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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Resource-Related Research Projects (R24)
Project #
5R24DK090963-02
Application #
8209034
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O3))
Program Officer
Sechi, Salvatore
Project Start
2011-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$2,132,046
Indirect Cost
$334,947
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Dagdeviren, Sezin; Jung, Dae Young; Friedline, Randall H et al. (2017) IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle. FASEB J 31:701-710
Soltis, Anthony R; Kennedy, Norman J; Xin, Xiaofeng et al. (2017) Hepatic Dysfunction Caused by Consumption of a High-Fat Diet. Cell Rep 21:3317-3328
Soltis, Anthony R; Motola, Shmulik; Vernia, Santiago et al. (2017) Hyper- and hypo- nutrition studies of the hepatic transcriptome and epigenome suggest that PPAR? regulates anaerobic glycolysis. Sci Rep 7:174
Vernia, Santiago; Cavanagh-Kyros, Julie; Barrett, Tamera et al. (2016) Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK. Cell Rep 14:2273-80
Dagdeviren, Sezin; Jung, Dae Young; Lee, Eunjung et al. (2016) Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance. Mol Cell Biol 36:2956-2966
Friedline, Randall H; Ko, Hwi Jin; Jung, Dae Young et al. (2016) Genetic ablation of lymphocytes and cytokine signaling in nonobese diabetic mice prevents diet-induced obesity and insulin resistance. FASEB J 30:1328-38
Johnson, Matthew L; Distelmaier, Klaus; Lanza, Ian R et al. (2016) Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults. Diabetes 65:74-84
Min, So Yun; Kady, Jamie; Nam, Minwoo et al. (2016) Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 22:312-8
Ip, Blanche; Cilfone, Nicholas A; Belkina, Anna C et al. (2016) Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNF? production. Obesity (Silver Spring) 24:102-12
Bryson, Bryan D; White, Forest M (2015) Quantitative Profiling of Lysine Acetylation Reveals Dynamic Crosstalk between Receptor Tyrosine Kinases and Lysine Acetylation. PLoS One 10:e0126242

Showing the most recent 10 out of 30 publications