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Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation
OBJECTIVE: Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORM...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762460/ https://www.ncbi.nlm.nih.gov/pubmed/34954108 http://dx.doi.org/10.1016/j.molmet.2021.101423 |
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author | Song, Yu Zan, Wenying Qin, Liping Han, Shuang Ye, Lili Wang, Molin Jiang, Baichun Fang, Pan Liu, Qiji Shao, Changshun Gong, Yaoqin Li, Peishan |
author_facet | Song, Yu Zan, Wenying Qin, Liping Han, Shuang Ye, Lili Wang, Molin Jiang, Baichun Fang, Pan Liu, Qiji Shao, Changshun Gong, Yaoqin Li, Peishan |
author_sort | Song, Yu |
collection | PubMed |
description | OBJECTIVE: Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORMDL3 in adipose tissue thermogenesis and high fat diet (HFD)-induced insulin resistance. METHODS: Ormdl3-deficient (Ormdl3(−/−)) mice were employed to delineate the function of ORMDL3 in brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Glucose and lipid homeostasis in Ormdl3(−/−) mice fed a HFD were assessed. The lipid composition in adipose tissue was evaluated by mass spectrometry. Primary adipocytes in culture were used to determine the mechanism by which ORMDL3 regulates white adipose browning. RESULTS: BAT thermogenesis and WAT browning were significantly impaired in Ormdl3(−/−) mice upon cold exposure or administration with the β3 adrenergic agonist. In addition, compared to WT mice, Ormdl3(−/−) mice displayed increased weight gain and insulin resistance in response to HFD. The induction of uncoupling protein 1 (UCP1), a marker of thermogenesis, was attenuated in primary adipocytes derived from Ormdl3(−/−) mice. Importantly, ceramide levels were elevated in the adipose tissue of Ormdl3(−/−) mice. In addition, the reduction in thermogenesis and increase in body weight caused by Ormdl3 deficiency could be rescued by inhibiting the production of ceramides. CONCLUSION: Our findings suggest that ORMDL3 contributes to the regulation of BAT thermogenesis, WAT browning, and insulin resistance. |
format | Online Article Text |
id | pubmed-8762460 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-87624602022-01-20 Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation Song, Yu Zan, Wenying Qin, Liping Han, Shuang Ye, Lili Wang, Molin Jiang, Baichun Fang, Pan Liu, Qiji Shao, Changshun Gong, Yaoqin Li, Peishan Mol Metab Original Article OBJECTIVE: Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORMDL3 in adipose tissue thermogenesis and high fat diet (HFD)-induced insulin resistance. METHODS: Ormdl3-deficient (Ormdl3(−/−)) mice were employed to delineate the function of ORMDL3 in brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Glucose and lipid homeostasis in Ormdl3(−/−) mice fed a HFD were assessed. The lipid composition in adipose tissue was evaluated by mass spectrometry. Primary adipocytes in culture were used to determine the mechanism by which ORMDL3 regulates white adipose browning. RESULTS: BAT thermogenesis and WAT browning were significantly impaired in Ormdl3(−/−) mice upon cold exposure or administration with the β3 adrenergic agonist. In addition, compared to WT mice, Ormdl3(−/−) mice displayed increased weight gain and insulin resistance in response to HFD. The induction of uncoupling protein 1 (UCP1), a marker of thermogenesis, was attenuated in primary adipocytes derived from Ormdl3(−/−) mice. Importantly, ceramide levels were elevated in the adipose tissue of Ormdl3(−/−) mice. In addition, the reduction in thermogenesis and increase in body weight caused by Ormdl3 deficiency could be rescued by inhibiting the production of ceramides. CONCLUSION: Our findings suggest that ORMDL3 contributes to the regulation of BAT thermogenesis, WAT browning, and insulin resistance. Elsevier 2021-12-22 /pmc/articles/PMC8762460/ /pubmed/34954108 http://dx.doi.org/10.1016/j.molmet.2021.101423 Text en © 2021 The Author(s) 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/). |
spellingShingle | Original Article Song, Yu Zan, Wenying Qin, Liping Han, Shuang Ye, Lili Wang, Molin Jiang, Baichun Fang, Pan Liu, Qiji Shao, Changshun Gong, Yaoqin Li, Peishan Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation |
title | Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation |
title_full | Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation |
title_fullStr | Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation |
title_full_unstemmed | Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation |
title_short | Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation |
title_sort | ablation of ormdl3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762460/ https://www.ncbi.nlm.nih.gov/pubmed/34954108 http://dx.doi.org/10.1016/j.molmet.2021.101423 |
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