Nutrient intake in excess of energy expenditure is a major contributing factor to the world-wide epidemic of obesity and type 2 diabetes. Traditionally nutrients have been considered to be precursors for the biosynthesis of macromolecules and as substrates for the production of molecules involved in energy metabolism. However, they are now understood to act through signal transduction cascades to regulate various cellular processes including protein synthesis. The nutrient-sensing pathways are not only interconnected at multiple levels but are tightly coupled to the insulin receptor signaling pathway. Thus, nutrient-sensing and insulin receptor signaling pathways do not function in isolation, but rather as components of a larger, integrated system of intracellular communication. The project proposed herein focuses on the liver, which is an especially important organ in regards to the body's response to nutrient intake because of its position in relation to the gastrointestinal tract, affording it immediate access to the products of digestion appearing in the portal vein. The project also focuses on protein synthesis because the liver, in combination with the gastrointestinal tract, accounts for 25% of the whole body protein synthetic response to a mixed meal. Finally, the project focuses on translational control mechanisms, an area of research for which the expertise of the PI's laboratory is well recognized and one becoming increasingly recognized as playing a prominent role in the regulation of gene expression. The project will employ non-diabetic and diabetic mice maintained on four different diets designed to increase both the fat and caloric intake. The hypothesis to be tested is that chronic nutrient excess and diabetes, alone and in combination, acting through translational control mechanisms, cause both global and specific changes in hepatic protein expression patterns that contribute to pathologies associated with maladapted metabolism. The hypothesis will be tested by pursuing the three following specific aims: (1) define the effects of different dietary regimens and diabetes, alone and in combination, on global and specific changes in protein expression patterns, the translational control mechanisms mediated by eIF2 and eIF4F, and the activation state of nutrient- sensing and insulin receptor signaling pathways in the liver of nondiabetic and diabetic mice;(2) quantitate expression of the mTORC1 repressor REDD1 in the liver of nondiabetic and diabetic mice in response to nutrient excess, define regulatory mechanisms contributing to its upregulated expression, and define its mechanisms of action;and (3) elucidate the signaling pathways and molecular mechanisms through which diabetes-induced hyperglycemia and nutrient excess mediate increased hepatic expression of the translational repressor 4E-BP1. Overall, the project is expected to produce new knowledge that will provide insight into designing strategies for the treatment of pathologies resulting from the maladapted whole body metabolism associated with obesity and diabetes.

Public Health Relevance

Chronic intake of excess nutrients leads to accumulation of lipid in tissues, resulting in the development of insulin resistance and the pathological progression to type 2 diabetes and other metabolic diseases. The project proposed herein will employ a number of novel experimental models and specialized techniques to define effects of nutrient excess and diabetes, alone and in combination, on molecular events that modulate the pattern of protein expression in the liver. Knowledge gained from the project will provide insight into designing strategies for treatment of pathologies resulting from the maladapted whole body metabolism associated with obesity and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK013499-44
Application #
8442901
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Laughlin, Maren R
Project Start
1996-09-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
44
Fiscal Year
2013
Total Cost
$389,597
Indirect Cost
$136,465
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Dai, Weiwei; Miller, William P; Toro, Allyson L et al. (2018) Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation. FASEB J :fj201800413RR
Miller, William P; Ravi, Suhana; Martin, Tony D et al. (2017) Activation of the Stress Response Kinase JNK (c-Jun N-terminal Kinase) Attenuates Insulin Action in Retina through a p70S6K1-dependent Mechanism. J Biol Chem 292:1591-1602
Kimball, Scot R (2017) Leucine-Induced Upregulation of Terminal Oligopyrimidine mRNA Translation in Skeletal Muscle: Just the Tip of the Iceberg? J Nutr 147:1603-1604
Guan, Bo-Jhih; van Hoef, Vincent; Jobava, Raul et al. (2017) A Unique ISR Program Determines Cellular Responses to Chronic Stress. Mol Cell 68:885-900.e6
Pettit, Ashley P; Jonsson, William O; Bargoud, Albert R et al. (2017) Dietary Methionine Restriction Regulates Liver Protein Synthesis and Gene Expression Independently of Eukaryotic Initiation Factor 2 Phosphorylation in Mice. J Nutr 147:1031-1040
Black, Adam J; Gordon, Bradley S; Dennis, Michael D et al. (2016) Regulation of protein and mRNA expression of the mTORC1 repressor REDD1 in response to leucine and serum. Biochem Biophys Rep 8:296-301
Gordon, Bradley S; Steiner, Jennifer L; Williamson, David L et al. (2016) Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism. Am J Physiol Endocrinol Metab 311:E157-74
Kimball, Scot R; Gordon, Bradley S; Moyer, Jenna E et al. (2016) Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal 28:896-906
Miller, William P; Mihailescu, Maria L; Yang, Chen et al. (2016) The Translational Repressor 4E-BP1 Contributes to Diabetes-Induced Visual Dysfunction. Invest Ophthalmol Vis Sci 57:1327-37
Dennis, Michael D; Kimball, Scot R; Fort, Patrice E et al. (2015) Regulated in development and DNA damage 1 is necessary for hyperglycemia-induced vascular endothelial growth factor expression in the retina of diabetic rodents. J Biol Chem 290:3865-74

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