CPT1a-Dependent Long-Chain Fatty Acid Oxidation Contributes to Maintaining Glucagon Secretion from Pancreatic Islets

TY - JOUR

T1 - CPT1a-Dependent Long-Chain Fatty Acid Oxidation Contributes to Maintaining Glucagon Secretion from Pancreatic Islets

AU - Briant, Linford J B

AU - Dodd, Michael S

AU - Chibalina, Margarita V

AU - Rorsman, Nils J G

AU - Johnson, Paul R V

AU - Carmeliet, Peter

AU - Rorsman, Patrik

AU - Knudsen, Jakob G

N1 - Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2018/6/12

Y1 - 2018/6/12

N2 - Glucagon, the principal hyperglycemic hormone, is secreted from pancreatic islet α cells as part of the counter-regulatory response to hypoglycemia. Hence, secretory output from α cells is under high demand in conditions of low glucose supply. Many tissues oxidize fat as an alternate energy substrate. Here, we show that glucagon secretion in low glucose conditions is maintained by fatty acid metabolism in both mouse and human islets, and that inhibiting this metabolic pathway profoundly decreases glucagon output by depolarizing α cell membrane potential and decreasing action potential amplitude. We demonstrate, by using experimental and computational approaches, that this is not mediated by the KATP channel, but instead due to reduced operation of the Na+-K+ pump. These data suggest that counter-regulatory secretion of glucagon is driven by fatty acid metabolism, and that the Na+-K+ pump is an important ATP-dependent regulator of α cell function. Glucagon is secreted from pancreatic α cells in hypoglycemic conditions. Briant et al. demonstrate that this response is fueled by fatty acid oxidation. The energy generated by oxidation is used to maintain membrane potential dynamics, action potential morphology, and Na+-K+ pump activity.

AB - Glucagon, the principal hyperglycemic hormone, is secreted from pancreatic islet α cells as part of the counter-regulatory response to hypoglycemia. Hence, secretory output from α cells is under high demand in conditions of low glucose supply. Many tissues oxidize fat as an alternate energy substrate. Here, we show that glucagon secretion in low glucose conditions is maintained by fatty acid metabolism in both mouse and human islets, and that inhibiting this metabolic pathway profoundly decreases glucagon output by depolarizing α cell membrane potential and decreasing action potential amplitude. We demonstrate, by using experimental and computational approaches, that this is not mediated by the KATP channel, but instead due to reduced operation of the Na+-K+ pump. These data suggest that counter-regulatory secretion of glucagon is driven by fatty acid metabolism, and that the Na+-K+ pump is an important ATP-dependent regulator of α cell function. Glucagon is secreted from pancreatic α cells in hypoglycemic conditions. Briant et al. demonstrate that this response is fueled by fatty acid oxidation. The energy generated by oxidation is used to maintain membrane potential dynamics, action potential morphology, and Na+-K+ pump activity.

U2 - 10.1016/j.celrep.2018.05.035

DO - 10.1016/j.celrep.2018.05.035

M3 - Journal article

C2 - 29898400

SN - 2639-1856

VL - 23

SP - 3300

EP - 3311

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -