Obesity and type 2 diabetes (2DM) affect millions of people and are the cause of major health problems in the United States. Both conditions have a long array of life threatening complications, including cardiovascular diseases. Despite intense research, the primary defects causing obesity and/or 2DM are still largely unknown. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic physiology, neuroendocrinology and behavior of body energy and glucose homeostasis is needed. The hypothalamus and metabolic-sensor proteins exert important functions on energy and glucose balance. Here, by employing neuron-specific, Cre/loxP-mediated manipulations, unique animal models in which SIRT1 (a metabolic-sensor protein) is either overexpressed or deleted only in restricted hypothalamic neurons will be generated. These mice will be subjected to several phenotypic tests to determine whether SIRT1 in hypothalamic neurons is required for normal body weight and glucose homeostasis. Results from these studies are expected to increase our understanding of the molecular mechanisms and neurocircuits that underlie coordinated control of energy and glucose homeostasis.

Public Health Relevance

Obesity and type 2 diabetes affect millions of people and are the cause of major health problems in the United States. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic mechanisms of body energy and glucose homeostasis is needed. The study proposed here is aimed at identifying these mechanisms (proteins and neurons) that in concert govern body weight and glucose balance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080836-04
Application #
8251164
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Hyde, James F
Project Start
2009-04-20
Project End
2012-11-30
Budget Start
2012-04-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$334,680
Indirect Cost
$121,508
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Coppari, Roberto; Bjørbæk, Christian (2012) Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 11:692-708
Coppari, Roberto (2012) Metabolic actions of hypothalamic SIRT1. Trends Endocrinol Metab 23:179-85
Price, Nathan L; Gomes, Ana P; Ling, Alvin J Y et al. (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675-90
Ramadori, Giorgio; Coppari, Roberto (2011) Does hypothalamic SIRT1 regulate aging? Aging (Albany NY) 3:325-8
Ramadori, Giorgio; Fujikawa, Teppei; Anderson, Jason et al. (2011) SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab 14:301-12
Vianna, Claudia R; Coppari, Roberto (2011) A treasure trove of hypothalamic neurocircuitries governing body weight homeostasis. Endocrinology 152:11-8
Fujikawa, Teppei; Chuang, Jen-Chieh; Sakata, Ichiro et al. (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391-6
Ramadori, Giorgio; Coppari, Roberto (2010) Pharmacological manipulations of CNS sirtuins: potential effects on metabolic homeostasis. Pharmacol Res 62:48-54
Ramadori, Giorgio; Fujikawa, Teppei; Fukuda, Makoto et al. (2010) SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 12:78-87

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