Excessive caloric intake is sensed by the brain, which then activates thermogenesis as a means of preventing obesity. The sympathetic nervous system, through beta-adrenergic receptor (betaAR) action on target tissues, is likely the efferent arm of this homeostatic mechanism. To test this, mice lacking the three betaARs (beta-Iess mice) have been generated. Beta-less mice on a chow diet have reduced metabolic rate and are slightly obese. On a high-fat diet, beta-Iess mice develop massive obesity that is due entirely to failure of diet-induced thermogenesis. These findings establish that betaARs are necessary for diet-induced thermogenesis and that this pathway is critical in the defense against diet-induced obesity. Evidence supports the view that brown fat may be responsible for diet-induced thermogenesis, and that UCP1-driven uncoupled respiration is the intracellular mechanism. However, arguing strongly against this is the fact that UCP1 gene knockout mice, despite being cold sensitive, are lean and resist diet-induced obesity. The overall goal of this proposal is to identify the tissues and pathways which mediate diet-induced thermogenesis.
Specific Aim #1 : To establish which betaAR subtypes mediate diet-induced thermogenesis and protection from diet-induced obesity.
Specific Aim #2 : To identify the target tissue mediating diet-induced thermogenesis and protection from diet-induced obesity.
Specific Aim #3 """""""" To establish a model of complete and specific brown adipose tissue deficiency in order to determine if brown fat plays a role in diet-induced thermogenesis and protection from diet-induced obesity.
Specific Aim #4 : To determine the role of betaAR signaling in mediating thermogenesis caused by central activation of leptin and melanocortin-4 (MC4) receptors.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Nutrition Study Section (NTN)
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Yanovski, Susan Z
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Beth Israel Deaconess Medical Center
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