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J Clin Invest. 2019 Feb 1;129(2):694-711. doi: 10.1172/JCI120606. Epub 2019 Jan 14.

Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission.

Author information

1
Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
2
Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, Utah, USA.
3
Nutrition and Geriatrics Division, and.
4
Cardiology Division, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
5
Veterans Affairs St. Louis Healthcare System, John Cochran Division, St. Louis, Missouri, USA.

Abstract

Peroxisomes perform essential functions in lipid metabolism, including fatty acid oxidation and plasmalogen synthesis. Here, we describe a role for peroxisomal lipid metabolism in mitochondrial dynamics in brown and beige adipocytes. Adipose tissue peroxisomal biogenesis was induced in response to cold exposure through activation of the thermogenic coregulator PRDM16. Adipose-specific knockout of the peroxisomal biogenesis factor Pex16 (Pex16-AKO) in mice impaired cold tolerance, decreased energy expenditure, and increased diet-induced obesity. Pex16 deficiency blocked cold-induced mitochondrial fission, decreased mitochondrial copy number, and caused mitochondrial dysfunction. Adipose-specific knockout of the peroxisomal β-oxidation enzyme acyl-CoA oxidase 1 (Acox1-AKO) was not sufficient to affect adiposity, thermogenesis, or mitochondrial copy number, but knockdown of the plasmalogen synthetic enzyme glyceronephosphate O-acyltransferase (GNPAT) recapitulated the effects of Pex16 inactivation on mitochondrial morphology and function. Plasmalogens are present in mitochondria and decreased with Pex16 inactivation. Dietary supplementation with plasmalogens increased mitochondrial copy number, improved mitochondrial function, and rescued thermogenesis in Pex16-AKO mice. These findings support a surprising interaction between peroxisomes and mitochondria regulating mitochondrial dynamics and thermogenesis.

KEYWORDS:

Adipose tissue; Cell Biology; Metabolism; Mitochondria

PMID:
30511960
PMCID:
PMC6355224
DOI:
10.1172/JCI120606
[Indexed for MEDLINE]
Free PMC Article

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