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(Received for publication, November 6, 1995; and in revised form, January 30, 1996) From the
Mutation of the obese (ob) gene results in severe
hereditary obesity and diabetes in the C57BL/6J and related strains of
mice. In this study we examined the expression of the ob gene
in a dietary model in which moderate obesity develops in response to
fat (58% of calories from fat) without mutation of the ob gene, and in four genetic models of obesity in mice: ob/ob, db/db, tubby, and fat.
Several white and brown adipose depots were examined (epididymal,
subcutaneous, perirenal, and interscapular). Northern blot analysis
shows that levels of ob mRNA are increased in all adipose
depots examined in every model of obesity. The average fold increases
were 12.0 ± 2.1 (ob/ob), 4.8 ± 1.5 (db/db), 2.8 ± 0.1 (tubby), 2.4 ± 0.3 (fat), and 2.1 ± 0.2 (high fat diet-induced A/J).
Moreover, we found that the expression of the ob gene could be
manipulated by pharmacologically blocking the development of
diet-induced obesity. Supplementation of a high fat diet with a
The recent cloning of the ob gene has led to renewed
interest in the genetic basis of obesity(1) . This autosomal
recessive mutation is most often expressed on the C57BL/6J (B/6J)
background strain and is associated with severe obesity,
hyperinsulinemia, hyperglycemia, hypercorticosteronemia, and
infertility. Early studies by Coleman and Hummel (2) and
Coleman (3) led to the proposal that ob may encode a
diffusable signaling factor, while the product of a separate obesity
mutation, db (``diabetic''), residing at a different
chromosomal location, has been postulated to receive the signal from
the diffusable factor; perhaps encoding a receptor for ob(4) . The cloning and sequence analysis of the ob locus suggests that the ob gene indeed encodes a
protein that is secreted from adipocytes(1) . In the ob/ob mouse, a nonsense mutation in the coding region appears to prevent
the production of a functional OB protein, and a marked up-regulation
of ob mRNA has been observed in adipose tissue of ob/ob mice(1) . From these data, and because it is widely
believed that obesity in the ob/ob mouse is caused by
hyperphagia(5) , it has been proposed that this protein
normally serves as a feedback regulator of satiety(1) . Support
for this hypothesis has been provided by several recent studies in
which ob/ob or db/db mice were administered
recombinant OB protein(6, 7, 8) . Decreased
food intake and body weight were observed in ob/ob mice, but
the OB protein had no effect in db/db mice(7, 8) . However, in order to demonstrate
that the OB protein truly serves a sensor function, the expression of ob protein must be shown to be modulated through alteration of
fat mass. We now report that the expression of the ob gene can
be increased by diet and adipocyte hypertrophy, and reduced by
stimulation of
As previously reported(1, 17) , ob gene expression was elevated in obese, diabetic ob/ob and db/db mice (Fig. 1). In the ob/ob mice, the
increase ranged from 10- to 14-fold, while the overexpression in db/db mice was 4- to 8-fold. These values are somewhat less
than reported by other investigators but consistent with their
findings. Based upon the early studies by Coleman (2, 3) he proposed that ob encodes a
diffusable signaling factor and that the db locus might encode
the receptor for ob. Thus, persistently up-regulated
expression of ob mRNA in the db/db diabetic mouse
would be consistent with this model, in which db would be
incapable of receiving the signal from ob. Support for this
original hypothesis has recently been obtained from studies in which
recombinant OB protein was administered to ob/ob and db/db mice(6, 7, 8) . In these studies,
decreased food intake and body weight were observed in ob/ob mice, but the OB protein had no effect in db/db mice(7, 8) . These latter results support the
notion that the db locus is down-stream in the pathway from ob. However, we and others have also observed significantly
increased expression of the ob gene in other genetic models of
obesity that do not possess mutations in the ob locus. For
example, the levels of expression and nucleotide sequence of the ob gene from the Zucker ``fatty'' (fa/fa) rat have
been examined(18, 19) . While similar increases in ob mRNA are observed in obese fa/fa rats, unlike ob/ob mice the ob gene from the Zucker fa/fa is not mutated. More recently, increased expression of ob in overweight humans without mutations of the ob gene has
also been reported(20) . We examined ob expression in
several white and brown adipose tissues from ``tubby'' (tub/tub) and ``fat'' (fat/fat) mutant
mice(21) , including gonadal, subcutaneous, perirenal, and
interscapular. The fat locus has recently been identified as
carboxypeptidase E(22) , but the nature of the mutation in tubby has not yet been reported. These two animal models
develop obesity more gradually with age and do not possess the severe
hypercorticism that is such a prominent feature in ob/ob or db/db mice (21) . (
Figure 1:
Overexpression of ob mRNA in
genetically obese ob/ob and db/db mice. Northern
blots containing 40 µg of total RNA from epididymal white adipose
tissue (EWAT), or interscapular brown adipose tissue (IBAT) were prepared as pools from two or three animals as
described under ``Experimental Procedures'' and hybridized
successively with
Figure 2:
Overexpression of ob mRNA in tubby and fat mutant mice. A, comparison of
genetically lean (+) C57BL/6J mice and tubby (tub) mice. B, comparison of genetically lean (+) C57BL/KsJ mice and
fat (fat) mice. Northern blots containing 30 µg of total
RNA from the indicated adipose tissue depots were prepared as described
under ``Experimental Procedures'' and hybridized successively
with
Unlike these mutant strains of mice which
develop severe obesity on laboratory chow, which is quite low in fat
(4.5% of calories from fat, according to manufacturer, Purina), most
human obesity is thought to occur in response to high fat
diets(23, 24) . For this reason we have been studying
the physiological and biochemical features of diet-induced obesity in
genetically ``lean'' normal mice. We have previously reported
that A/J mice will develop moderate obesity on a high fat
diet(11) . Attempts to develop effective treatments for obesity
have included several reports that
Figure 3:
Obesity induced by high fat feeding and
its prevention by a
We next examined the levels of ob mRNA in epididymal,
subcutaneous, and perirenal white adipose tissue and interscapular
brown adipose tissue from these animals (Fig. 4). Levels of ob mRNA in high fat-fed obese mice increased 1.48 ±
0.07-fold in epididymal, 2.45 ± 0.32-fold in subcutaneous, and
1.78 ± 0.13-fold in perirenal depots compared to low fat-fed
control animals. In interscapular brown adipose tissue from high
fat-fed animals some samples showed a modest elevation, but overall
there was no significant increase (1.07 ± 0.19-fold) compared
with low fat-fed mice. Most likely the levels of ob expression
observed in this brown adipose depot are derived from small amounts of
white adipocytes present in the tissue that we were unable to separate
by visual inspection alone. By contrast to these increases seen in
adipose tissue from the high fat-fed mice, these same adipose tissue
regions from mice consuming the high fat diet supplemented with the
Figure 4:
Increased expression of ob mRNA
in diet-induced obese A/J mice and its repression by a
In our studies
as well as those of other investigators, the fold increases in ob mRNA observed in either diet-induced obese A/J mice, or the
severely obese ob/ob or db/db, are consistently
greater than would be predicted based upon increase in total body
weight alone. For example, we observe a In a
previous study we have shown that high fat feeding in A/J mice causes
adipocyte hypertrophy, but not hyperplasia(11) . Therefore, the
differences in weight in A/J mice raised on high fat diets with and
without the Recent research has emphasized the role of
leptin in satiety(6, 7, 8) . In these studies
decreased food intake and body weight were observed in ob/ob mice, but the OB protein had no effect in db/db mice.
Campfield et al.(8) also found that administration of
recombinant OB protein to diet-induced obese AKR/J mice caused
reductions in food intake and body weight, although to a more modest
degree than in ob/ob mice. To understand the relationship
between food intake and ob gene expression in our dietary
model and the effects of a
Figure 5:
Food intake. Food intake measurements over
a 24-h period were made for individual animals at three different times
during study (2, 6, and 16 weeks on the diets). Each group of 10
animals was housed individually and grams of food consumed over 24 h
were measured. Caloric content of each diet was calculated based on
5.55 kcal/g for the high fat diets and 4.07 kcal/g for the low fat
diet. #, significantly different from low fat-fed animals at p < 0.05. *, significantly different from low fat-fed and high
fat-fed animals at week 6 and from low fat-fed animals at week 16, p < 0.005.
Volume 271,
Number 16,
Issue of April 19, 1996 pp. 9437-9440
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
-adrenergic receptor agonist (CL316,243) prevented
obesity, but not hyperphagia associated with high fat feeding (body
weights of high fat-fed A/J mice = 34.0 ± 1.0 g; high fat
plus CL316,243-fed mice = 26.8 ± 0.5 g; n = 10). CL316,243-treated, high fat-fed animals contained
levels of ob mRNA in all adipose depots that were equal to or
less than levels in low fat-fed mice (average levels in high fat plus
CL316,243-fed mice relative to low fat-fed mice: 0.93 ± 0.09).
Inasmuch as fat cell size, but not number, was increased in a previous
study in diet-induced obese A/J mice, these results indicate that
expression of the ob gene serves as a sensor of fat cell
hypertrophy, independent of any effects on food intake.
-adrenergic receptors
(AR), (
)independent of effects on food
intake. These data suggest that changes in ob gene expression
do not predict changes in food intake.
Animals
All mice were obtained from The Jackson
Laboratory (Bar Harbor, ME). ``Obese'' (ob/ob) and
``tubby'' (tub/tub) mutant mice on the C57Bl/6J
(B/6J) background, and ``diabetic'' (db/db) and
``fat'' (fat/fat) mutants on the C57Bl/KsJ
background, were obtained together with genetically lean
(+/+) control animals at 10 weeks of age unless otherwise
indicated in the text. These animals were provided free access to
Purina mouse chow and water. For dietary obesity studies, the standard
protocol of Surwit was followed(9, 10, 11) .
A/J male mice were obtained at 4 weeks of age and were housed five per
cage in a temperature-controlled room with reverse 12-h light/dark
cycle. Water was available ad libitum. The animals were fed
one of three diets as follows: 10 mice from each strain were placed on
a low fat diet (10.5% calories from fat), a high fat diet (58% calories
from fat), or a high fat diet containing 0.001% of the
AR agonist CL316,243 as described
previously(12, 13) . (
)The detailed
composition of the diets and their caloric content has been described
previously(11) . Body weight was assessed biweekly. Food intake
measurements for individual animals, 10 per diet group, were performed
for 24-h periods at weeks 2, 6, and 16 of the diet regimen. More
frequent measurements were not performed due to the stress to the
animals as a result of individual housing. All procedures were
conducted in accordance with principles and guidelines established by
the NIH for the care and use of laboratory animals.RNA Preparation and Analysis
Adipose tissue was
collected from the gonadal, subcutaneous, perirenal, and interscapular
regions. Total cellular RNA was prepared from freshly isolated adipose
tissue by the cesium chloride gradient method as previously
detailed(14) . For Northern blot hybridization, RNA was
denatured by the glyoxal procedure, fractionated through 1.2% agarose
gels, and blotted onto Biotrans nylon membranes (ICN, Irvine, CA) as
described previously (15) . A probe for the murine ob gene sequence was prepared by reverse transcriptase-polymerase
chain reaction (PCR). The primers used were 5`-AAAACCCTCATCAAGACC-3`
(sense) and 5`-CAACTGTTGAAGAATGTCC-3` (antisense) corresponding to
nucleotide 209-226 and 598-580 of the sequence reported by
Zhang et al.(1) . The reaction conditions were as
follows. Epididymal adipose tissue RNA from C57BL/6J mice were
incubated in a 20-µl reaction containing 50 mM Tris, 10
mM MgCl, and 1 unit of RNase-free DNase (U. S.
Biochemical Corp., Cleveland, OH) for 30 min at 37 °C. The DNase
was denatured by heating to 95 °C for 5 min. Two hundred and fifty
ng of the RNA were then annealed to the antisense primer in a 20-µl
reaction containing Moloney murine leukemia virus reverse transcriptase
and 5 mM MgCl, and incubated at 42 °C for 15
min, followed by 99 °C for 5 min to denature the enzyme. PCR was
initiated by addition of the sense strand primer, 2.5 units of AmpliTaq
polymerase and 10 
PCR buffer (final concentrations: 10 mM Tris, 50 mM KCl, 1.5 mM MgCl): 94
°C for 30 s, 57.5 °C for 30 s and 72 °C for 1.5 min; 35
cycles. Amplification reactions without the initial reverse
transcriptase step were included as controls. The 390-nucleotide PCR
product was purified by agarose gel electrophoresis and subcloned into
the plasmid vector T7-Blue (Novagen, Madison, WI). A probe for mouse
glyceraldehyde 3-phosphate dehydrogenase was obtained from Clontech
(San Diego, CA) and a rat cDNA probe for cyclophilin was obtained from
J. Douglas. Radiolabeled probes for hybridization were prepared by
nick-translation with [
P]deoxyCTP to a specific
activity of between 3 and 7 10
dpm/µg of DNA.
Blots were hybridized and washed as described previously(16) .
Quantitation of hybridizing species was by exposure to Molecular
Dynamics PhosphorImager screens. Permanent data records were generated
by exposing the blots to Kodak X-AR film at -80 °C.
)As shown in Fig. 2, ob mRNA was significantly increased in adipose
tissue from tubby and fat mice as compared with
genetically lean (``+'') littermates, although the
degree of overexpression is less dramatic than in ob and db mice. Table 1presents the quantitative comparisons
for individual adipose depots. The results demonstrate that, similar to ob and db animals, a high degree of adiposity in tubby and fat mice is associated with elevated levels
of ob expression.
P-labeled probes for the mouse ob coding region and glyceraldehyde 3-phosphate dehydrogenase (gapdh). The position of the ob or gapdh mRNA is
indicated by the arrowhead. A, comparison of
genetically lean (+) C57BL/6J mice and obese (ob) mice.
In the data shown, the level of ob mRNA is increased 14-fold
in the ob/ob mutant (average of two experiments = 12.0
± 2.1-fold increase). B, comparison of genetically lean
(+/+) C57BL/KsJ mice and diabetic (db/db) mice. In
the data shown, the level of ob mRNA is increased 4-fold in
EWAT and 8-fold in the IBAT of the db/db mutant. The data
shown are representative of two
experiments.
P-labeled probes for the mouse ob coding
region and cyclophilin (cyclo): epididymal white adipose
tissue (EWAT), interscapular brown adipose tissue (IBAT), subcutaneous (SQ), and perirenal (PR). The position of the ob or cyclo mRNA is
indicated by the arrowhead.
AR agonists are
effective in reducing body weight and adipose tissue mass following
acute treatment of ob/ob mice or diet-induced obese rats (13, 25, 26, 27) . Therefore we
decided to test whether chronic supplementation of the high fat diet
with a highly selective AR agonist, CL
316,243(12) , could prevent diet-induced obesity in A/J mice
and whether the effect could be sustained over prolonged treatment. The
body weights of animals on the three diets are shown in Fig. 3.
Compared with animals fed the low fat diet, the high fat-fed animals
exhibited significant increases in total body weight even within the
first 2 weeks. This trend continued throughout the 16 weeks of the
experiment. However, animals consuming the high fat diet supplemented
with the AR agonist were resistant to the
obesity-inducing effects of the fat in the diet (Fig. 3). In
fact, they tended to weigh even less than animals consuming the low fat
diet.
AR agonist. Thirty A/J male mice
were obtained from The Jackson Laboratories at 4 weeks of age. Groups
of 10 mice were randomly assigned to a low fat diet (
), high fat
diet (
), or high fat diet containing 0.001% CL316,243 (
).
Animals were weighed at biweekly intervals through the 16-week period
on the diets.
AR agonist expressed levels of ob mRNA that
were equal to, or slightly less than, that observed in animals fed the
low fat diet (0.93 ± 0.09-fold). Thus, these data suggest that
we were able to manipulate the expression of the ob gene by
pharmacologically blocking the development of diet-induced obesity,
despite the consumption of a calorically rich diet.
AR agonist. Northern blots containing 40
µg of total RNA from the indicated adipose tissue depots were
prepared from A/J animals consuming the low fat (LF) diet, or
the high fat (HF) diet alone or supplemented with the
AR agonist CL316,243 (HF+CL): epididymal
white adipose tissue (EWAT), interscapular brown adipose
tissue (IBAT), subcutaneous (SQ), and perirenal (PR). The blots were hybridized successively with P-labeled probes for the mouse ob coding region
and cyclophilin (cyclo). The position of the ob or
cyclo mRNA is indicated by the arrowhead. The data shown are
representative of three experiments. The average fold changes in ob mRNA are described in the text.
25% increase in body
weight of A/J mice consuming a high fat diet, but there is a
50-250% increase in ob mRNA levels. Similarly, ob/ob mice generally display a 75-100% increase in body
weight(4) , but a 10-20-fold increase in ob mRNA
levels (1, 17) (Fig. 1). When we examined fat
pad weights in A/J mice raised on these three diets, the average
increase over all depots in high fat fed animals increased by 2.30
± 0.30 (n = 3), while in the presence of the
AR agonist, average fat pad weights were essentially
identical to low fat-fed animals (fold change = 1.03 ±
0.13; n = 3). These values are very similar to the
changes observed in ob mRNA levels in this study.AR agonist CL316,243 are most likely due
to differences in adipocyte size between the groups, but not in number.
Thus, the difference in ob mRNA in these mice, compared to
those raised on fat alone, suggests that OB is a
``sensor'' of fat cell size presumably sending a signal,
either autocrine, paracrine, or endocrine to elicit some metabolic
response; possibly to control energy partitioning and utilization.
Interestingly, A/J animals consuming the high fat diet supplemented
with the AR agonist, CL316,243, also display increases
in brown adipose tissue content and AR gene
expression. (
)AR agonist, we examined
food intake in individual animals from all three diet groups at three
times during the study period (Fig. 5). These data show that the
caloric intake of animals on either of the high fat diets was
equivalent and greater than that consumed by animals fed the low fat
diet. However, despite this greater caloric density of the high fat
diet, animals supplemented with CL316,243 actually weighed less than
low fat fed animals. Therefore, our experiments appear to highlight a
disassociation between ob gene expression and caloric
consumption. In summary, we have shown that A/J mice consuming a high
fat diet produce more leptin and become moderately obese, while mice
consuming the high fat diet supplemented with CL316,243 do not become
obese or show increases in ob gene expression, despite the
fact that they consumed as much, or more, food than animals on high fat
alone. It is possible that treatment with CL316,243 may serve to mimic
effects of OB protein involved in enhancing metabolic and/or
thermogenic activity, as recently speculated(28) . Therefore,
because food intake in animals fed high fat diets with and without the
-agonist was similar, these results indicate that
there is no apparent obligatory effect of OB protein on satiety.
)AR,
-adrenergic receptor; PCR, polymerase chain reaction.)))
We thank Drs. Thomas Claus and Elliott Danforth for
the gift of CL316,243, Dr. Patsy Nishina for tubby and fat mice, and Kiefer Daniel and Ann Petro for excellent technical
assistance.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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