Organisms reprogram metabolic pathways to adapt to changes in nutrient availability, hormonal milieu and energy demands. This requires that stimuli are sensed and highly specific responses engaged. We propose that in the liver, the mitogen-activated protein kinase, c-Jun N-terminal kinase (JNK), links excessive nutrient metabolism with impaired insulin regulation of glucose production. The liver, by virtue of its anatomic position and selective regulatory features, buffers and is highly responsive to changes in nutrients. In particular sugars, such as sucrose and fructose, uniquely regulate and are selective metabolized by the liver. In the present application we show that chronic and acute sucrose ingestion, intraportal fructose infusion under controlled hyperglycemic conditions, and overexpression of hepatic glucokinase in vivo, and controlled fructose delivery in primary rat and human hepatocytes selectively increased hepatic JNK, the interaction of JNK with the scaffold protein, JIP1, and the interaction of JNK with insulin receptor substrate proteins. Normalization of the increased JNK activity improved insulin action and signaling. We propose that when hepatic sugar uptake exceeds requirements for glycogen and energy (hepatic sugar excess) the JNK signaling pathway is engaged as part of the adaptive response. Although a considerable amount of work has been done to establish the role of JNK as a mediator of insulin signaling, less is known about the mechanisms that link extracellular signals to the activation of JNK and the induction of insulin resistance in the liver.
The aims of this proposal are to a) determine the cellular effectors of fructose-induced activation of JNK and insulin resistance and b) examine the role and regulation of the JNK signaling module in fructose- induced insulin resistance. The results from these studies will provide novel insight into nutrient regulation of signaling networks within the hepatocyte and to the etiology of metabolic diseases, such as obesity and type 2 diabetes, that have environmentally-based etiologies and are characterized by hepatic insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047416-13
Application #
7564049
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Laughlin, Maren R
Project Start
1994-03-01
Project End
2012-01-31
Budget Start
2009-02-01
Budget End
2012-01-31
Support Year
13
Fiscal Year
2009
Total Cost
$227,710
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Nutrition
Type
Other Domestic Higher Education
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
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