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

doi:10.1172/JCI169152

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Yesian, A. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Chalom, M. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Knudsen, N. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Hyde, A. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Personnaz, J. in: JCI | PubMed | Google Scholar |

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Cho, H. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Liou, Y. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Starost, K. in: JCI | PubMed | Google Scholar |

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Lee, C. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Tsai, D. in: JCI | PubMed | Google Scholar |

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Ho, H. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Lin, J. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Li, J. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Hu, F. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Banks, A. in: JCI | PubMed | Google Scholar

¹Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, United States of America

²Genomics Research Center, Academia Sinica, Taipei, Taiwan

³Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan

⁴Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, United States of America

⁵Division of Endocrinology, Diabetes and Metabolism, lism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America

Find articles by Lee, C. in: JCI | PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI169152.
Copyright © 2025, Yesian et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published April 8, 2025 - Version history

Type 2 innate lymphoid cells (ILC2) regulate the proliferation of preadipocytes that give rise to beige adipocytes. Whether and how ILC2 downstream Th2 cytokines control beige adipogenesis remain unclear. We employed cell systems and genetic models to examine the mechanism through which interleukin-13 (IL-13), an ILC2-derived Th2 cytokine, controls beige adipocyte differentiation. IL-13 priming in preadipocytes drives beige adipogenesis by upregulating beige-promoting metabolic programs, including mitochondrial oxidative metabolism and PPARγ-related pathways. The latter is mediated by increased expression and activity of PPARγ through IL-13 receptor α1 (IL-13Rα1) downstream effectors, STAT6 and p38 MAPK, respectively. Il13 knockout (Il13KO) or preadipocyte Il13ra1 knockout (Il13ra1KO) mice are refractory to cold- or β-3 adrenergic agonist-induced beiging in inguinal white adipose tissue, whereas Il4 knockout mice show no defects in beige adipogenesis. Il13KO and Il13ra1KO mouse models exhibit increased body weight/fat mass and dysregulated glucose metabolism but have a mild cold intolerant phenotype, likely due to their intact brown adipocyte recruitment. We also find that genetic variants of human IL13RA1 are associated with body mass index 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.

Version 1 (April 8, 2025): In-Press Preview

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

Alexandra R. Yesian,¹ Mayer M. Chalom,¹ Nelson H. Knudsen,¹ Alec L. Hyde,¹ Jean Personnaz,¹ Hyunjii Cho,¹ Yae-Huei Liou,¹ Kyle A. Starost,¹ Chia-Wei Lee,¹ Dong-Yan Tsai,² Hsing-Wei Ho,² Jr-Shiuan Lin,³ Jun Li,⁴ Frank B. Hu,⁴ Alexander S. Banks,⁵ and Chih-Hao Lee¹

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

Alexandra R. Yesian,1 Mayer M. Chalom,1 Nelson H. Knudsen,1 Alec L. Hyde,1 Jean Personnaz,1 Hyunjii Cho,1 Yae-Huei Liou,1 Kyle A. Starost,1 Chia-Wei Lee,1 Dong-Yan Tsai,2 Hsing-Wei Ho,2 Jr-Shiuan Lin,3 Jun Li,4 Frank B. Hu,4 Alexander S. Banks,5 and Chih-Hao Lee1

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Alexandra R. Yesian,¹ Mayer M. Chalom,¹ Nelson H. Knudsen,¹ Alec L. Hyde,¹ Jean Personnaz,¹ Hyunjii Cho,¹ Yae-Huei Liou,¹ Kyle A. Starost,¹ Chia-Wei Lee,¹ Dong-Yan Tsai,² Hsing-Wei Ho,² Jr-Shiuan Lin,³ Jun Li,⁴ Frank B. Hu,⁴ Alexander S. Banks,⁵ and Chih-Hao Lee¹