Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission
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
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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Research Article Cell biology Metabolism

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

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 8

Peroxisome-derived lipids are present in mitochondria, and inhibition of their synthesis reduces mtDNA content and impairs mitochondrial function.

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Peroxisome-derived lipids are present in mitochondria, and inhibition of...
(A) Ether lipid synthetic pathway. The initial steps for synthesis of ether lipids, including plasmalogens, take place in peroxisomes, generating 1-O-alkyl-glycerol-3-phosphate (AGP), a precursor for ether-linked analogs of PC and phosphatidylethanolamine. DHAP, dihydroxyacetone phosphate. (B and C) Western blot analysis suggesting that ether lipid synthetic enzymes are degraded in BAT (B) and iWAT (C) of Pex16-AKO mice (D) Targeted lipidomics analysis of mitochondrial phospholipids in BAT of WT C57 mice. PS, phosphatidylserine; PG, phosphatidylglycerol; aPC, alkyl ether PC; pPC, plasmalogen PC; PE, phosphatidylethanolamine; pPE, plasmalogen PE; n = 5. (E) Levels of various plasmalogen PE species in the mitochondrial fraction of BAT; n = 9–10. (F) Total diacyl and plasmalogen PE content in BAT mitochondria. (G) BAT SVF cells stably expressing Mito-roGFP were differentiated into adipocytes and then treated with scrambled or GNPAT shRNA and analyzed 5 days later for mitochondrial morphology using confocal microscopy. Images are representative of 3 separate experiments. Original magnification, ×60. (H) Differentiated BAT SVF cells were treated with scrambled or GNPAT shRNA. Five days later, mtDNA copy number normalized to nuclear DNA was measured by qPCR; n = 5. (I) Effect of shRNA-mediated knockdown of GNPAT on OCR was measured in BAT SVF cells using a Seahorse XF24 Extracellular Flux Analyzer; n = 8. Data are expressed as mean ± SEM and were analyzed by Student’s t test. *P < 0.05.