Adipocyte lipolysis contributes significantly to the pathogenesis of obesity-associated diseases by increasing levels of circulating free fatty acids (FFA). FFA promote insulin resistance and type 2 diabetes. My laboratory's long-term goal is to elucidate molecular mechanisms of lipolysis regulation. The proposed studies will investigate structure / function relationships of Perilipin A (Peri A), a lipid droplet- associated phosphoprotein that regulates lipolysis mediated by hormone sensitive lipase (HSL) and non-HSL lipase(s). Peri A acts dually as a suppressor of basal lipolysis (in the absence of hormonal stimulation) and as a potent enhancer of protein kinase A (PKA)-stimulated lipolysis (in the presence of hormonal stimulation). Despite its important regulatory role, the primary sequences and the mechanism(s) by which Peri A regulates lipase actions have not been determined. Our preliminary studies indicate that Perilipin regulates lipolysis via multiple regulatory domains, which exhibit surprising lipase specificity. The proposed studies will 1) identify the minimal domains of Peri A that modulate basal and PKA-stimulated lipolysis by HSL and non-HSL lipase(s), 2) determine the relative role of PKA phosphorylation sites in PKA- stimulated lipolysis by HSL and non-HSL lipase, and 3) define the in vivo effects of altered Peri A expression, Peri A truncations and Peri A PKA site mutants using Peri A transgenic and Peri null mice. Our adipocyte and systemic studies will measure basal lipolysis, lipolytic response to beta-adrenergic agents, and antilipolytic response to insulin. These studies will provide in vivo proof of concept tests of how Peri A expression levels, regulatory domains, and phosphorylation sites regulate basal and stimulated lipolysis. These data will be directed to the prevention and treatment of diabetes, hyperlipidemia and other obesity - associated disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050647-06
Application #
6898761
Study Section
Metabolism Study Section (MET)
Program Officer
Haft, Carol R
Project Start
1999-01-15
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$340,775
Indirect Cost
Name
Tufts University
Department
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Rogers, Nicole H; Perfield 2nd, James W; Strissel, Katherine J et al. (2010) Loss of ovarian function in mice results in abrogated skeletal muscle PPARdelta and FoxO1-mediated gene expression. Biochem Biophys Res Commun 392:1-3
Miyoshi, Hideaki; Souza, Sandra C; Endo, Mikiko et al. (2010) Perilipin overexpression in mice protects against diet-induced obesity. J Lipid Res 51:975-82
Rogers, Nicole H; Perfield 2nd, James W; Strissel, Katherine J et al. (2009) Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology 150:2161-8
Rogers, Nicole H; Witczak, Carol A; Hirshman, Michael F et al. (2009) Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochem Biophys Res Commun 382:646-50
Danilova, Olga V; Tai, Albert K; Mele, Deanna A et al. (2009) Neurogenin 3-specific dipeptidyl peptidase-2 deficiency causes impaired glucose tolerance, insulin resistance, and visceral obesity. Endocrinology 150:5240-8
Shen, Wen-Jun; Patel, Shailja; Miyoshi, Hideaki et al. (2009) Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. J Lipid Res 50:2306-13
D'Eon, Tara M; Rogers, Nicole H; Stancheva, Zlatina S et al. (2008) Estradiol and the estradiol metabolite, 2-hydroxyestradiol, activate AMP-activated protein kinase in C2C12 myotubes. Obesity (Silver Spring) 16:1284-8
Miyoshi, Hideaki; Perfield 2nd, James W; Obin, Martin S et al. (2008) Adipose triglyceride lipase regulates basal lipolysis and lipid droplet size in adipocytes. J Cell Biochem 105:1430-6
Gauthier, Marie-Soleil; Miyoshi, Hideaki; Souza, Sandra C et al. (2008) AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte: potential mechanism and physiological relevance. J Biol Chem 283:16514-24
Strissel, Katherine J; Stancheva, Zlatina; Miyoshi, Hideaki et al. (2007) Adipocyte death, adipose tissue remodeling, and obesity complications. Diabetes 56:2910-8

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