Journal article
Ceramides are necessary and sufficient for diet-induced impairment of thermogenic adipocytes
Molecular metabolism (Germany), Vol.45, 101145
03/01/2021
DOI: 10.1016/j.molmet.2020.101145
PMCID: PMC7807150
PMID: 33352310
Abstract
Objective: Aging and weight gain lead to a decline in brown and beige adipocyte functionality that exacerbates obesity and insulin resistance. We sought to determine whether sphingolipids, such as ceramides, a class of lipid metabolites that accumulate in aging and overnutrition, are sufficient or necessary for the metabolic impairment of these thermogenic adipocytes.
Methods: We generated new mouse models allowing for the conditional ablation of genes required for ceramide synthesis (i.e., serine palmitoyltransferase subunit 2, Sptlc2)or degradation (i.e., acid ceramidase 1, Asah1) from mature, thermogenic adipocytes (i.e., from cells expressing uncoupling protein-1). Mice underwent a comprehensive suite of phenotyping protocols to assess energy expenditure and glucose and lipid homeostasis. Complementary studies were conducted in primary brown adipocytes to dissect the mechanisms controlling ceramide synthesis or action.
Results: Depletion of Sptlc2 increased energy expenditure, improved glucose homeostasis, and prevented diet-induced obesity. Conversely, depletion of Asah1 led to ceramide accumulation, diminution of energy expenditure, and exacerbation of insulin resistance and obesity. Mechanistically, ceramides slowed lipolysis, inhibited glucose uptake, and decreased mitochondrial respiration. Moreover, b-adrenergic receptor agonists, which activate thermogenesis in brown adipocytes, decreased transcription of enzymes required for ceramide synthesis.
Conclusions: These studies support our hypothesis that ceramides are necessary and sufficient for the impairment in thermogenic adipocyte function that accompanies obesity. Moreover, they suggest that implementation of therapeutic strategies to block ceramide synthesis in thermogenic adipocytes may serve as a means of improving adipose health and combating obesity and cardiometabolic disease.
(c) 2020 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Details
- Title: Subtitle
- Ceramides are necessary and sufficient for diet-induced impairment of thermogenic adipocytes
- Creators
- Bhagirath Chaurasia - University of UtahLi Ying - University of UtahChad Lamar Talbot - University of UtahJohn Alan Maschek - University of UtahJames Cox - University of UtahEdward H. Schuchman - Icahn School of Medicine at Mount SinaiYoshio Hirabayashi - RIKEN Center for Brain ScienceWilliam L. Holland - University of UtahScott A. Summers - University of Utah
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.45, 101145
- DOI
- 10.1016/j.molmet.2020.101145
- PMID
- 33352310
- PMCID
- PMC7807150
- NLM abbreviation
- Mol Metab
- ISSN
- 2212-8778
- eISSN
- 2212-8778
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- American Heart Association 2019-6701829250 / USDA; United States Department of Agriculture (USDA) JDRF 3-SRA-2019-768-A-B / Juvenile Diabetes Research Foundation DK115824; DK116888; DK116450; DK124326; DK108833 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Margolis Foundation American Diabetes Association
- Language
- English
- Date published
- 03/01/2021
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359906802771
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