Preadipocyte IL-13/IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARγ activity
Alexandra R. Yesian, … , Alexander S. Banks, Chih-Hao Lee
Alexandra R. Yesian, … , Alexander S. Banks, Chih-Hao Lee
Published April 8, 2025
Citation Information: J Clin Invest. 2025;135(11):e169152. https://doi.org/10.1172/JCI169152.
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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 3

IL-13 potentiates PPARγ-mediated beige adipogenesis.

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IL-13 potentiates PPARγ-mediated beige adipogenesis. (A) Immunoblot of P...
(A) Immunoblot of PPARγ protein in Il13ra1-KO and Il13ra1-RE preadipocytes treated with IL-13 or vehicle for 24 hours. n = 3, experiment repeated twice. (B) RT-qPCR of Pparg1 and PPARγ target genes in Il13ra1-KO and Il13ra1-RE preadipocytes treated with or without IL-13 for 24 hours. n = 3, experiment performed 3 times. (C) RT-qPCR of Pparg and PPARγ target genes in WT preadipocytes with indicated treatments for 24 hours. n = 3, experiment performed 4 times. (D) RT-qPCR analyses of WT cells with indicated treatments for 24 hours, followed by 2 days of differentiation. n = 3, experiments performed 3 times. (E) Immunoblotting in WT cells with indicated treatments for 24 hours, followed by differentiation for 5 days. n = 3/condition, experiments repeated twice. (F) WT preadipocytes were transfected with a Gal4 control or Gal4-PPARγ-LBD expression vector, together with a Gal4-binding site containing luciferase reporter and a β-gal internal control. Graph shows PPARγ LBD transactivation on the luciferase reporter with indicated treatments for 24 hours. Luciferase activity was normalized to β-gal activity to determine the RLU. n = 4, experiments performed 3 times. (G) Schematic shows 2 sets of ChIP primer pairs (C1 and C2) flanking 2 potential PPREs on the Lipe gene promoter ( the transcriptional start site designated as 1). Arrows indicate 2 direct repeats of the PPRE. Graphs show ChIP analyses of preadipocytes treated overnight with indicated treatments and of adipocytes differentiated for 3 days after overnight Rosi or IL-13+Rosi pretreatment using antibodies against the IgG control, PPARγ, or H3ac. n = 3 technical replicates, experiments performed 3 times. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA with Tukey’s multiple-comparison test (B) and 1-way ANOVA with Tukey’s multiple-comparison test (C and D).