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Research Summary
Lipid and energy metabolism, insulin resistance, and diabetes
Research Activities
Our research is primarily concerned with cellular and tissue dysfunctions related to aberrant triglyceride (TG) metabolism. Significant emphases are placed on insulin resistance and other metabolic disorders. To better understand the link between increased cellular triglyceride (TG) synthesis in specific tissues and systemic metabolic derangements, we have generated transgenic mice that overexpress a key enzyme in TG biosynthesis, diacylglycerol acyltransferase-1 (DGAT1). Our current research is focused on a mouse model with adipose-specific overexpression of DGAT1. Increase in adiposity and derangements in systemic glucose and lipid metabolism are being investigated. We will also develop transgenic mice that overexpress DGAT1 in muscle to address issues related to muscle lipotoxicity and systemic insulin resistance. Finally, a mouse model with myocardial overexpression of DGAT1 is being developed. Such a mouse model will allow us to study the relationship between abnormal cardiac fuel partition and lipotoxic cardiomyopathy.
In addition to DGAT-related studies, we are also interested in the following two areas related to adipose metabolism and function. 1) Adipocyte aging. This research relates to the hypothesis that adipocytes turn over regularly in adipose tissue, and functions of adipose tissue are in part modulated via tissue remodeling. Age-related functional changes are being characterized in cultured adipocytes, and our further studies will be focused on animal models to measure cell-aging and to determine adipocyte half-lives in vivo. 2) Local rennin-angiotensin system (RAS) in adipose tissue. The presence of a local RAS in adipose tissue is supported by the fact that adipose tissue is capable of producing all necessary components of the RAS, including angiotensinogen, the processing enzymes, and angiotensin receptors. With the availability of ACE (angiotensin converting enzyme) inhibitors and angiotensin receptor antagonists, experiments are designed and will be carried out, first in tissue culture, then in an animal model, to disable the local RAS. Consequences of adipose ARS blockage will be investigated. Specifically, adipocyte turnover, cellular metabolism, and secretory functions will be examined.
Selected Publications:
1. Y. Yu, Y. Zhang, S.L. Sturley, P. Oelkers, D.J. Rader and H.N. Ginsberg. (2002) Posttranscriptional control of the expression and function of diacylglycerol acyltransferase-1 in mouse adipocytes. J Biol Chem
277:50876
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