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214. 
GENETICS OF OBESITY AND TYPE II DIABETES 
Jeffrey M. Friedman, M.D., Ph.D., Assistant Investigator 
The assimilation, storage, and disposition of nu- 
trient energy constitute a complex homeostatic sys- 
tem central to the survival of metazoa. In vertebrates 
and particularly among land-dwelling mammalian 
species, the ability to store large quantities of food 
in the form of adipose tissue triglycerides is crucial 
for surviving long periods of food deprivation. To 
maintain such food stores without sustaining contin- 
ual alterations in the size and shape of the organism, 
a balance between energy intake and expenditure 
must be achieved. Despite intensive investigation, 
the molecular mechanisms that regulate energy in- 
take and energy expenditure remain to be eluci- 
dated. It is anticipated that the identification of mol- 
ecules that transduce nutritional information and 
regulate these functions will be critical to the un- 
derstanding of the regulation of body weight in 
health and in disease states such as cancer. 
Detailed metabolic and behavioral studies in hu- 
mans and other mammals have suggested that spe- 
cific central and peripheral neural circuits sense 
and react to both the overall nutritional state and 
recent food intake of an organism. From this work a 
hypothesis has emerged that posits a "set point" for 
determining how much the individual should 
weigh. Deviations in weight from the set point re- 
sult in compensatory changes in food intake and en- 
ergy expenditure that generally return the individ- 
ual's weight to some genetically determined level. 
This set point hypothesis predicts that the levels 
of peripherally synthesized molecules (hormones 
perhaps) reflect the nutritional state of an individ- 
ual and that these levels, these "satiety factors," are 
sensed by feeding control centers in the hypothala- 
mus and elsewhere. The identity of satiety factors, 
however, remains to be elucidated. Dr. Friedman's 
laboratory is taking a genetic approach in the analy- 
sis of factors involved in the control of feeding be- 
havior. This involves ongoing attempts to clone sev- 
eral rodent obesity genes: obese (ob), diabetes 
(db),fat, and tubby (tub). To date, the most inten- 
sive efforts have been aimed at the molecular clon- 
ing of the recessive ob and db mutations that result 
in profound obesity. (This work is funded by the 
National Institute of Diabetes and Digestive and Kid- 
ney Diseases, National Institutes of Health.) 
The obesity in these mutant animals is the result 
of abnormalities in feeding behavior and energy ex- 
GENETICS 1 9 1 
