University of California, San Francisco School of Medicine
Our laboratory has a longstanding interest in the impact of genetic and psychological factors on the central nervous system regulation of feeding and energy balance. Our focus on the brain serotonin system led us to identify the serotonin 5-HT2C receptor as a key contributor to the suppression of appetite by this neurotransmitter system. We have characterized an eating disorder in animals bearing mutations of the gene encoding this receptor. 5-HT2C receptor mutant mice overeat and develop a late onset ("middle-age") obesity associated with physiological changes characteristic of common human obesity syndromes. We have recently identified a novel physiological mechanism underlying the late onset development of obesity in these animals: although their resting metabolic rates do not change during this period, the energy efficiency of their physical activity ("miles per gallon") increases with age. Thus regulation of activity-related energy expenditure may be dissociable from resting metabolism, and contribute to the predisposition of mice, and possibly people, to develop increased adiposity with age. In addition, the reduced sensitivity of these mice to serotonergic appetite suppressants has resulted in widespread efforts to target drugs to this receptor for the treatment of obesity.
In the course of this work, we pursue novel approaches that combine genetic manipulation, detailed behavioral assessment, and information technology for a "behavioral informatics" approach permitting comprehensive examination of mouse feeding habits and "lifestyles". We have developed automated high resolution data collection hardware and analytical algorithms to examine behavioral patterns, including patterns of food-seeking and ingestion. Such examination of "lifestyles' in obese strains of mice reveals heterogeneity in eating and activity patterns reflecting diversity in the neuropsychological mechanisms through which genetic factors can lead to obesity. In addition, our laboratory participates in the "Mouse Phenome Project", an international effort for characterizing genetic influences on biological processes, such as feeding and energy balance in inbred mouse strains. Our analysis of behavioral patterns in diverse inbred strains reveals that daily patterns of food intake are extremely variable among strains and highly sensitive to genetic endowment. We are developing novel analytical and computational modeling approaches for these complex behavioral datasets and have established a "mouse lifestyle database" that will provide insights into the impact of genes, drugs and environment on feeding behavior and energy balance.
1550 4th Street, Bldg 19B
San Francisco CA 94158
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