Obesity, diabetes, and other metabolic diseases have known underlying genetic causes; however, environmental factors also play an important role in the onset and development of metabolic dysfunction. In this episode, Mitchell Lazar and Raymond Soccio discuss their study, which compared high fat-diet-induced effects on gene expression and the epigenome in mice genetically prone to diet-induced obesity and in animals that are resistant to diet-induced metabolic disease. They find that the thermogenic gene Ucp1 is repressed in the obesity-prone mice, but that either cold-exposure or treatment with the insulin-sensitizing drug rosiglitazone restores Ucp1 expression to levels similar to that in obesity-resistant strains. The results of this study demonstrate that genetic defects in metabolism can be rescued by environmentally-driven epigenomic modifications.
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
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