Mark A. Smith, Loukia Katsouri, Samuel Virtue, Agharul I. Choudhury, Antonio Vidal-Puig, Michael L. J. Ashford, Dominic J. Withers

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
135 Downloads (Pure)

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. Smith et al. show that an R-type calcium channel containing the pore subunit Cacna1e mediates long-term depolarization of hypothalamic POMC neurons by leptin. Mice with POMC neuron knockdown of Cacna1e display elevated hepatic glucose production, demonstrating that leptin utilizes Cacna1e in POMC neurons to regulate glucose homeostasis.

Original languageEnglish
Pages (from-to)278-287.e4
Number of pages15
JournalCell Reports
Volume25
Issue number2
DOIs
Publication statusPublished - 9 Oct 2018

Keywords

  • calcium channel
  • diabetes
  • glucose
  • hypothalamus
  • insulin resistance
  • leptin
  • liver
  • POMC neuron

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