The Molecular Biology of Feeding Behavior 
Jeffrey M. Friedman, M.D., Ph.D. — Assistant Investigator 
Dr. Friedman is also Assistant Professor at the Rockefeller University. He received his B.S. and M.D. degrees 
upon completion of the Renssalaer Polytechnic Institute- Albany Medical College medical program. After 
completing a residency in internal medicine at Albany Medical College and a gastroenterology fellowship 
at Cornell University Medical College, Dr. Friedman enrolled in the graduate program at Rockefeller, 
where he received his Ph.D. degree for studies with James Darnell. 
EXTENSIVE studies of humans and other organ- 
isms have suggested that body weight, body 
composition (percent body fat) , and food intake 
are under strict physiologic control. The set 
point hypothesis predicts that both energy intake 
and expenditure are physiologically regulated in 
a particular individual to maintain a predeter- 
mined body weight. Implicit in this hypothesis is 
the notion that signal molecules that reflect the 
nutritional state of an individual are synthesized 
in the body (the periphery) . The levels of these 
signals are sensed by control centers in the brain 
so that an appropriate response is generated to 
maintain a stable body weight. Studies in which 
separate regions of the rodent brain have been 
lesioned suggest that this feeding control center 
resides at least in part in the hypothalamus. The 
site of synthesis of the molecules that signal nu- 
tritional state is unknown, although fat cells, in- 
testinal cells, or other cells of the gastrointestinal 
tract have been suggested. A knowledge of the 
site of synthesis and the molecular nature of the 
signals that aff'ect brain centers controlling 
appetite could have important implications for 
our understanding of nutritional disorders in 
humans. 
To understand more about these signaling 
mechanisms, we have been utilizing genetic and 
molecular biologic approaches to study the role 
of specific gene products in the control of feed- 
ing behavior and body composition. (The studies 
that aim to clone the mutant obesity genes ob and 
db from mice have been supported by the Na- 
tional Institute of Diabetes, Digestive, and Kid- 
ney Diseases.) 
Molecular Basis of Obesity in ob/ob 
and db/db Mice 
If one wishes to understand the basis for differ- 
ences in the complicated system of energy ho- 
meostasis, there are a number of experimental 
advantages to studying mutant mice, including 
the ability to control the animals' environment 
and to set up genetic crosses. In collaboration 
with Rudolph Leibel, we have begun a study of 
mice carrying recessive mutations that result in 
profound obesity. At least four different muta- 
tions in mice that cause obesity are available for 
study: obese {ob), diabetes {db), fatty (fat), and 
tubby {tub). In each case, a mouse becomes 
obese because of a defect in a single gene. 
We have focused on the ob and db mutations 
for several reasons. Mutant ob and db mice be- 
come profoundly obese, often weighing three 
times as much as normal mice. As in humans, the 
obese phenotype in mutant animals appears to 
result from both increased food intake and dimin- 
ished energy expenditure. Furthermore, Douglas 
Coleman at the Jackson Laboratory has suggested 
that ob mice are missing a circulating factor that 
suppresses appetite and that db mice, which are 
unable to respond to the ob factor, may be miss- 
ing the receptor for this factor. 
Current techniques in molecular genetics, 
such as Southern blots and chromosome walking, 
make it possible to clone genes, such as ob and 
db, whose function is known on the basis of 
a mutant phenotype but whose gene product is 
unknown. This approach makes extensive use 
of restriction fragment length polymorphisms 
(RFLPs), which are genetic markers defined by 
specific cloned pieces of DNA. The first step in 
this approach makes use of genetic crosses be- 
tween obese (or diabetic) mice and normal mice 
in which the pattern of inheritance of the obese 
phenotype is compared with that of RFLPs. Spe- 
cific RFLPs that are inherited along with the 
obese phenotype are said to be linked genetically 
to the obesity gene. 
By performing this analysis on several hundred 
mice with several dozen different RFLPs we have 
been able to identify a series of different RFLPs 
that are tightly linked to the ob and db genes. 
RFLPs that are genetically linked to these muta- 
tions are in physical proximity to ob and db and 
can be used as starting points to characterize the 
adjacent DNA and clone the mutant genes. In the 
case of ob mice, we have used three different 
RFLPs for several genes, including the met onco- 
gene, a pancreatic enzyme carboxypeptide A, the 
irp gene, and the cystic fibrosis gene, to generate 
a detailed genetic map around the ob locus. Simi- 
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