Isoform-specific functions of PPAR{gamma} in gene regulation and metabolism [Research Papers]

Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that is a vital regulator of adipogenesis, insulin sensitivity, and lipid metabolism. Activation of PPAR by antidiabetic thiazolidinediones (TZD) reverses insulin resistance but also leads to weight gain that limits the use of these drugs. There are two main PPAR isoforms, but the specific functions of each are not established. Here we generated mouse lines in which endogenous PPAR1 and PPAR2 were epitope-tagged to interrogate isoform-specific genomic binding, and mice deficient in either PPAR1 or PPAR2 to assess isoform-specific gene regulation. Strikingly, although PPAR1 and PPAR2 contain identical DNA binding domains, we uncovered isoform-specific genomic binding sites in addition to shared sites. Moreover, PPAR1 and PPAR2 regulated a different set of genes in adipose tissue depots, suggesting distinct roles in adipocyte biology. Indeed, mice with selective deficiency of PPAR1 maintained body temperature better than wild-type or PPAR2-deficient mice. Most remarkably, although TZD treatment improved glucose tolerance in mice lacking either PPAR1 or PPAR2, the PPAR1-deficient mice were protected from TZD-induced body weight gain compared with PPAR2-deficient mice. Thus, PPAR isoforms have specific and separable metabolic functions that may be targeted to improve therapy for insulin resistance and diabetes.

Source: Genes and Development - March 22, 2022 Category: Genetics & Stem Cells Authors: Hu, W., Jiang, C., Kim, M., Xiao, Y., Richter, H. J., Guan, D., Zhu, K., Krusen, B. M., Roberts, A. N., Miller, J., Steger, D. J., Lazar, M. A. Tags: Research Papers Source Type: research