Hepatic Dysfunction Caused by Consumption of a High-Fat Diet

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. [Display omitted] •Multi-omic profiling of high-fat-diet-induced hepatic insulin resistance•Integrative modeling of omic data identifies features of hepatic insulin resistance•Obesity induces hepatocellular injury and disrupts hepatic cell-cell interactions•Enhanced hepatocyte apoptosis is a feature of obesity-induced insulin resistance 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.