Time-dependent network analysis reveals molecular targets underlying the development of diet-induced obesity and non-alcoholic steatohepatitis

Abstract

Prolonged high-fat diet leads to the development of obesity and multiple comorbidities including non-alcoholic steatohepatitis (NASH), but the underlying molecular basis is not fully understood. We combine molecular networks and time course gene expression profiles to reveal the dynamic changes in molecular networks underlying diet-induced obesity and NASH. We also identify hub genes associated with the development of NASH. Core diet-induced obesity networks were constructed using Ingenuity pathway analysis (IPA) based on 332 high-fat diet responsive genes identified in liver by time course microarray analysis (8 time points over 24 weeks) of high-fat diet-fed mice compared to normal diet-fed mice. IPA identified five core diet-induced obesity networks with time-dependent gene expression changes in liver. These networks were associated with cell-to-cell signaling and interaction (Network 1), lipid metabolism (Network 2), hepatic system disease (Network 3 and 5), and inflammatory response (Network 4). When we merged these core diet-induced obesity networks, Tlr2, Cd14, and Ccnd1 emerged as hub genes associated with both liver steatosis and inflammation and were altered in a time-dependent manner. Further, protein-protein interaction network analysis revealed Tlr2, Cd14, and Ccnd1 were interrelated through the ErbB/insulin signaling pathway. Dynamic changes occur in molecular networks underlying diet-induced obesity. Tlr2, Cd14, and Ccnd1 appear to be hub genes integrating molecular interactions associated with the development of NASH. Therapeutics targeting hub genes and core diet-induced obesity networks may help ameliorate diet-induced obesity and NASH.

A history of obesity leaves an inflammatory fingerprint in liver and adipose tissue

“…In addition to steatosis, prolonged HFD feeding also induces other hallmarks of NAFLD, such as inflammation, fibrosis or hepatocellular ballooning. 52 Similar to previous studies, 53 we find increased liver weights, triglyceride contents, accumulation of macrovesicular fat droplets, increased inflammatory marker expression and portal-to portal as well as pericellular, so-called ‘chicken-wire fibrosis’ in obese mice.…”

Hepatoprotective and Antioxidant Potential of Organic and Conventional Grape Juices in Rats Fed a High-Fat Diet

“…Among the risk factors for the development of these diseases are hypertension, excess alcohol intake, hereditary factors, smoking, sedentary lifestyle, stress and obesity [ 2 , 3 , 4 ]. In this context, visceral fat accumulation plays an important role in the associated deleterious effects of excess body fat, including dyslipidemia and hepatic steatosis [ 5 , 6 ]. Although the complex relationship between visceral fat accumulation and hepatic steatosis is not completely understood, it is well described that an imbalance in lipid metabolism in the liver is associated with hepatic steatosis [ 7 , 8 ]…”

Time-course microarrays reveal modulation of developmental, lipid metabolism and immune gene networks in intrascapular brown adipose tissue during the development of diet-induced obesity

“…15 In addition, recently time-dependent changes in molecular networks were reported in liver in association with the development of nonalcoholic steatohepatitis triggered by a HFD. 16 Furthermore, molecular networks have been identified in adipose tissue of obese humans, 17 but our understanding of the timing and dynamics of network modulation especially in brown adipose tissue is limited.…”