Disorders of body mass regulation such as obesity are increasingly common causes of morbidity and mortality. Despite significant progress, many cellular and molecular details of energy homeostasis remain unknown. Increased understanding of the molecular signaling mechanisms will aid in the development of more effective therapies for obesity and its associated disorders, such as type 2 diabetes. Protein tyrosine phosphorylation and dephosphorylation is a fundamental signaling mechanism in cells, and is tightly controlled by the opposing actions of protein-tyrosine kinases and protein-tyrosine phosphatases (PTPs). Protein-tyrosine phophatase 1B (PTP1B) is an important physiological regulator of metabolism. PTP1B whole-body knockout (KO) mice are hypersensitive to insulin and leptin, and are resistant to high fat diet-induced obesity. Additional studies using tissue-specific deletion, revealed a diverse and complex function of PTP1B in various peripheral insulin-responsive tissues (liver and muscle) and brain. However, the metabolic role of adipose PTP1B remains largely unexplored. To fully assess the physiological role of adipose PTP1B, we will employ three complementary approaches. We will generate adipose-specific PTP1B KO mice which will enable assessment of consequences of PTP1B loss in adipose tissue in vivo. Equally important are the dissection of molecular mechanisms mediating PTP1B function, and characterization of the dynamic PTP1B-substrate(s) interaction with high spatial and temporal resolution. In preliminary studies, we show that: (i) mice with adipose-PTP1B deletion are resistant to high fat diet-induced obesity, (ii) this is a result, at least in part, of increased energy expenditure in these mice. (iii) In addition, adipose PTP1B deletion improves systemic insulin sensitivity and glucose homeostasis. (iv) Indentify pyruvate kinase M2 as a novel substrate of PTP1B. Thus, our preliminary studies indicate that adipose PTP1B is a major regulator of body mass and glucose homeostasis. The broad goals of this proposal are to investigate the metabolic role of adipose PTP1B. PTP1B is an attractive target for therapy of obesity and diabetes with many pharmaceutical companies developing PTP1B inhibitors. Therefore, understanding how adipose PTP1B acts is vital for its evaluation of use as a target for therapeutic intervention.

Public Health Relevance

Obesity and type 2 diabetes are very prevalent metabolic diseases affecting millions of people in the United States and worldwide. The goal of this proposal is to utilize genetically engineered mouse models and advanced biochemical and imaging approaches to determine the physiological role of adipose protein-tyrosine phosphatase 1B in glucose homeostasis and body mass regulation. Data generated from this proposal will aid in the identification of therapeutic targets for prevention and treatment of obesity and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090492-03
Application #
8495330
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2011-09-20
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$322,178
Indirect Cost
$112,290
Name
University of California Davis
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Bettaieb, Ahmed; Koike, Shinichiro; Chahed, Samah et al. (2016) Pancreatic Protein Tyrosine Phosphatase 1B Deficiency Exacerbates Acute Pancreatitis in Mice. Am J Pathol 186:2043-54
Sirish, Padmini; Li, Ning; Timofeyev, Valeriy et al. (2016) Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:
Tomilov, Alexey; Tomilova, Natalia; Shan, Yuxi et al. (2016) p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria. J Biol Chem 291:12575-85
Cremonini, Eleonora; Bettaieb, Ahmed; Haj, Fawaz G et al. (2016) (-)-Epicatechin improves insulin sensitivity in high fat diet-fed mice. Arch Biochem Biophys 599:13-21
Bettaieb, Ahmed; Hosein, Ellen; Chahed, Samah et al. (2015) Decreased adiposity and enhanced glucose tolerance in shikonin treated mice. Obesity (Silver Spring) 23:2269-77
Bettaieb, Ahmed; Chahed, Samah; Bachaalany, Santana et al. (2015) Soluble Epoxide Hydrolase Pharmacological Inhibition Ameliorates Experimental Acute Pancreatitis in Mice. Mol Pharmacol 88:281-90
Harris, Todd R; Bettaieb, Ahmed; Kodani, Sean et al. (2015) Inhibition of soluble epoxide hydrolase attenuates hepatic fibrosis and endoplasmic reticulum stress induced by carbon tetrachloride in mice. Toxicol Appl Pharmacol 286:102-11
Vazquez Prieto, Marcela A; Bettaieb, Ahmed; Rodriguez Lanzi, Cecilia et al. (2015) Catechin and quercetin attenuate adipose inflammation in fructose-fed rats and 3T3-L1 adipocytes. Mol Nutr Food Res 59:622-33
McGavigan, Anne K; Garibay, Darline; Henseler, Zachariah M et al. (2015) TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice. Gut :
Jialal, Ishwarlal; Devaraj, Sridevi; Bettaieb, Ahmed et al. (2015) Increased adipose tissue secretion of Fetuin-A, lipopolysaccharide-binding protein and high-mobility group box protein 1 in metabolic syndrome. Atherosclerosis 241:130-7

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