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 5

Adult mice deficient in IL-13 signaling exhibit impaired responses to β3-adrenergic stimulation.

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Adult mice deficient in IL-13 signaling exhibit impaired responses to β3...
(A) Representative H&E staining of iWAT from WT and Il13-KO mice injected with PBS or CL for 10 days. n = 3–4/group (3-month-old males). The experiment was performed once. (B) Immunoblotting showing UCP1 protein levels in iWAT of the WT and Il13-KO mice in A. Tubulin was used as a loading control. (C) H&E staining and (D) immunoblotting of iWAT from control and Il13ra1-KO mice injected with CL for 10 days. n = 4 (30-week-old males). For H&E-stained images, samples from 1 mouse of each group are shown, with HSP60 used as a loading control. (E) H&E staining and (F) immunoblotting of iWAT from control and bIl13ra1-KO mice injected with or without CL once daily for 7 consecutive days. n = 3 for noninjected control mice; n = 6–7 for CL-injected mice (5-month-old females). The experiment was performed once. Representative tissue samples are shown. (G) Immunoblotting for HSL, p-HSL (S660), and p-PKA substrates in iWAT explants from control and bIl13ra1-KO mice. Tissue was stimulated with CL for 0, 20, 40, and 60 minutes ex vivo. Pooled analysis of 2 mice/genotype (5-month-old females). The experiment was performed 3 times. Scale bars: 200 μm (A, C, and E).