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 February 1, 2019; First 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

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 9

Dietary supplementation of plasmalogens rescues mitochondrial morphology and function and improves cold tolerance in Pex16-AKO mice.

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Dietary supplementation of plasmalogens rescues mitochondrial morphology...
(A) Mass spectrometric analysis of PE plasmalogens in the mitochondrial fractions from control and Pex16-AKO mice treated with or without AG for 8 weeks; n = 5. (B) TEM analysis of mitochondrial morphology in BAT of control and Pex16-AKO treated with or without AG, followed by cold exposure. Scale bar: 500 nm. (C) Aspect ratio measured in BAT mitochondria from control and Pex16-AKO mice. The data are based on 26 mitochondria per condition. (D) Number of mitochondria per cell based on TEM images of BAT taken at ×1000–×2000 magnification. The data are average of 6–8 cells per condition. (E) mtDNA measured by PCR in BAT of control and Pex16-AKO mice treated with or without AG, followed by cold exposure; n = 6–7. (F) VO2 was measured using indirect calorimetry before and after intraperitoneal NE injection; n = 8–9. (G). Cold tolerance was determined by measuring rectal temperature prior to and after 6 hours of cold exposure; n = 6–8. (H and I) Fatty acid and pyruvate oxidation assays in BAT; n = 3–4. Data are expressed as mean ± SEM and were analyzed by 1-way ANOVA, followed by Fisher’s LSD test (A, C–E, and G–I), or 2-way ANOVA with Bonferroni’s post hoc test (F); *P < 0.05; **P < 0.01; ***P < 0.001.