Distinct functions of PPARγ isoforms in regulating adipocyte plasticity

Abstract

A better understanding of the mechanisms underlying obesity and its comorbidities is key to designing new therapies and treatments. PPARγ is a master regulator of adipocyte biology but the functions of its isoforms are poorly distinguished. Here we demonstrated that PPARγ1 is preferentially expressed in catabolic fat depots while PPARγ2 presents itself at a higher level in browning-resistant depots. PPARγ2, but not PPARγ1, responds to endogenous ligands to induce adipogenesis, and the isoforms regulate distinct sets of white and brown adipocyte genes. Moreover, PPARγ1 negatively correlates while PPARγ2 positively correlates with adiposity in human subcutaneous and visceral fat. These results together indicate that PPARγ1 and PPARγ2 have distinct functions in regulating adipocyte plasticity, and future research should take into account the binary roles of both isoforms in order to identify druggable gene targets and pathways relevant for treatment of metabolic disorders.

Keywords: Adipocyte; Beiging; Browning; Obesity; PPARγ; PPARγ isoforms.

Figure 1. The Differential Expression of PPAR Isoforms in Fat

PPARg expression in three fat depots from chronic cold challenged mice on different genetic backgrounds. *: p<0.05, **: p<0.01 vs. C57BL/6, (n=8, 8, 8). Data is represented as Mean ± SD.

Figure 2. The Distinct Regulations of Adipocyte Plasticity by PPARγ1 and PPARγ2

PPARγ1 or PPARγ2 was reconstituted in PPARγ KO MEFs by using a doxycycline-inducible lentiviral system. (A) Oil Red O staining of cells differentiated at indicated conditions; (B) Western blot analyses of adipocyte markers in differentiated cells. (C–F) qPCR analysis of expressions of adipocyte genes (C), brown adipocyte genes (D), PPARα target genes (E) and white adipocyte genes (F) in adipocytes differentiated in the presence of Rosi on D9. (G–H) In fully differentiated adipocytes, qPCR analysis of thermogenic responses induced by β agonist (βAR) or PPARα agonist WY14643 + forskolin (WF). *: p<0.05, **: p<0.01, for PPARγ1 vs. PPARγ2 under same treatment (n=4). Data is represented as Mean ± SD.

Figure 3. The Opposite Correlations of PPAR Isoforms with Obesity in Humans

(A–B) The correlations of body fat content to PPARγ1 and PPARγ2 expression in subcutaneous fat from non-obese subjects. The levels of PPARγ isoforms were quantified as FPKM from RNA-sequencing. (C–D) The correlations of BMI to PPARγ isoforms in visceral fat from non-obese subjects. The levels of PPARγ isoforms were determined by qPCR analyses.

Figure 4. The distinct correlations of PPAR isoforms with adipocyte genes in human visceral fat

The correlations of adipocyte genes to PPARγ isoforms in visceral fat from non-obese subjects. The levels of PPARγ isoforms were determined by qPCR analyses.