title: 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.forename: Raymond E
authors.initials: RE
authors.lastname: Soccio
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Li
authors.forename: Eric R
authors.initials: ER
authors.lastname: Chen
authors.forename: Yee Hoon
authors.initials: YH
authors.lastname: Foong
authors.forename: Kiara K
authors.initials: KK
authors.lastname: Benson
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Dispirito
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Mullican
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Emmett
authors.forename: Erika R
authors.initials: ER
authors.lastname: Briggs
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Peed
authors.forename: Richard K
authors.initials: RK
authors.lastname: Dzeng
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Medina
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Jolivert
authors.forename: Megan
authors.initials: M
authors.lastname: Kissig
authors.forename: Satyajit R
authors.initials: SR
authors.lastname: Rajapurkar
authors.forename: Manashree
authors.initials: M
authors.lastname: Damle
authors.forename: Hee-Woong
authors.initials: HW
authors.lastname: Lim
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.forename: Patrick
authors.initials: P
authors.lastname: Seale
authors.forename: David J
authors.initials: DJ
authors.lastname: Steger
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D044127:Epigenesis, Genetic; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology*; D011485:Protein Binding; D050436:Regulatory Elements, Transcriptional; D000077154:Rosiglitazone; D050507:Subcutaneous Fat, Abdominal / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D015533:Transcriptional Activation; D059467:Transcriptome; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000077154:Rosiglitazone