Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity
Alexandra R. Yesian, Mayer M. Chalom, Nelson H. Knudsen, Alec L. Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A. Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B. Hu, Alexander S. Banks, Chih-Hao Lee
Alexandra R. Yesian, Mayer M. Chalom, Nelson H. Knudsen, Alec L. Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A. Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B. Hu, Alexander S. Banks, Chih-Hao Lee
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Research Article Cell biology Metabolism

Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity

Abstract

Type 2 innate lymphoid cells (ILC2s) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We used cell systems and genetic models to examine the mechanism through which IL-13, an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drove beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter was mediated by increased expression and activity of PPARγ through the IL-13 receptor 1 (IL-13R1) downstream effectors STAT6 and p38 MAPK, respectively. Il13-KO or preadipocyte Il13ra1-KO mice were refractory to cold- or β3-adrenergic agonist–induced beiging in inguinal white adipose tissue, whereas Il4-KO mice showed no defects in beige adipogenesis. Il13-KO and Il13ra1-KO mouse models exhibited increased body weight and fat mass and dysregulated glucose metabolism but had a mild cold-intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also found that genetic variants of human IL13RA1 were associated with BMI and type 2 diabetes. These results suggest that IL-13 signaling–regulated beige adipocyte function may play a predominant role in modulating metabolic homeostasis rather than in thermoregulation.

Authors

Alexandra R. Yesian, Mayer M. Chalom, Nelson H. Knudsen, Alec L. Hyde, Jean Personnaz, Hyunjii Cho, Yae-Huei Liou, Kyle A. Starost, Chia-Wei Lee, Dong-Yan Tsai, Hsing-Wei Ho, Jr-Shiuan Lin, Jun Li, Frank B. Hu, Alexander S. Banks, Chih-Hao Lee

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Figure 2

Regulation of mitochondria-related metabolic programs by IL-13 in preadipocytes enhances the oxidative capacity of mature adipocytes.

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Regulation of mitochondria-related metabolic programs by IL-13 in preadi...
(A) WT preadipocytes were treated with IL-13 or vehicle for 24 hours before induction of differentiation for 6 days, followed by RNA-Seq analysis. The top enriched categories upregulated by IL-13 pretreatment are shown. RNA-Seq was performed once but was repeated in a separate clonal line (n = 4). Bioinformatics was processed using the CLC Genomics Workbench. (B) STRING protein-protein interaction map of genes in the KEGG thermogenesis pathway upregulated by IL-13 pretreatment. (C) Immunoblotting of mitochondrial OXPHOS complex proteins in WT adipocytes (n = 3; 3-day differentiation; experiments were repeated twice) and (D) UCP1 protein in mature WT adipocytes (n = 2; 6-day differentiation) with or without IL-13 pretreatment. (E) Mitochondrial respiration of mature WT adipocytes with or without IL-13 pretreatment. CL, CL316,243. n = 10; experiments were repeated 3 times. (F) WT preadipocytes were treated with IL-13 or vehicle for 24 hours, followed by RNA-Seq. The top enriched categories upregulated by IL-13 are shown (n = 4). (G) STRING protein-protein interaction map of genes in the KEGG thermogenesis pathway upregulated by IL-13 treatment in preadipocytes. (H) Immunoblotting showing PPARγ and mitochondrial OXPHOS complex proteins by IL-13 in WT preadipocytes. n = 3/group. Experiments repeated more than 3 times. (I) Mitochondrial respiration of WT preadipocytes treated with IL-13 for 24 hours. n = 5; experiments were repeated 3 times. (J) Mitochondrial respiration of primary preadipocytes treated with IL-13 for 24 hours. n = 10; experiments were repeated twice. (K) RT-qPCR analyses to assess the expression of OXPHOS and PPARγ target genes in iWAT of WT and Il13-KO mice. n = 6 WT and 5 Il13-KO 8-week-old female mice. *P <0.05 and **P < 0.01, by 2-way ANOVA (E, I, and J) and 2-tailed, unpaired t test (K).