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UCP2-dependent redox sensing in POMC neurons regulates feeding
Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885759/ https://www.ncbi.nlm.nih.gov/pubmed/36577374 http://dx.doi.org/10.1016/j.celrep.2022.111894 |
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author | Yoon, Nal Ae Jin, Sungho Kim, Jung Dae Liu, Zhong Wu Sun, Qiushi Cardone, Rebecca Kibbey, Richard Diano, Sabrina |
author_facet | Yoon, Nal Ae Jin, Sungho Kim, Jung Dae Liu, Zhong Wu Sun, Qiushi Cardone, Rebecca Kibbey, Richard Diano, Sabrina |
author_sort | Yoon, Nal Ae |
collection | PubMed |
description | Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2(PomcKO)), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2(PomcKO) mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism. |
format | Online Article Text |
id | pubmed-9885759 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-98857592023-01-30 UCP2-dependent redox sensing in POMC neurons regulates feeding Yoon, Nal Ae Jin, Sungho Kim, Jung Dae Liu, Zhong Wu Sun, Qiushi Cardone, Rebecca Kibbey, Richard Diano, Sabrina Cell Rep Article Paradoxically, glucose, the primary driver of satiety, activates a small population of anorexigenic pro-opiomelanocortin (POMC) neurons. Here, we show that lactate levels in the circulation and in the cerebrospinal fluid are elevated in the fed state and the addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration, and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. POMC-specific downregulation of Ucp2 (Ucp2(PomcKO)), a molecule regulated by fatty acid metabolism and shown to play a role as transporter in the malate-aspartate shuttle, abolishes lactate- and glucose-sensing of POMC neurons. Ucp2(PomcKO) mice have impaired glucose metabolism and are prone to obesity on a high-fat diet. Altogether, our data show that lactate through redox signaling and blocking mitochondrial glucose utilization activates POMC neurons to regulate feeding and glucose metabolism. 2022-12-27 /pmc/articles/PMC9885759/ /pubmed/36577374 http://dx.doi.org/10.1016/j.celrep.2022.111894 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Yoon, Nal Ae Jin, Sungho Kim, Jung Dae Liu, Zhong Wu Sun, Qiushi Cardone, Rebecca Kibbey, Richard Diano, Sabrina UCP2-dependent redox sensing in POMC neurons regulates feeding |
title | UCP2-dependent redox sensing in POMC neurons regulates feeding |
title_full | UCP2-dependent redox sensing in POMC neurons regulates feeding |
title_fullStr | UCP2-dependent redox sensing in POMC neurons regulates feeding |
title_full_unstemmed | UCP2-dependent redox sensing in POMC neurons regulates feeding |
title_short | UCP2-dependent redox sensing in POMC neurons regulates feeding |
title_sort | ucp2-dependent redox sensing in pomc neurons regulates feeding |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885759/ https://www.ncbi.nlm.nih.gov/pubmed/36577374 http://dx.doi.org/10.1016/j.celrep.2022.111894 |
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