Download Leukocytes fighting against obesity

Molecular Psychiatry (1998) 3, 8–9
 1998 Stockton Press All rights reserved 1359–4184/98 $12.00
NEWS & VIEWS
Leukocytes fighting against obesity
Mice deficient in the leukocyte adhesion receptor ICAM-1 or MAC-1 become obese without
overeating.
There are many indications that obesity is a genetic
disease which results when a variety of environmental
factors act on multiple genes to influence our eating,
metabolism and energy expenditure.1,2 During the past
several years, researchers have linked mutations in five
different genes (ob, db, tub, Ay, and fat) to obesity in
mice.3 Isolated cases of obesity in humans have
recently been identified which also result from a
mutation in some of these genes.4 However, all of these
known genes regulate body fat mainly by affecting
appetite. Mutations in any of these five genes cause a
significant increase in food intake.5–7 Considering the
fact that some individuals remain fat despite constant
dieting while others eat whatever they want without
gaining a pound,8 researchers have begun to speculate
whether some genes contribute to obesity without
increasing appetite. We have now found two candidate
genes of this kind in mice.9 These genes encode for the
intercellular adhesion molecule 1 (ICAM-1, CD54) and
the integrin Mac-1 (aMb2, CD11b/CD18).
Both ICAM-1 and Mac-1 were discovered more than
a decade ago.10 They form a receptor and counterreceptor pair. ICAM-1 is expressed on leukocytes, endothelium and many other types of cells to which leukocytes need to adhere.11 Mac-1 is found only on the
surface of leukocytes.10 Because they both mediate leukocyte adhesion to endothelial cells, many studies
have focused on determining their role in inflammatory
and immune responses. As expected, researchers have
found that both molecules are involved in a number of
inflammatory diseases.11,12 But no one expected that
they also play a role in obesity.
Our recent finding that these two known molecules
are involved in obesity was accidental. Initially, our
study examined the role of ICAM-1 in atherosclerosis
(the narrowing of the arteries) by comparing lesion
development in wild-type mice and mice deficient in
ICAM-1 (ICAM-1 −/−) that were obtained by targeted
disruption of the ICAM-1 gene.13 Because it was a longterm experiment in which mice were fed on high fat
diets for several months, we were lucky to notice that
Correspondence: DD Wagner, Center for Blood Research, Harvard
Medical School, 800 Huntington Avenue, Boston, MA 02115,
USA. E-mail: wagnerKcbr.med.harvard.edu
ICAM-1 −/− mice became obese on the diet while wildtype mice gained significantly less weight. Later we
noticed that the ICAM-1 −/− mice became spontaneously obese in old age on normal mouse chow.
We allowed two groups of mice, wild-type and
ICAM-1 mutants, to eat unlimited amounts of mouse
chow which only contained 5% fat. Every 2 weeks, we
weighed the mice and measured the amount of food
they had eaten. ICAM-1 −/− mice maintained a body
weight comparable to wild-type animals until 16 weeks
of age, after which they gradually put on more weight.
At 24 weeks of age, both male and female ICAM-1 −/−
mice weighed about 21% more than the wild-type controls even though they ate the same amount of food.
As the mutants aged, their weight gain still progressed;
this occurred especially among the female mice. At 45
weeks of age, female mutants were heavier than controls by about 47% (see the cover of this issue of Molecular Psychiatry). By taking out the white fat pads
from the mice and weighing them, we also confirmed
that the excess body weight in ICAM-1 −/− mice was
due to increased white fat. Compared to the other five
known genetically obese mice, ICAM-1 −/− mice begin
to gain weight at an older age. The tub mice become
obese starting at 9–12 weeks of age,14 whereas the other
four mouse mutants (fat, Ay, ob, and db) become obese
at an age younger than 9 weeks.6 The ob and db mice
actually begin rapid weight gain soon after birth.6
Because maturity-onset obesity is reminiscent of the
pattern of weight gain commonly observed in human
populations, we expect that ICAM-1 −/− obese mice
will become an interesting animal model for studying
human obesity. Furthermore, as mentioned earlier, all
five known genetically obese mice have big appetites.
For example, ob mice eat 62% more food than normal
mice,5 and agouti yellow (Ay) mice consume 36% more
food than controls.6 Recent studies suggest that most
of these mice have a problem maintaining normal brain
function for controlling food intake.2 Unlike these
mice, ICAM-1 −/− mice develop a maturity-onset obesity without an obvious increase in appetite. Therefore,
we suspect that ICAM-1 regulates adiposity by a
mechanism(s) independent of affecting function of the
brain’s food center.
Considering that a high fat diet is one of the accelerating factors which contribute to obesity,1 we also
News & Views
observed the body weight response of ICAM-1 −/− mice
when offered a Western-type diet containing a similar
amount of fat to foods found in the Western World
(21% fat). Even at 7 weeks of age, mutant mice rapidly
gained more weight than controls while consuming the
same amount of Western-type diet. Female mutants
were more susceptible to weight gain. Furthermore, the
sexes also put on weight in different places. The excess
white fat in males was composed mainly of subcutaneous fat. In females, the major component was intraabdominal fat resulting in prominent abdominal obesity. The gender response in ICAM-1 −/− mice does not
mimic human obesity very well, because it is men who
usually develop the beer bellies.
We have further characterized ICAM-1 −/− mice in
an obesity-related phenotype. Like most obese animals
and humans, they had fatty livers, hyperlipemia and
hyperglycemia.2,6 But even when they finally
developed an obesity-diabetes syndrome, they did not
have obvious hyperinsulinemia. Because these mice
became spontaneously obese at a mature age, they
therefore did not show any severe fertility defects.
Since ICAM-1 is not restricted to leukocytes, it was
difficult to conclude which type of cells are involved
in the obesity phenotype. To search for a cell target,
we examined the susceptibility of the mice deficient
in Mac-1 to diet-induced obesity because Mac-1 is a
counterreceptor for ICAM-1 and it is a leukocyte-specific molecule.10 Mac-1 mutants indeed showed a similar obesity phenotype. Our results suggest that the Mac1/ICAM-1 pathway(s) of leukocyte adhesion play a role
in regulating body weight and adiposity.
For now, the molecular mechanisms responsible for
the absence of ICAM-1 or Mac-1 which results in obesity in mice are not clear. We suspect that there are multiple events which combine together to decrease energy
expenditure and/or increase efficiency of fat accumulation in these mice. For example, a defect in leukocyte
communication with fat cells in adipose tissues or with
hepatocytes in the liver due to a reduction of some special cytokines or chemical mediators may influence the
efficiency of fat storage or metabolism. We have begun
to search for the ICAM-1 or Mac-1 mutations in
obese humans.
ZM Dong and DD Wagner
Center for Blood Research
Dept of Pathology, Harvard Medical School,
Boston, MA 02115, USA
References
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