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 4

IL-13/IL-13R1 increases the expression and activity of PPARγ through STAT6 and p38 MAPK.

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IL-13/IL-13R1 increases the expression and activity of PPARγ through STA...
(A) Schematic of the 1-hybrid system to assess PGC-1α coactivation on PPARγ LBD activity. AD293 cells were transfected with Gal4-PPARγ-LBD and Ppargc1 expression vector, together with Gal4 binding site containing a luciferase reporter and β-gal as an internal control. Graph shows quantification of PPARγ LBD transactivation on the luciferase reporter in AD293 cells cotransfected with 0, 2.5, or 10 ng Ppargc1a expression vector in the presence of vehicle or P38i (10 μM). Luciferase activity was measured 48 hours after transfection and normalized to β-gal activity to determine the RLU. n = 3. The experiment was performed 3 times. (B) Quantification of PPARγ LBD transactivation in AD293 cells cotransfected with luciferase/β-gal reporters, Gal4-PPARγ-LBD, and a control vector or Ppargc1a expression vector (10 ng). Cells were treated with vehicle, IL-13, P38i, or IL-13+P38i overnight. RLU was determined 48 hours after transfection. n = 3. The the experiment was performed 3 times. (C and D) Expression of PPARγ target genes measured by RT-qPCR in WT preadipocytes treated with IL-13, Rosi, or IL-13+Rosi for 24 hours with or without P38i. n = 3. The experiment was performed twice. (E and F) Expression of PPARγ target genes by RT-qPCR in WT preadipocytes treated with IL-13, Rosi, or IL-13+Rosi for 24 hours ± STAT6i (10 μM). n = 3. The experiment was performed once. (G) Immunoblotting showing HSL protein in preadipocytes treated with IL-13+Rosi or vehicle with or without P38i for 24 hours. n = 3, with quantifications shown. The experiment was performed twice. (H) Immunoblotting showing HSL protein in WT preadipocytes treated with IL-13+Rosi or vehicle with or without STAT6i for 24 hours. n = 3, with quantifications shown. The experiment was performed twice. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA (A and B), 2-way ANOVA with Tukey’s multiple-comparison test (C–F), and 1-way ANOVA with Tukey’s multiple-comparison test (G and H).