Ceramides are necessary and sufficient for diet-induced impairment of thermogenic adipocytes
| Autor: | James E. Cox, Edward H. Schuchman, Li Ying, John Alan Maschek, Yoshio Hirabayashi, William L. Holland, Bhagirath Chaurasia, Scott A. Summers, Chad Lamar Talbot |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine lcsh:Internal medicine medicine.medical_specialty Ceramide Acid Ceramidase Adipose Tissue White Serine C-Palmitoyltransferase Adipose tissue 030209 endocrinology & metabolism Ceramides Diet High-Fat Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Insulin resistance Internal medicine Adipocyte Brown adipose tissue Adipocytes medicine Animals Glucose homeostasis Obesity Adipocytes Beige lcsh:RC31-1245 Molecular Biology Uncoupling Protein 1 Mice Knockout Sphingolipids Diabetes brown adipose tissue Thermogenesis Cell Biology medicine.disease Sphingolipid Fatty Liver Adipocytes Brown 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Lipidomics Original Article Energy Metabolism Transcriptome |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 45, Iss, Pp 101145-(2021) |
| ISSN: | 2212-8778 |
| Popis: | 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, β-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. Highlights • β-Adrenergic agonists lower ceramide levels in brown adipocytes by decreasing expression of Sptlc2 and CerS6. • Selective inhibition of ceramide synthesis in UCP1+ cells confers resistance to obesity and increases energy expenditure. • Selectively inducing ceramide accumulation in UCP1+ cells impairs thermogenesis to exacerbate obesity and insulin resistance. • Brown adipocyte ceramides alter mitochondrial ultrastructure and activity and influences rates of fatty acid uptake. |
| Databáze: | OpenAIRE |
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