Isoform-specific functions of PPARγ in gene regulation and metabolism. Genes Dev 2022 Mar 01;36(5-6):300-312
Date
03/12/2022Pubmed ID
35273075Pubmed Central ID
PMC8973844DOI
10.1101/gad.349232.121Scopus ID
2-s2.0-85127852299 (requires institutional sign-in at Scopus site) 49 CitationsAbstract
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.
Author List
Hu W, Jiang C, Kim M, Xiao Y, Richter HJ, Guan D, Zhu K, Krusen BM, Roberts AN, Miller J, Steger DJ, Lazar MAAuthor
Yang Xiao Assistant Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdipocytesAnimals
Gene Expression Regulation
Insulin Resistance
Mice
PPAR gamma
Protein Isoforms
Thiazolidinediones
