The current obesity epidemic is driving a dramatic increase in the metabolic syndrome (syndrome X), a constellation of disorders that includes diabetes, dyslipidemias and hypertension. This proposal takes a broad approach to understanding the molecular mechanisms that account for effects of the orphan receptor SHP in most, if not all of the primary aspects of this syndrome. When subjected to appropriate stresses, SHP null mice exhibit a number of intriguing phenotypes including loss of negative feedback regulation of bile acid biosynthesis, loss of an acute inhibitory effect of bile acids on hepatic triglyceride production, resistance to diet induced obesity, increased insulin sensitivity, and resistance to the combined hypertensive effects of increased aldosterone and renin and decreased expression of the atrial and B-type natriuretic peptide genes. The overall goal of this proposal is to characterize the physiologic effects of the loss of SHP and define the molecular basis for these effects.
The specific aims are to: 1) Generate appropriate specific knockout and transgenic gain of function models to facilitate studies of tissue specific effects of SHP. 2) Characterize the role of increased brown adipose tissue activity in the obesity resistance of the SHP deficient mice and define the molecular basis for this increased activity. 3) Characterize the physiologic basis for the increased insulin sensitivity of the SHP-/- mice and identify molecular mechanisms that contribute to this effect. 4) Characterize the basis for the increased activity of multiple hypertensive pathways in the SHP knockouts and their resistance to the effects of these pathways. We believe that identifying the specific mechanisms that account for the effects of the loss of SHP function will provide new insights into the interlocking mechanisms that result in metabolic homeostasis and new approaches to addressing metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068804-03
Application #
7210533
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2005-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$441,263
Indirect Cost
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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