The basis for this proposal i the hypothesis that leptin regulates energy utilization through sympathetic modulation of uncoupling protein expression and function. Leptin is a small protein that is secreted by white adipocytes and widely thought to function as a lipostat which regulates the balance between energy intake and energy utilization to maintain nutritional homeostasis. Circulating leptin levels are positively correlated to fat stores. ob/ob mice do not produce leptin due to a point mutation that creates a premature stop codon in the leptin gene. These mice are characterized by morbid obesity, hyperphagia, low sympathetic output, compromised thermogenic capacity and enhanced energy efficiency. Leptin therap corrects the defects in part by stimulating energy utilization through a concomitant increase in thermogenic activity in adipose tissue. Thermogenic capacity, particularly of the brown adipose tissue (BAT), is conferred by the expression of uncoupling protein UCP. UCP causes a proton leak, thereby collapsing the mitochondrial proton gradient which normally drives ATP synthesis. This uncoupling of respiration from ATP synthesis generates heat instead of stored energy. It is thought that an important function of this mechanism is to dissipate surplus caloric energy. Recently two more uncoupling proteins UCP2 and UCP3 have been described that are expressed more widely, particularly in white adipose tissue WAT (UCP2) and skeletal muscle (UCP3).
Specific aims are proposed to test three hypotheses: (1) leptin regulates UCP1 UCP2 and UCP3 mRNA and expression in adipose tissue (brown adipose tissue and skeletal muscle in case of UCP3); (2) leptin regulates UCP1 (UCP3) expression by increasing sympathetic outflow and activating the beta3-adrenergic receptor and (3) induction of UCP1 and UCP2 expression enhances thermogenic responsiveness of white adipose tissue to cAMP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK053981-02
Application #
2906218
Study Section
Metabolism Study Section (MET)
Program Officer
Yanovski, Susan Z
Project Start
1998-07-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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