MORE GENETIC PIECES IN THE OBESITY PUZZLE
By Sean Henahan, Access Excellence
BAR HARBOR, MAINE-
The recent discovery of another gene
associated with obesity could help explain the physiological
mechanisms of overeating, obesity and certain types of diabetes,
Late last year researchers identified the 'obese gene' or
'ob'. The 'ob' gene appears to play a role in the signaling
pathway from adipose tissue that in turn regulates the amount of
stored body fat. Mutation of this single gene is associated with
development of profound obesity and non-insulin dependent
diabetes in mice. The syndrome in mice closely parallels morbid
obesity in humans,
The researchers also cloned and sequenced the human
homologue of the 'ob' gene. The human homologue matches 84% of
the murine nucleotide sequence. Moreover, further investigations
revealed that the ob gene appears to be conserved in most if not
all vertebrate DNA, suggesting a long heritage.
Now, researchers at Jackson Laboratories, Bar Harbor,
Maine, have discovered another gene in mice that affects both
obesity and diabetes, dubbed 'fat' , on Chromosome 8. Mutations
in the 'fat' gene appear to affect metabolism rather than
regulating appetite. Single mutations in the gene prevent mice
from synthesizing carboxypeptidase E, a key enzyme involved in
processing insulin. Carboxypeptidase E (CPE) helps convert the
insulin precursor proinsulin into insulin.
Contrary to expectations, the mice with the mutated 'fat'
gene, although obese, did not have insulin resistance, although
they did have elevated blood sugar levels. Insulin resistance is
seen in humans with adult-onset type II diabetes, the type often
seen in obese people. Rather, it appeared the poor biologic
function of the mice's own insulin was due to the build-up and
release of the less-active precursor, proinsulin.
"The fat mutation represents the first demonstration of
an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway.
What we set out to do was to find an obesity mutation, but what
we ended up finding was a generalized defect in hormone
processing. At this point, we don't really know what the cause
for the obesity is. It could be a defect in the insulin
processing, but it could equally as well be a defect in the
processing of a variety of other hormones in the brain. And that
is the next thing to find out.
"The problem we now have is to identify how many of these
hormones have to be processed normally by CPE if obesity is to be
avoided. I think that the significance of our discovery is that
is gives us a way to investigate this whole pathway and what
parts of the pathway are involved in obesity," said Dr. Jurgen
Naggert of the Jackson Laboratory.
The recent discoveries of 'ob' and 'fat' appear to support
the hypothesis that obesity is a heritable trait influenced by
several genes. Single locus mutations associated with obesity are
important they provide clues about pathways involved in fat depot
size in mammals. The current research is likely to lead to the
identification of other genes involved in the control of fat
deposition via interaction with obesity gene products, noted
Peter Keightley, Institute of Cell, Animal and Population
Biology, University of Edinburgh.
Another group of researchers reported further data
regarding the 'ob' gene. Dr. Jose Caro, chairman of the
department of medicine, Jefferson Medical College in
Philadelphia, and colleagues have completed a study suggesting
that in overweight people, the brain ignores appetite
suppression messages sent by the 'ob' gene. This contrasts with
earlier 'ob' gene research suggesting a mutation in the gene as
the root of obesity.
These findings are likely to fuel the ongoing debate on
the physiological mechanisms of appetite and satiety. While there
is a consensus that the hypothalamus plays role in energy balance
(i.e. food intake versus energy output) researchers disagree on
the nature of the feedback loop responsible for regulation of
Proponents of the lipostasis theory maintain that the amount
of body fat is regulated by the central nervous system via a
product of fat metabolism in plasma. Supporters of the
glucostasis theory believe that plasma glucose level is the key
to energy balance regulation. A third group advances the concept
that thermal regulation of food intake interacts with the
central nervous system center responsible for controlling
appetite and satiety.
Identification of the 'ob' and 'fat' genes will open many
new avenues of research into the regulatory mechanism of
adiposity and body weight. In addition to increasing current
understanding of the pathogenesis of obesity, this research could
lead to the development of bioengineered treatments for
nutritional and metabolic disorders.
For more information on 'fat' see Nature Genetics, 6/95,
v.10, Naggert et al., pp 135-141; and Keightley, pp125-126. Dr.
Caro's study appeared in the Journal of Clinical Investigation,
6/95. Also see Nature, 12/1/94, v.372, J. Friedman et al., for
info. on the 'ob' gene discovery.