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Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle

Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal–regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glu...

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Autores principales: Toda, Chitoku, Shiuchi, Tetsuya, Kageyama, Haruaki, Okamoto, Shiki, Coutinho, Eulalia A., Sato, Tatsuya, Okamatsu-Ogura, Yuko, Yokota, Shigefumi, Takagi, Kazuyo, Tang, Lijun, Saito, Kumiko, Shioda, Seiji, Minokoshi, Yasuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712028/
https://www.ncbi.nlm.nih.gov/pubmed/23530005
http://dx.doi.org/10.2337/db12-1629
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author Toda, Chitoku
Shiuchi, Tetsuya
Kageyama, Haruaki
Okamoto, Shiki
Coutinho, Eulalia A.
Sato, Tatsuya
Okamatsu-Ogura, Yuko
Yokota, Shigefumi
Takagi, Kazuyo
Tang, Lijun
Saito, Kumiko
Shioda, Seiji
Minokoshi, Yasuhiko
author_facet Toda, Chitoku
Shiuchi, Tetsuya
Kageyama, Haruaki
Okamoto, Shiki
Coutinho, Eulalia A.
Sato, Tatsuya
Okamatsu-Ogura, Yuko
Yokota, Shigefumi
Takagi, Kazuyo
Tang, Lijun
Saito, Kumiko
Shioda, Seiji
Minokoshi, Yasuhiko
author_sort Toda, Chitoku
collection PubMed
description Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal–regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle.
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spelling pubmed-37120282014-07-01 Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle Toda, Chitoku Shiuchi, Tetsuya Kageyama, Haruaki Okamoto, Shiki Coutinho, Eulalia A. Sato, Tatsuya Okamatsu-Ogura, Yuko Yokota, Shigefumi Takagi, Kazuyo Tang, Lijun Saito, Kumiko Shioda, Seiji Minokoshi, Yasuhiko Diabetes Original Research Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal–regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle. American Diabetes Association 2013-07 2013-06-14 /pmc/articles/PMC3712028/ /pubmed/23530005 http://dx.doi.org/10.2337/db12-1629 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Toda, Chitoku
Shiuchi, Tetsuya
Kageyama, Haruaki
Okamoto, Shiki
Coutinho, Eulalia A.
Sato, Tatsuya
Okamatsu-Ogura, Yuko
Yokota, Shigefumi
Takagi, Kazuyo
Tang, Lijun
Saito, Kumiko
Shioda, Seiji
Minokoshi, Yasuhiko
Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
title Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
title_full Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
title_fullStr Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
title_full_unstemmed Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
title_short Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
title_sort extracellular signal–regulated kinase in the ventromedial hypothalamus mediates leptin-induced glucose uptake in red-type skeletal muscle
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712028/
https://www.ncbi.nlm.nih.gov/pubmed/23530005
http://dx.doi.org/10.2337/db12-1629
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