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Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission
Hongsuk Park, … , Katsuhiko Funai, Irfan J. Lodhi
Hongsuk Park, … , Katsuhiko Funai, Irfan J. Lodhi
Published December 4, 2018
Citation Information: J Clin Invest. 2019;129(2):694-711. https://doi.org/10.1172/JCI120606.
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Research Article Cell biology Metabolism

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

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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.

Authors

Hongsuk Park, Anyuan He, Min Tan, Jordan M. Johnson, John M. Dean, Terri A. Pietka, Yali Chen, Xiangyu Zhang, Fong-Fu Hsu, Babak Razani, Katsuhiko Funai, Irfan J. Lodhi

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Figure 1

PRDM16 regulates cold-induced peroxisomal biogenesis in adipose tissue.

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PRDM16 regulates cold-induced peroxisomal biogenesis in adipose tissue.
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(A) Gene expression analysis in BAT, iWAT, and gWAT of WT mice kept at normal room temperature (RT) (22°C) or subjected to cold (4°C) exposure; n = 3–4. (B) Fluorescence microscopy analysis of COS-7 cells transfected with a GFP reporter under the control of a –2 kb Pex16 promoter alone or together with HA-PRDM16. Original magnification, ×20. (C) Luciferase reporter assay in COS-7 cells; n = 3. (D) BAT SVF cells expressing retrovirally encoded FLAG-PRDM16 were subjected to ChIP assay using an anti-FLAG antibody followed by qPCR using primers to amplify various regions of the Pex16 promoter; n = 6. *P < 0.05; **P < 0.01; ***P < 0.001. (E) Gene expression analysis in iWAT of control and adipose-specific PRDM16-KO (PRDM16-AKO) mice; n = 3. Data are expressed as mean ± SEM and were analyzed by Student’s t test. †P < 0.05 versus control RT; #P < 0.05 versus control cold.
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