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

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 3

Pex16-AKO mice have increased diet-induced obesity and impaired thermogenesis.

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Pex16-AKO mice have increased diet-induced obesity and impaired thermog...
(A) Body weight of mice fed normal chow diet; n = 7–9. (B) Body weight of mice fed an HFD and maintained at 22°C; n = 9–11. (C) Body weight of mice fed an HFD and maintained at 30°C; n = 8. (D) MRI analysis of body composition in mice kept at room temperature after 20 weeks of high-fat feeding; n = 10. (E) Weight of gWAT from HFD-fed mice; n = 3. (F) H&E staining of gWAT from chow- and HFD-fed control and Pex16-AKO mice. The images are representative of 3 mice per genotype. (G) OCR (VO2) before and after intraperitoneal NE injection; n = 3–4. (H) H&E staining of BAT mice kept at room temperature or subjected to cold exposure. The images are representative of 3 mice per genotype. (I) Representative images (n = 3) of BAT from cold-treated mice. Original magnification, F and H, ×10. (J) Quantification of triglycerides (TG) in BAT; n = 3–4. (K) Rectal temperature of mice subjected to a 6-hour cold challenge; n = 7–9. (L) Kaplan-Meier survival curves of mice individually housed in InfraMot (TSE Systems) activity monitors stored at 4°C; n = 7–8. Data are expressed as mean ± SEM. Student’s t test was used for analysis of the data in B, D, E, and J. Two-way ANOVA with Bonferroni’s post hoc test was used for analysis of the data in G and K. To assess statistical significance in L, Mantel-Cox (log-rank) test was used. *P < 0.05; ***P < 0.001.