Molecular Biology of Obesity and Diabetes 
Jeffrey M. Friedman, M.D., Ph.D. — Assistant Investigator 
Dr. Friedman is also Associate Professor and Head of Laboratory at the Rockefeller University. He received 
his B.S. and M.D. degrees from the Renssalaer Polytechnic Institute-Albany Medical College. After 
completing a residency in internal medicine at Albany Medical College and a gastroenterology fellowship 
at Cornell University Medical College, he enrolled in the graduate program at Rockefeller, where he 
received his Ph.D. degree in molecular biology. 
EXTENSIVE studies of humans and other organ- 
isms have suggested that body weight, body 
composition (percent body fat) , and food intake 
are under strict physiological control. The "set 
point" hypothesis holds that both the intake and 
expenditure of energy are physiologically regu- 
lated in the individual to maintain a predeter- 
mined body weight. Implicit in this hypothesis is 
the notion that signal molecules reflecting the 
nutritional state are synthesized in the periphery 
and sensed by brain centers whose appropriate 
response is set to stabilize body weight. 
Studies in which the rodent brain has been se- 
lectively lesioned suggest that this feeding con- 
trol center resides, at least in part, in the hypothal- 
amus. However, the site of synthesis of the 
molecules that signal nutritional state is un- 
known, though fat cells or cells of the gastrointes- 
tinal tract have been proposed. Knowledge of the 
site of synthesis and the molecular nature of sig- 
nals aff'ecting the control of appetite and body 
composition could have important implications 
for our understanding of nutritional disorders. 
To learn more about these signaling mecha- 
nisms, we have been taking a variety of ap- 
proaches, both genetic and molecular, to study 
the role of specific gene products in the control 
systems. 
Molecular Basis of Obesity in oh/ 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 for environment and to set 
up genetic crosses. For these reasons, we have 
begun a study of mice carrying recessive muta- 
tions that result in profound obesity. At least four 
obesity-causing mutations are available: obese 
(ob), diabetes (db),fat (fat), and tubby (tub). 
In each case, a mouse becomes obese because of a 
single-gene defect. We have focused on the ob 
and db mutations for several reasons. The mutant 
mice become very obese, often three times nor- 
mal weight; and the obese phenotype in mutant 
animals, as in humans, appears to result from 
both increased food intake and diminished en- 
ergy expenditure. Furthermore, Douglas Cole- 
man at the Jackson Laboratory has suggested that 
ob mice lack a circulating factor that suppresses 
appetite and that db mice, which are unable to 
respond to this factor, may lack its receptor. 
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 mu- 
tant phenotype but whose gene product is un- 
known. This approach, called positional cloning, 
utilizes restriction fragment length polymor- 
phisms (RFLPs) — genetic markers defined by spe- 
cific cloned pieces of DNA. These markers define 
genetic differences in inbred mouse strains. The 
first step in attempts to clone a mutant gene uti- 
lizes genetic crosses between normal and obese 
(or diabetic) mice. Inheritance of the obese phe- 
notype is compared in individual animals with 
that of individual RFLPs, which if inherited along 
with the obese phenotype, are said to be linked 
genetically to the obesity gene. 
By performing this analysis on several thousand 
mice with several dozen different RFLPs, we have 
been able to identify a series of DNA probes that 
are very tightly linked to the ob and db genes. 
RFLPs linked genetically to these mutations 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 first used three dif- 
ferent RFLPs to generate a detailed genetic map 
around the ob locus. The genes represented were 
the met oncogene carboxypeptidase A, which 
codes for a pancreatic enzyme; the trp gene; and 
the cystic fibrosis gene. Similarly, the mouse db 
gene has been mapped relative to RFLPs for inter- 
feron-a and a complement gene. We have also 
found that the rat obesity mutation fatty (fa) is 
also flanked by the genes for interferon-a and 
* Studies aimed at cloning the mutant obesity genes ob and 
db from mice have been supported by the National Institute 
of Diabetes and Digestive and Kidney Diseases. 
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