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Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis

The G protein–coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands, such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the s...

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Autores principales: Mukai, Satoru, Mizokami, Akiko, Otani, Takahito, Sano, Tomomi, Matsuda, Miho, Chishaki, Sakura, Gao, Jing, Kawakubo-Yasukochi, Tomoyo, Tang, Ronghao, Kanematsu, Takashi, Takeuchi, Hiroshi, Jimi, Eijiro, Hirata, Masato
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949034/
https://www.ncbi.nlm.nih.gov/pubmed/33428938
http://dx.doi.org/10.1016/j.jbc.2021.100274
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author Mukai, Satoru
Mizokami, Akiko
Otani, Takahito
Sano, Tomomi
Matsuda, Miho
Chishaki, Sakura
Gao, Jing
Kawakubo-Yasukochi, Tomoyo
Tang, Ronghao
Kanematsu, Takashi
Takeuchi, Hiroshi
Jimi, Eijiro
Hirata, Masato
author_facet Mukai, Satoru
Mizokami, Akiko
Otani, Takahito
Sano, Tomomi
Matsuda, Miho
Chishaki, Sakura
Gao, Jing
Kawakubo-Yasukochi, Tomoyo
Tang, Ronghao
Kanematsu, Takashi
Takeuchi, Hiroshi
Jimi, Eijiro
Hirata, Masato
author_sort Mukai, Satoru
collection PubMed
description The G protein–coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands, such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the susceptibility of mice to diet-induced obesity and related metabolic disorders. However, given that GPRC6A is expressed in many tissues and responds to a variety of hormonal and nutritional signals, the cellular and molecular mechanisms underlying the development of metabolic disorders in conventional knockout mice have remained unclear. On the basis of our previous observation that long-term oral administration of GluOC markedly reduced adipocyte size and improved glucose tolerance in WT mice, we examined whether GPRC6A signaling in adipose tissue might be responsible for prevention of metabolic disorders. We thus generated adipocyte-specific GPRC6A knockout mice, and we found that these animals manifested increased adipose tissue weight, adipocyte hypertrophy, and adipose tissue inflammation when fed a high-fat and high-sucrose diet compared with control mice. These effects were associated with reduced lipolytic activity because of downregulation of lipolytic enzymes such as adipose triglyceride lipase and hormone-sensitive lipase in adipose tissue of the conditional knockout mice. Given that, among GPR6CA ligands tested, GluOC and ornithine increased the expression of adipose triglyceride lipase in cultured 3T3-L1 adipocytes in a manner dependent on GPRC6A, our results suggest that the constitutive activation of GPRC6A signaling in adipocytes by GluOC or ornithine plays a key role in adipose lipid handling and the prevention of obesity and related metabolic disorders.
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spelling pubmed-79490342021-03-19 Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis Mukai, Satoru Mizokami, Akiko Otani, Takahito Sano, Tomomi Matsuda, Miho Chishaki, Sakura Gao, Jing Kawakubo-Yasukochi, Tomoyo Tang, Ronghao Kanematsu, Takashi Takeuchi, Hiroshi Jimi, Eijiro Hirata, Masato J Biol Chem Research Article The G protein–coupled receptor GPRC6A regulates various physiological processes in response to its interaction with multiple ligands, such as extracellular basic amino acids, divalent cations, testosterone, and the uncarboxylated form of osteocalcin (GluOC). Global ablation of GPRC6A increases the susceptibility of mice to diet-induced obesity and related metabolic disorders. However, given that GPRC6A is expressed in many tissues and responds to a variety of hormonal and nutritional signals, the cellular and molecular mechanisms underlying the development of metabolic disorders in conventional knockout mice have remained unclear. On the basis of our previous observation that long-term oral administration of GluOC markedly reduced adipocyte size and improved glucose tolerance in WT mice, we examined whether GPRC6A signaling in adipose tissue might be responsible for prevention of metabolic disorders. We thus generated adipocyte-specific GPRC6A knockout mice, and we found that these animals manifested increased adipose tissue weight, adipocyte hypertrophy, and adipose tissue inflammation when fed a high-fat and high-sucrose diet compared with control mice. These effects were associated with reduced lipolytic activity because of downregulation of lipolytic enzymes such as adipose triglyceride lipase and hormone-sensitive lipase in adipose tissue of the conditional knockout mice. Given that, among GPR6CA ligands tested, GluOC and ornithine increased the expression of adipose triglyceride lipase in cultured 3T3-L1 adipocytes in a manner dependent on GPRC6A, our results suggest that the constitutive activation of GPRC6A signaling in adipocytes by GluOC or ornithine plays a key role in adipose lipid handling and the prevention of obesity and related metabolic disorders. American Society for Biochemistry and Molecular Biology 2021-01-09 /pmc/articles/PMC7949034/ /pubmed/33428938 http://dx.doi.org/10.1016/j.jbc.2021.100274 Text en © 2021 THE AUTHORS https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Mukai, Satoru
Mizokami, Akiko
Otani, Takahito
Sano, Tomomi
Matsuda, Miho
Chishaki, Sakura
Gao, Jing
Kawakubo-Yasukochi, Tomoyo
Tang, Ronghao
Kanematsu, Takashi
Takeuchi, Hiroshi
Jimi, Eijiro
Hirata, Masato
Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis
title Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis
title_full Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis
title_fullStr Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis
title_full_unstemmed Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis
title_short Adipocyte-specific GPRC6A ablation promotes diet-induced obesity by inhibiting lipolysis
title_sort adipocyte-specific gprc6a ablation promotes diet-induced obesity by inhibiting lipolysis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949034/
https://www.ncbi.nlm.nih.gov/pubmed/33428938
http://dx.doi.org/10.1016/j.jbc.2021.100274
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