The mammalian target of rapamycin (mTOR) is a central growth controller. Recent studies have elucidated a conserved signaling pathway consisting of TSC1/TSC2-Rheb-mTOR. TSC1 and TSC2 are two tumor suppressor genes mutated in the tuberous sclerosis. The TSC1/TSC2 complex functions as a GTPase activating protein (GAP) to inhibit the Rheb small GTPase, which is a potent activator of mTOR. This signaling pathway integrates a wide range of extracellular and intracellular signals to regulate cell growth. mTOR activity is rapidly and dramatically regulated by the availability of cellular energy and amino acids. Previous studies have established that the TSC-mTOR pathway plays a critical role in the coordination between cell growth and nutrient availability at the cellular level. The major focus of this proposal is to investigate the function of TSC- Rheb-mTOR pathway in organismal energy balance and to elucidate the mechanism of this pathway in regulation of leptin signaling, appetite control, and energy expenditure. We will use mouse genetics and cell biological techniques to achieve these goals.
The specific aims for this proposal are:
Aim 1. To determine the function of TSC1 in POMC neurons in appetite and metabolic control and obesity Aim 2. To determine the function of TSC1 in AGRP/NPY neurons in regulation of appetite Aim 3. To elucidate the mechanism of mTOR activation in inducing leptin resistance and hyperphagia Aim 4. To determine the effect of low mTOR activity on food intake, metabolism, obesity, leptin sensitivity, and resistant to high fat diet-induced obesity.

Public Health Relevance

The TSC-mTOR pathway plays a major role in hormonal and nutritional signals to regulate cell growth. This proposal will investigate the function of TSC-mTOR in affecting leptin signaling and appetite control. The information generated from this project will provide new insights into to appetite regulation, obesity, and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108941-10
Application #
8384856
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Spalholz, Barbara A
Project Start
2004-09-03
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
10
Fiscal Year
2013
Total Cost
$285,875
Indirect Cost
$99,318
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Wang, Pu; Wu, Jing; Ma, Shenghong et al. (2015) Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep 13:2353-61
Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163:811-28
Jewell, Jenna L; Flores, Fabian; Guan, Kun-Liang (2015) Micro(RNA) managing by mTORC1. Mol Cell 57:575-6
Hansen, Carsten Gram; Ng, Yuen Lam Dora; Lam, Wai-Ling Macrina et al. (2015) The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1. Cell Res 25:1299-313
Kim, Young Chul; Guan, Kun-Liang (2015) mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 125:25-32
Yuan, Hai-Xin; Guan, Kun-Liang (2015) The SIN1-PH Domain Connects mTORC2 to PI3K. Cancer Discov 5:1127-9
Plouffe, Steven W; Hong, Audrey W; Guan, Kun-Liang (2015) Disease implications of the Hippo/YAP pathway. Trends Mol Med 21:212-22
Zha, Zhengyu; Han, Xiaoran; Smith, Matthew D et al. (2015) A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation. Mol Cell 58:794-803
Yang, Hui; Zhou, Lisha; Shi, Qian et al. (2015) SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J 34:1110-25
Jewell, Jenna L; Kim, Young Chul; Russell, Ryan C et al. (2015) Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 347:194-8

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