Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice
Raymond E. Soccio, … , David J. Steger, Mitchell A. Lazar
Raymond E. Soccio, … , David J. Steger, Mitchell A. Lazar
Published February 27, 2017
Citation Information: J Clin Invest. 2017;127(4):1451-1462. https://doi.org/10.1172/JCI91211.
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Research Article Endocrinology Metabolism

Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice

Abstract

Obesity causes insulin resistance, and PPARγ ligands such as rosiglitazone are insulin sensitizing, yet the mechanisms remain unclear. In C57BL/6 (B6) mice, obesity induced by a high-fat diet (HFD) has major effects on visceral epididymal adipose tissue (eWAT). Here, we report that HFD-induced obesity in B6 mice also altered the activity of gene regulatory elements and genome-wide occupancy of PPARγ. Rosiglitazone treatment restored insulin sensitivity in obese B6 mice, yet, surprisingly, had little effect on gene expression in eWAT. However, in subcutaneous inguinal fat (iWAT), rosiglitazone markedly induced molecular signatures of brown fat, including the key thermogenic gene Ucp1. Obesity-resistant 129S1/SvImJ mice (129 mice) displayed iWAT browning, even in the absence of rosiglitazone. The 129 Ucp1 locus had increased PPARγ binding and gene expression that were preserved in the iWAT of B6x129 F1–intercrossed mice, with an imbalance favoring the 129-derived alleles, demonstrating a cis-acting genetic difference. Thus, B6 mice have genetically defective Ucp1 expression in iWAT. However, when Ucp1 was activated by rosiglitazone, or by iWAT browning in cold-exposed or young mice, expression of the B6 version of Ucp1 was no longer defective relative to the 129 version, indicating epigenomic rescue. These results provide a framework for understanding how environmental influences like drugs can affect the epigenome and potentially rescue genetically determined disease phenotypes.

Authors

Raymond E. Soccio, Zhenghui Li, Eric R. Chen, Yee Hoon Foong, Kiara K. Benson, Joanna R. Dispirito, Shannon E. Mullican, Matthew J. Emmett, Erika R. Briggs, Lindsey C. Peed, Richard K. Dzeng, Carlos J. Medina, Jennifer F. Jolivert, Megan Kissig, Satyajit R. Rajapurkar, Manashree Damle, Hee-Woong Lim, Kyoung-Jae Won, Patrick Seale, David J. Steger, Mitchell A. Lazar

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Figure 2

HFD alters PPARγ occupancy and gene regulation in visceral fat of C57BL/6 mice.

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HFD alters PPARγ occupancy and gene regulation in visceral fat of C57BL/...
(A) Scatterplot of approximately 36,000 PPARγ sites identified in 5 ChIP-seq experiments comparing occupancy in eWAT from mice on HFD for 12 weeks versus control mice on LFD. Colored sites indicate a 3-fold diet-dependent difference in average occupancy, even when corrected for the overall decline on HFD. (B) Of the approximately 36,000 PPARγ sites identified in eWAT, approximately 26,000 were found by ChIP-seq of cultured 3T3-L1 adipocytes (Ads) and/or elicited peritoneal macrophages (Macs), and sites were identified as common versus 4-fold selective for either cell type. (C) For HFD-upregulated sites from A, there was enrichment of macrophage-selective sites (pie chart). Average profiles show differential PPARγ occupancy at 12 but not 4 weeks of HFD and increased histone acetylation (H3K27ac) at these sites after 12 weeks of HFD. (D) For HFD-downregulated sites from A, there was enrichment of adipocyte-selective sites (pie chart). Average profiles show differential PPARγ occupancy at 12 and 4 weeks of HFD and decreased H3K27ac at these sites on the HFD. (E) Time dependence of H3K27ac changes at HFD-downregulated and HFD-upregulated PPARγ sites (error bars indicate the mean and 95% CI). (F) Heatmap sorted by HFD regulation of each PPARγ site, showing whether the nearest gene within 100 kb was significantly diet regulated.