Hepatic Dysfunction Caused by Consumption of a High-Fat Diet
Author(s)
Kennedy, Norman J.; Zhou, Feng; Ficarro, Scott B.; Marto, Jarrod A.; Davis, Roger J.; Soltis, Anthony Robert; Xin, Xiaofeng; Yap, Yoon Sing; Matthews, Bryan; Lauffenburger, Douglas A; White, Forest M; Fraenkel, Ernest; ... Show more Show less
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Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet-induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease. Soltis et al. performed a systems biology study of obesity-induced hepatic insulin resistance in mice. They collected a variety of omic datasets, including metabolomics, and integrated these into a network model. They tested model predictions and identified widespread hepatocellular injury and enhanced hepatocyte apoptosis as features of hepatic insulin resistance. Keywords: insulin resistance; high-fat diet; obesity; systems biology; computational biology;
integrative modeling; omic data
Date issued
2017-12Department
Massachusetts Institute of Technology. Department of Biological EngineeringJournal
Cell Reports
Publisher
Elsevier
Citation
Soltis, Anthony R. et al. “Hepatic Dysfunction Caused by Consumption of a High-Fat Diet.” Cell Reports 21, 11 (December 2017): 3317–3328 © 2017 The Author(s)
Version: Final published version
ISSN
2211-1247