Write your abstract here.Gene deficiency is a protective barrier to
obesity.
A
search for the molecular
clues of longevity has taken Mayo Clinic
researchers down another path that could explain why some people who
consume excessive calories don’t gain
weight. The study, which was done
in laboratory mouse models, points to the absence of a gene called
CD38. When absent, the gene prevented mice on high-fat diets from
gaining weight, but when present, the mice became obese.
The
findings were published this month in the online issue of The FASEB
Journal, the journal of the Federation of American Societies for
Experimental Biology. The study will appear in the November 2007 print
issue of the journal.
“
Obesity is a complex problem compounded by multiple factors, one of which is
our genes. Genes play a role in about 50 percent of cases, and in this
study, we demonstrate that CD38 regulates body weight,” states Eduardo
Chini, M.D., Ph.D., an anesthesiologist at Mayo Clinic and
corresponding author of the study.
Identifying
the signaling mechanisms that lead to obesity caused by a high-fat,
high-calorie diet is a critical part of understanding and developing
new treatments for obesity, Dr. Chini says.
THE ROLE OF CD38
Research
in animal models has shown that caloric restriction can lower
cholesterol and blood pressure — often considered the biomarkers of
aging. In addition, published research in animal models shows that
caloric restriction, defined as consuming 30 percent to 40 percent less
than your average daily intake, can turn on the SIRT1 gene, one of a
family of seven genes linked to longevity.
In
addition, recent studies have shown that the chemical receptor PGC1
(peroxisome proliferator-activated receptor coactivator) plays a key
role in the development of obesity and control of metabolism. The SIRT
genes activate PGC1 and in doing so, can offset the negative effects of
obesity — at least in mice. But how the SIRT-PGC1 reaction works,
hasn’t quite been explained until now.
In
previous laboratory studies by the Mayo Clinic research team, CD38 was
shown to be involved in regulating a wide variety of signaling
pathways, such as those that regulate energy metabolism. In addition,
recent studies in humans also show a possible connection between CD38
and metabolism, specifically metabolic syndrome. Metabolic syndrome
includes metabolic-related health issues that usually afflict people
who are obese. These health issues include high blood pressure,
elevated insulin levels and high cholesterol levels.
In
this study, researchers investigated and confirmed that CD38 inhibits
SIRT and the expression of PGC1 in mouse models and, as a result,
regulates body weight. In the absence of CD38, the SIRT-PGC1 pathway
was activated and protected mice models from developing obesity.
THE STUDY
Researchers
studied two groups of mice: one with the gene CD38 and the other
without. Each group was fed a high-calorie diet with 60 percent of
calories from fat. In a second test, each group was fed a standard diet
in which 4 percent of calories came from fat.
As
a result, the body fat of mice that carried CD38 and were on a high-fat
diet nearly quadrupled and their body weight almost doubled. After
eight weeks on a high-fat diet, mice with CD38 began to show signs of
glucose intolerance, one of the first indicators of diabetes onset. In
addition, this group of mice lived for only four-to-six months compared
to the second group of mice that lived for 12 months.
For
the group of mice that did not carry CD38, their body fat and weight
did not change even though they were on a high fat diet. These mice
burned more energy, were leaner and otherwise healthy.
“These
changes contributed to the ability of these mice to fend off weight
gain despite a high-fat diet and lack of exercise. Together these
results suggest that a CD38 deficiency has a protective effect against
high-fat, diet-induced obesity,” Dr. Chini says.
RESVERATROL
Dr.
Chini and colleagues also examined the effects of resveratrol in mice.
Resveratrol is a naturally occurring substance found in some plants
such as mulberries, peanuts and red grapes used to make wine. It has
been marketed as a drug that mimics the effects of moderate exercise
without the physical act of exercising and also as a longevity drug,
despite the lack of evidence that resveratrol is safe and effective in
humans.
Mice
with CD38 were treated with 30 milligrams (mg) of resveratrol per day.
And, to determine the effects of the SIRT genes on obesity, mice
without CD38 received the same dose of sirtinol, a drug that shuts down
the SIRT genes.
Researchers
found that mice with CD38 that were treated with resveratrol for two
weeks were protected from high-fat, diet-induced obesity. By contrast,
the protective effect against high-fat, diet-induced obesity in the
absence of CD38 in mice was invalidated by sirtinol. Mice without CD38
that were treated with sirtinol gained a statistically significant
amount of weight when compared with mice without the gene who were not
treated with sirtinol.
This data supports the novel notion that CD38 modulates high-fat, diet-induced obesity by a SIRT- dependent mechanism.
“Together
these results identify a novel pathway regulating body weight and
clearly show that CD38 is a nearly obligatory component of the cellular
cascade that led to diet-induced obesity,” the authors write.
The
authors say the study’s results are promising and should be explored in
follow-up studies that will focus on the quality of life and longevity
in mice.
Source: Mayo Clinic