Interactions of sympathetic nervous and melanocortin systems in obesity reversal

Georgia State University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): An estimated 65% of American adults are overweight or obese and this number is rising. There is emerging evidence that high amounts of visceral fat increases a person's risk for developing cardiovascular disease, hypertension and diabetes. More is known about the transition from lean to obese than the reverse. We use the Siberian hamster (Phodopus sungorus) animal model because they are obese during long 'summer-like'days in nature and naturally reverse to a leaner state in short 'winter-like'days. Therefore, these animals can be studied in the obese, lean and transition states by altering their lighting conditions in the laboratory thereby providing a biologically meaningful model without genetic manipulation. Reports from the Bartness laboratory have been instrumental in delineating connections between body fat and the brain and ascribing function to these connections. Neuronal influence on the sympathetic nervous system has been found to be the principle initiator of fat mobilization (lipolysis) in a fat depot specific manner;this is true in hamsters and humans. Changes in the processes involved in lipid mobilization can be assayed by measuring sympathetic drive and by-products of intracellular cascades (phosphorylation of perilipin, adipose triglyceride lipase) after sympathetic activation. The first specific aim proposes looking at changes in lipolysis using a new in vivo marker of phosphorylation -- perilipin, an intracellular protein that in the non-phosphorylated state protects lipid droplets from breakdown, as well as measuring sympathetic drive via norepinephrine turnover and finally glycerol and free fatty acid (products of lipolysis) concentrations in blood of food deprived hamsters. To our knowledge, this will be the first in vivo measure of phosphorylation of perilipin though it is well established as one of the last necessary steps of lipolysis in vitro. The second specific aim will test how specific brain sites involving the melanocortin system and the sympathetic nervous system circuits to fat is involved in lipolysis using the same measures as the first aim. This is important to understand because mutations of melanocortin peptides or receptors account for 6-8% cases of obesity seen in humans. Collectively, these experiments will test how regional changes in fat depots occur in response to environmental stimuli and neurochemical stimulation that activate brain-sympathetic nervous system-white fat connections to trigger lipolysis and thus are important to understand for obesity reversal. This will be accomplished using a unique, naturally occurring, intact, obese animal model employing innovative markers of lipolysis. Thus, the results of these studies will contribute important and relevant knowledge of the mechanisms of lipid mobilization and of the process of obesity reversal.