As the prevalence of obesity is rapidly growing in this country and throughout the world, understanding the mechanisms of weight control becomes an urgent biomedical problem. The adipose-derived hormone, leptin, plays a central role in regulation of body weight and energy expenditure. Food intake and accumulation of energy stores in adipocytes result in an increase in leptin production thus leading to inhibition of appetite and elevation of energy expenditure. Conversely, when fat stores decline, adipocytes reduce leptin production, and food intake is increased. However, the biochemical connection between nutrient intake/storage in adipocytes and the level of leptin secretion remains largely unknown. In the previous funding period, we found that production of leptin is regulated at the level of translation via the mTOR-mediated pathway as well as at the level of secretion. Since mTOR (mammalian target of rapamycin) represents a nutrient sensor in the cell, the first pathway may provide a long sought after physiological connection between food intake and leptin expression. Thus, our first goal for the next funding period is to determine how to manipulate expression levels of leptin mRNA stored in adipose cells using specific nutrient signals. For that, we propose to explore the mTOR-mediated mechanism of the translational control of leptin mRNA by various nutrients. This will give us the opportunity to maintain high levels of circulating endogenous leptin without increasing fat stores in adipocytes. Our second goal is to understand the molecular mechanisms of secretion from adipose cells. In particular, we will test the hypothesis that newly discovered Golgi-localized, gamma-ear-containing, Arf-binding proteins participate in the formation of secretory vesicles in adipocytes and regulate secretion from these cells. We will also determine whether or not Glut4-vesicles contain novel secreted proteins as their soluble cargo and continue our search for novel proteins secreted from adipocytes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK056736-09S1
Application #
7996959
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2009-12-14
Project End
2011-02-28
Budget Start
2009-12-14
Budget End
2011-02-28
Support Year
9
Fiscal Year
2010
Total Cost
$98,600
Indirect Cost
Name
Boston University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Kim, Ju Youn; Kandror, Konstantin V (2012) The first luminal loop confers insulin responsiveness to glucose transporter 4. Mol Biol Cell 23:910-7
Karki, Shakun; Chakrabarti, Partha; Huang, Guanrong et al. (2011) The multi-level action of fatty acids on adiponectin production by fat cells. PLoS One 6:e28146
Chakrabarti, Partha; English, Taylor; Karki, Shakun et al. (2011) SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. J Lipid Res 52:1693-701
Chakrabarti, Partha; Kandror, Konstantin V (2011) Adipose triglyceride lipase: a new target in the regulation of lipolysis by insulin. Curr Diabetes Rev 7:270-7
Chakrabarti, Partha; English, Taylor; Shi, Jun et al. (2010) Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage. Diabetes 59:775-81
Bakirtzi, Kyriaki; Belfort, Gabriel; Lopez-Coviella, Ignacio et al. (2009) Cerebellar neurons possess a vesicular compartment structurally and functionally similar to Glut4-storage vesicles from peripheral insulin-sensitive tissues. J Neurosci 29:5193-201
Li, Lin V; Bakirtzi, Kyriaki; Watson, Robert T et al. (2009) The C-terminus of GLUT4 targets the transporter to the perinuclear compartment but not to the insulin-responsive vesicles. Biochem J 419:105-12, 1 p following 112
Chakrabarti, Partha; Kandror, Konstantin V (2009) FoxO1 controls insulin-dependent adipose triglyceride lipase (ATGL) expression and lipolysis in adipocytes. J Biol Chem 284:13296-300
Shi, Jun; Huang, Guanrong; Kandror, Konstantin V (2008) Self-assembly of Glut4 storage vesicles during differentiation of 3T3-L1 adipocytes. J Biol Chem 283:30311-21
Chakrabarti, Partha; Anno, Takatoshi; Manning, Brendan D et al. (2008) The mammalian target of rapamycin complex 1 regulates leptin biosynthesis in adipocytes at the level of translation: the role of the 5'-untranslated region in the expression of leptin messenger ribonucleic acid. Mol Endocrinol 22:2260-7

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