TY - JOUR

T1 - Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice

AU - Soccio, Raymond E

AU - Li, Zhenghui

AU - Chen, Eric R

AU - Foong, Yee Hoon

AU - Benson, Kiara K

AU - Dispirito, Joanna R

AU - Mullican, Shannon E

AU - Emmett, Matthew J

AU - Briggs, Erika R

AU - Peed, Lindsey C

AU - Dzeng, Richard K

AU - Medina, Carlos J

AU - Jolivert, Jennifer F

AU - Kissig, Megan

AU - Rajapurkar, Satyajit R

AU - Damle, Manashree

AU - Lim, Hee-Woong

AU - Won, Kyoung-Jae

AU - Seale, Patrick

AU - Steger, David J

AU - Lazar, Mitchell A

PY - 2017/4/3

Y1 - 2017/4/3

N2 - 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.

AB - 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.

KW - Animals

KW - Diet, High-Fat/adverse effects

KW - Epigenesis, Genetic

KW - Hypoglycemic Agents/pharmacology

KW - Intra-Abdominal Fat/metabolism

KW - Male

KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - Obesity/metabolism

KW - PPAR gamma/physiology

KW - Protein Binding

KW - Regulatory Elements, Transcriptional

KW - Subcutaneous Fat, Abdominal/metabolism

KW - Thiazolidinediones/pharmacology

KW - Transcriptional Activation

KW - Transcriptome

KW - Uncoupling Protein 1/genetics

U2 - 10.1172/JCI91211

DO - 10.1172/JCI91211

M3 - Journal article

C2 - 28240605

VL - 127

SP - 1451

EP - 1462

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -