Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of insulin resistance, hyperglycemia, and metabolic syndrome that can lead to cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. A significant challenge to understanding diet-induced obesity is the complexity of the signal transduction pathways that mediate the response. Indeed, these signaling pathways function within an interacting network. Here we propose to employ a systems biology approach to understanding the response to feeding a high fat diet by combining physiological analysis together with quantitative analysis of the signal transduction networks and the genomic response. This analysis requires the coordinated collaborative efforts of several laboratories with complementary expertise together with robust data analysis and computational modeling. We will focus our analysis on the liver. The overall goal of this research program is to understand the mechanism of the hepatic response to diet-induced obesity. Achievement of the goals of this proposal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of nodes in the signaling network that may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type II diabetes.
The Specific Aims of this proposal are to: 1. Examine the hepatic response to feeding a high fat diet. 2. Integrate data analysis using computational modeling. 3. Test predictions obtained from computational modeling.

Public Health Relevance

Metabolic syndrome and type II diabetes are serious diseases that have a profound impact on the health of many Americans;it is essential that we develop new treatment options for these diseases. The purpose of this research proposal is to perform a systems biology analysis of the hepatic response to diet-induced obesity. We anticipate that this information will provide a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type II diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZDK1-GRB-2 (O3))
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Sechi, Salvatore
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University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
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Vernia, Santiago; Cavanagh-Kyros, Julie; Garcia-Haro, Luisa et al. (2014) The PPAR?-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway. Cell Metab 20:512-25
Sabio, Guadalupe; Davis, Roger J (2014) TNF and MAP kinase signalling pathways. Semin Immunol 26:237-45
Janes, Kevin A; Lauffenburger, Douglas A (2013) Models of signalling networks - what cell biologists can gain from them and give to them. J Cell Sci 126:1913-21
Lo, Kinyui Alice; Labadorf, Adam; Kennedy, Norman J et al. (2013) Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance. Cell Rep 5:259-70
Hong, Eun-Gyoung; Kim, Brian W; Jung, Dae Young et al. (2013) Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice. Endocrinology 154:3937-46
Han, Myoung Sook; Jung, Dae Young; Morel, Caroline et al. (2013) JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339:218-22
Jung, Dae Young; Chalasani, Umadevi; Pan, Ning et al. (2013) KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance. PLoS One 8:e77851
Vernia, Santiago; Cavanagh-Kyros, Julie; Barrett, Tamera et al. (2013) Diet-induced obesity mediated by the JNK/DIO2 signal transduction pathway. Genes Dev 27:2345-55
Kant, Shashi; Barrett, Tamera; Vertii, Anastassiia et al. (2013) Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity. Cell Rep 4:681-8
Miraldi, Emily R; Sharfi, Hadar; Friedline, Randall H et al. (2013) Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice. Integr Biol (Camb) 5:940-63

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