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Research Mission

The academic mission of our laboratory is to forward the understanding and treatment of obesity and related metabolic disorders by combining basic science research with clinical expertise. Obesity has reached epidemic proportions and is frequently associated with multiple metabolic abnormalities including insulin resistance, glucose intolerance, dyslipidemia, and hypertension. These metabolic abnormalities, known as the metabolic syndrome, are major contributors to morbidity and mortality. Our research focuses on defining the mechanisms by which intracellular steroid and lipid metabolism contribute to obesity and the metabolic syndrome with a current emphasis on the following research areas:
1) The role of tissue-specific glucocorticoid metabolism in the pathogenesis of obesity and the metabolic syndrome;
2) The role of tissue-specific lipid metabolism in obesity and the metabolic syndrome.

Metabolic Syndrome

Fig 1: Pathogenesis of the metabolic syndrome

Tissue-specific abnormalities in intracellular steroid and lipid metabolism lead to local metabolic abnormalities and eventually to systemic metabolic abnormalities. Metabolic dysfunction in specific tissues may be primary and/or secondary to dysfunction in other tissues. The metabolic syndrome (visceral obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension) is a major contributor to morbidity and mortality from a variety of causes including cardiovascular disease, liver disease, and diabetes. Understanding tissue-specific lipid and steroid metabolism will contribute to the understanding and treatment of these increasingly prevalent metabolic disorders.

1) The role of tissue-specific glucocorticoid metabolism in the pathogenesis of obesity and the metabolic syndrome.

Glucocorticoids are steroid hormones that have profound influences on metabolic processes. Glucocorticoid action, however, depends not only on circulating glucocorticoid concentrations and glucocorticoid receptor expression, but also on tissue specific glucocorticoid metabolism by 11βhydroxysteroid dehydrogenase enzymes (11βHSDs). We have demonstrated that overexpression of the glucocorticoid-inactivating 11βHSD2 isoform exclusively in adipocytes protects against obesity and the metabolic syndrome in mice (Kershaw et al., Diabetes, 2005). Conversely, overexpression of the glucocorticoid-activating 11βHSD1isoform exclusively in adipocytes promotes obesity and the metabolic syndrome in mice (Masuzaki et al., Science, 2001). These data underscore the importance of tissue-specific glucocorticoid metabolism in systemic metabolic disease, and implicate adipose tissue as a key effector tissue in this process. In addition, these animal models are invaluable tools to study the pathogenesis of the metabolic syndrome. We are currently working to define the mechanisms by which tissue-specific glucocorticoid action contributes to the metabolic syndrome in adipose tissue as well as other metabolically relevant tissues (i.e. skeletal muscle). These studies will provide important insights into the understanding and treatment of obesity and the metabolic syndrome.

Glucocorticoid Metabolism

Fig 2: Tissue-specific regulation of glucocorticoid (GC) action by 11 beta hydroxysteroid dehydrogenases (11βHSDs)

Glucocorticoids (GCs) are adrenal steroid hormones that are well known to regulate multiple metabolic processes. Serum GC concentrations are regulated by the classical hypothalamic-pituitary-adrenal feedback loop. GC action in target tissues, however, depends not only on circulating GC concentrations and cellular GC receptor expression, but also on tissue-specific intracellular GC metabolism by 11βHSDs. 11βHSDs catalyze the interconversion of hormonally active 11β-hydroxylated GCs and their hormonally inactive 11β-keto metabolites. The type 1 isoform (11βHSD1) functions as a NADPH-dependent reductase to activate GCs and is expressed in GC-dependent target tissues such as adipose tissue, liver, skeletal muscle, and the central nervous system. The type 2 isoform (11βHSD2) functions as a NAD+-dependent dehydrogenase to inactivate GCs and is expressed in mineralocorticoid-dependent target tissues such as kidney, colon, and sweat glands. Thus, 11βHSD1 amplifies while 11βHSD2 reduced GC action in a tissue-specific manner. Dysregulation of these enzymes has been proposed to contribute to metabolic disease.

2) The role of tissue-specific lipid metabolism in obesity and the metabolic syndrome.

Lipids serve a variety of critical metabolic functions including energy storage, cell signaling, and membrane composition. Abnormalities in lipid metabolism and intracellular lipid accumulation are highly associated with insulin resistance and its complications (i.e. heart disease). Using the above animal models of the metabolic syndrome in combination with microarray analysis of genes induced during adipogenesis, we have identified several novel glucocorticoid-regulated adipocytes genes that are potential pathogenic factors and/or therapeutic targets for the metabolic syndrome. Two such genes, adipose triglyceride lipase (ATGL, PNPLA2) and adiponutrin (PNPLA3), are the founding members of a novel family of lipid-metabolizing enzymes in mammals known as the patatin-like phospholipase A domain containing (PNPLA) family. Our work, in combination with the work of others, has established ATGL as the rate-limiting enzyme mediating triglyceride hydrolysis arguably one of the most essential functions in metabolism. We have also demonstrated that ATGL and related PNPLA family membranes are highly regulated by important nutritional and hormonal factors (Kershaw et al., Diabetes, 2006 and Kershaw et al., Am J Physiol Endocrinol Metab, 2007), suggesting that these proteins play critical roles in metabolism. We are currently working to define the function and physiological relevance of ATGL and related PNPLA family members. These studies will provide important insights into the contribution of lipid metabolism to metabolic disease with the goal of identifying novel targets for therapeutic intervention.

Lipolysis

Fig 3: The revised model of lipolysis in adipocytes

The identification of adipose triglyceride lipase (ATGL, PNPLA2) has led to a complete revision of the traditional model of lipolysis: In the basal state, CGI-58 is closely associated with perilipin A on the lipid droplet where perlipin A has a barrier function to lipolysis. Hormone sensitive lipase (HSL) is primarily located in the cytosol and ATGL is primarily localized to the lipid droplet but not in proximity CGI-58. Here, ATGL mediates basal triacylglycerol (TG) hydrolysis, which in the absence of further HSL-mediated diacylglycerol (DG) hydrolysis, allows for generation of glycerophospholipids and/or re-esterification into TG. In the stimulated state, phosphorylation of perilipin A promotes the release of CGI-58 which then translocates to ATGL to promote ATGL-mediated TG hydrolysis. At the same time phosphorylation of HSL promotes its translocation to the lipid droplet where it interacts with perilipin A to promote DG hydrolysis and hence complete lipolysis. The above model applies to adipocyte lipolysis. The mechanisms mediating lipolysis and the proteins involved in the process in other tissues remain largely unknown.