Isoform-specific functions of PPARγ in gene regulation and metabolism
- Wenxiang Hu1,5,6,
- Chunjie Jiang1,2,6,
- Mindy Kim1,
- Yang Xiao1,
- Hannah J. Richter1,
- Dongyin Guan1,2,
- Kun Zhu1,
- Brianna M. Krusen1,
- Arielle N. Roberts3,
- Jessica Miller1,
- David J. Steger1 and
- Mitchell A. Lazar1,4
- 1Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
- 2Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA;
- 3Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania 19131, USA;
- 4Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA
- Corresponding authors: lazar{at}pennmedicine.upenn.edu, hu_wenxiang{at}gzlab.ac.cn
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↵6 These authors contributed equally to this work.
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPARγ by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPARγ isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPARγ1 and PPARγ2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPARγ1 or PPARγ2 to assess isoform-specific gene regulation. Strikingly, although PPARγ1 and PPARγ2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPARγ1 and PPARγ2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPARγ1 maintained body temperature better than wild-type or PPARγ2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPARγ1 or PPARγ2, the PPARγ1-deficient mice were protected from TZD-induced body weight gain compared with PPARγ2-deficient mice. Thus, PPARγ isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.349232.121.
- Received November 22, 2021.
- Accepted February 15, 2022.
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