CPT1a-Dependent Long-Chain Fatty Acid Oxidation Contributes to Maintaining Glucagon Secretion from Pancreatic Islets
| Autor: | Linford J B, Briant, Michael S, Dodd, Margarita V, Chibalina, Nils J G, Rorsman, Paul R V, Johnson, Peter, Carmeliet, Patrik, Rorsman, Jakob G, Knudsen |
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| Rok vydání: | 2018 |
| Předmět: |
Blood Glucose
endocrine system fasting liver Article Membrane Potentials Islets of Langerhans Mice Adenosine Triphosphate KATP Channels Animals Humans Protein Isoforms RNA Small Interfering glucose Mice Knockout Carnitine O-Palmitoyltransferase islet Fatty Acids Glucagon KATP Mice Inbred C57BL Ca2+ RNA Interference Sodium-Potassium-Exchanging ATPase metabolism Metabolic Networks and Pathways |
| Zdroj: | Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary 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. Graphical Abstract Highlights • Glucagon secretion in low glucose is maintained by CPT1a-dependent FAO • Loss of CPT1a-dependent FAO in mouse and human islets decreases glucagon secretion • CPT1a-dependent FAO maintains glucagon secretion by supplying ATP to the Na+-K+-ATPase • CPT1a-dependent FAO contributes to the counter-regulatory secretion of glucagon 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. |
| Databáze: | OpenAIRE |
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