2010-ASCB-Press-Book - page 8

T h e A m e r i c a n s o c i e t y f o r C e l l B i o l o g y
News from
The American Society
for Cell Biology
50th Annual Meeting
Philadelphia, PA
December 11–15, 2010
Deletion of ghrelin receptor
turns up the heat
Deleting the ghrelin receptor,
but not ghrelin, keeps aging mice
youthfully thin
f you’ve been avoiding the scales in
the locker room, be reassured that fit-
ness encompasses more than diet and
exercise. For example, take ghrelin, the
only circulating peptide known to stimu-
late appetite and promote obesity in both
humans and rodents. The discovery in
1999 of ghrelin’s role in appetite and en-
ergy balance ignited hopes that it was the
body’s long-sought hunger thermostat.
But the ghrelin story has taken some
unexpected turns—partly because appe-
tite is such a complex biological equation
and because ghrelin plays other roles,
such as regulating growth and metabo-
lism. Now comes evidence that it’s not
ghrelin, but the ghrelin receptor, that is
the better candidate for regulating overall
fitness—or at least burning fat to keep
warm and stay thin.
Dr. Yuxiang Sun and her colleagues
at the Baylor College of Medicine in
Houston say that ghrelin itself may not
be as critical to energy expenditure as
its receptor, the growth hormone secret-
agogue receptor (GHS-R). GHS-R acts as
the lock for the keylike ligand ghrelin to
dock; GHS-R then activates downstream
metabolic signal pathways. It’s the ghrelin
receptor, GHS-R, says Sun, that seems to
possess a crucial role in controlling fat
metabolism. GHS-R deletion activates
brown adipose tissue to increase heat
production, which in turn diminishes
white adipose tissues, preventing obesity.
The Baylor researchers were origi-
nally drawn into exploring the relation-
ship between ghrelin and its receptor by
the question of body temperature. Their
laboratory models were two sets of ge-
netically modified mice: one set lacking
the gene to produce ghrelin and the other
lacking the gene for GHS-R. Challenged
by cold and fasting, the mice without
ghrelin could not maintain a normal
body temperature, whereas the mice
without ghrelin’s receptor, GHS-R, kept
themselves nice and toasty.
To see how obesity and physical
activity levels played out over age, the
researchers generated two additional
sets of these mice in two cohorts, one
young (3–4 months) and one older (10–12
months). The researchers compiled a
complete energy metabolic profile for
every mouse, balancing its food intake
against its energy output. Neither food
intake nor activity levels were different
for the mice with the knocked out genes
versus those of normal mice, regardless
of age. Similar to humans, mice gain
weight by accumulating fat as they age.
In contrast, the older GHS-R–null mice
maintained a youthfully lean physiologi-
cal profile with lower circulating lipids.
They exhibited higher energy expenditure
levels, similar to young mice. Older GHS-
R–null mice weren’t more active, only
more exothermic. They burned off more
calories and fat with no extra effort. The
ghrelin-deleted mice, on the other hand,
followed the “older is fatter” pattern.
The researchers compared levels of
UCP1, an uncoupling protein known as
a hallmark regulator of thermogenesis in
brown fat. UCP1 was significantly higher
in the brown fat of GHS-R–deleted mice
but not in ghrelin-deleted mice.
Says Sun, “All this shows the complex-
ity of ghrelin and its signaling pathway
and suggests the existence of additional
unidentified regulators mediating the
effect of ghrelin and/or GHS-R.” Still, Sun
believes that GHS-R clearly has a unique
ability to regulate energy metabolism
without affecting appetite or activity. If so,
it offers a new option for the prevention
or treatment of obesity.
Morphology of interscapular brown fat of older wild-
type (WT), ghrelin-/- , and GHS-R-/- mice. The mor-
phology was very similar between old ghrelin-/- and
their WT counterparts; older GHS-R-/- mice showed
higher percentages of multilobular adipocytes (smaller
fat droplets) and increased cellularity (dark blue nuclei)
indicating higher heat-producing capacity.
10:00 am, U.S. Eastern Time
Monday, December 13, 2010
Yuxiang Sun
Departments of Pediatrics and
Molecular and Cellular Biology
Baylor College of Medicine
One Baylor Plaza, MS 320
1100 Bates, Rm. 5024
Houston, TX 77030
Author presents
Monday, December 13, 2010
1:00 pm–2:30 pm
Session: Aging and Aging-
Related Diseases
Exhibit Halls A/B/C
Program: 1717
Board: B1240
Ablations of Ghrelin and Ghrelin
Receptor Exhibit Differential Meta-
bolic Phenotype and Thermogenic
Gene Expression during Aging
Xiaojun Ma
, Ligen Lin
Marta Fiorotto
, Vishwa D.
, Yuxiang Sun
1 Division of Endocrinology, Depart-
ment of Internal Medicine, First
Affiliated Hospital of Zhengzhou
University, Zhengzhou, China
2 USDA/ARS Children’s Nutrition
Research Center, Department of
Pediatrics, Baylor College of
Medicine, Houston, TX
3 Laboratory of Neuroendocrine-
Immunology, Pennington Biomedical
Research Center, Louisiana State
University System, Baton Rouge, LA
4 Huffington Center on Aging, Depart-
ment of Molecular and Cellular
Biology, Baylor College of Medicine,
Houston, TX
This work was supported by the
USDA/ARS CRIS fund, ARS 6250-
51000-055 (Y.S.), and NIH/NIA grant
1R03AG029641-01 (Y.S.).
1,2,3,4,5,6,7 9,10,11,12,13
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