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Departments of Medicine (T.W.G., P.M.W., L.S., M.P., I.L.T.) and Biochemistry and Molecular Biology (T.W.G.), Medical University of South Carolina, Charleston, South Carolina 29425
Address all correspondence and requests for reprints to: Dr. Thomas W. Gettys, 655 Thurmond Research Building, Medical University of South Carolina, 171 Ashley Avenue, Charleston, South Carolina 29425. E-mail: Gettystw{at}musc.edu
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(5, 6), but the underlying
cause of dysregulation of these genes has not been established. Recent
work with cultured 3T3-F442A adipocytes showing dexamethasone-mediated
down-regulation of the ß3-adrenergic receptor (7, 8)
suggests that the characteristic hypercorticism of ob/ob
mice may have special relevance to the development of signaling defects
in adipose tissue. Hypercorticism develops slightly before or around
the time of weaning (9), but it is unclear when expression of the
ß3-AR becomes compromised in ob/ob mice. Thus,
the goals of the present study were to examine the development of
ß-adrenergic signaling in WAT immediately after weaning and determine
whether adrenalectomy would restore expression of the
ß3-AR in WAT of ob/ob mice. Using this
experimental approach, it is shown that adrenalectomy of
ob/ob mice immediately after weaning fully restores the
expression and function of ß3-AR in this tissue. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-[32P]deoxy-CTP were
purchased from DuPont-New England Nuclear Radiochemicals (Boston, MA).
RIA kits for rodent insulin were purchased from Linco Research
Laboratories (St. Charles, MO). The ß3-adrenergic
receptor (ß3-AR) agonist, BRL-37344A, was a gift from
SmithKline Beecham Pharmaceuticals (Surrey, UK). The
ß1-AR-specific antagonist, CGP-20712A, was a gift from
Ciba-Geigy (Summit, NJ). The ß3-AR-selective agonist,
CL316,243, was a gift from Wyeth Ayerst Research (Princeton, NJ).
Cyanopindolol was provided by Research Biochemicals International
(Natick, MA) as part of the Chemical Synthesis Program of the NIMH
(Contract N01MH30003).
Experimental animal protocol
Lean (+/+) and obese (ob/ob) C57BL/6J mice
were obtained from Jackson Laboratories (Bar Harbor, ME) at 4 and 7
weeks of age and used in an initial comparative study of the
phenotypes. In this study, the mice were killed immediately upon
arrival, and epididymal fat pads were removed into warm 0.9% saline.
Isolated adipocytes were prepared as described below. In a second
experiment, ob/ob mice were adrenalectomized immediately
after weaning by Jackson Laboratories and shipped for use 1 and 3 weeks
after the surgery. Age-matched lean and ob/ob mice were
included in each shipment. All animals were killed upon receipt.
Epididymal fat pads were obtained as described above, and blood samples
were obtained from the second group of animals (3 weeks after surgery)
for assay of glucose and insulin as previously described (10). All
procedures were conducted in accordance with principles and guidelines
established by the NIH for the care and use of laboratory animals.
Isolation of adipocytes
Adipocytes were prepared from the epididymal fat pads of male
mice as previously described by Rodbell (11) with slight modification
(5, 12). The cells were washed and resuspended in Krebs-Ringer-HEPES
buffer containing 1 mM CaCl2.
Preparation of adipocyte membranes
Cells were broken in a Dounce homogenizer in hypotonic buffer
containing 10 mM TES (pH 7.0) and 1 mM EDTA.
Unbroken cells and nuclei were removed by an initial low speed spin at
3,000 x g, and crude membranes were collected from the
supernatant by a 20-min spin at 48,000 x g. The
pelleted membranes were resuspended at 1 mg/ml in 25 mM
HEPES (pH 7.4) containing 140 mM NaCl, 40 µM
leupeptin, 1 µg/ml soybean trypsin inhibitor, and 1 mM
EDTA and stored at -80 C.
Competition binding assay for ß1- and
ß2-AR
Radioreceptor binding assays were conducted with adipocyte
membranes according to previously described methods (13, 14) with
slight modification. [125I]Cyanopindolol (ICYP) was
prepared by iodination of 25 µg cyanopindolol using the chloramine-T
procedure (15). Monoiodinated ICYP was purified by C18
reverse phase HPLC and eluted as a single symetrical peak. In the
binding assay, 10 µg adipocyte membranes (mbs) were incubated with 30
pM ICYP in 25 mM HEPES buffer (pH 7.4)
containing 12.5 mM MgCl2, 5 µM
CL316,243, and various concentrations of the
ß1-AR-specific antagonist, CGP-20712A. The
ß3-AR-selective agonist, CL316,243, was included to block
low affinity binding of ICYP by ß3-ARs (16). After
incubation at 37 C for 1 h, the mb suspensions were filtered
through Whatman GF/C filters (Whatman, Clifton, NJ) on a Skatron cell
harvester (Skatron Instruments, Inc., Sterling, VA) and washed with 12
ml assay buffer. Radioactivity retained on the filters was counted on a
-counter. The components of ICYP binding by ß1-ARs and
ß2-ARs were resolved by fitting a two-site competition
curve to the data by least squares analysis, as previously described
(16). This fitting procedure provided an estimate of total
ß1- and ß2-AR binding sites as well as the
proportion of total binding contributed by each receptor subtype
(GraphPad Prism, San Diego, CA).
Ribonuclease protection assay of ß3-AR
messenger RNA (mRNA)
The epididymal fat pads were removed and homogenized in 8 ml
guanidinium thiocyanate buffer, followed by centrifugation through a
CsCl2 cushion to pellet total RNA. Five micrograms of
RNA were combined with 32P-labeled riboprobe complementary
to the junctions of exons 1, 2, and 3 in the mouse ß3-AR
mRNA (17). RNA was then denatured at 65 C and hybridized at 55 C
overnight. Unhybridized RNA was digested with ribonuclease T1 at 37 C
for 1 h, and the reaction was stopped with 5 mM EDTA.
The protected fragments of 171 and 123 bp were visualized by
autoradiography after fractionation on 6% acrylamide-urea gels. The
amount of ß3-AR mRNA was quantitated by including known
amounts of sense strand riboprobe and constructing standard curves
after autoradiography and densitometry. A riboprobe complementary to
the 18S ribosomal RNA was included in the hybridization to correct for
differences in the amount of total RNA loaded on the gel.
Adenylyl cyclase (AC) assay
AC activity was determined in adipocyte membranes by methods
described previously (5). In brief, 10 µg purified plasma membranes
were incubated for 10 min at 30 C in a buffer containing 50
mM TES (pH 7.4), 4.0 mM MgCl2, 2
mM creatine phosphate, 25 U/ml creatine phosphokinase, 100
µM ATP, 10 µM GTP, and 1 U/ml adenosine
deaminase. The reaction was conducted in a final volume of 300 µl and
initiated by adding 50 µl of the membrane preparation to each
incubation tube. Reactions were terminated by adding 50 µl cold 25%
trichloroacetic acid and centrifuging for 15 min at 3000 rpm. The cAMP
formed in the reaction was measured in the supernatant by RIA according
to methods described previously (5).
Methods of analysis
Agonist-induced activation of AC and antagonist-induced
inhibition of ICYP binding were characterized using relationship
functions appropriate to the shape of the response surfaces (5). Least
squares analysis was used to fit curves to the original observations,
and F tests were used to test the adequacy of one- vs.
two-component models in each case. The simpler model was adopted unless
the more complex model provided a better representation of the change
in response variable over the range of agonist concentrations
(P < 0.05). Parameter estimates and their
SEs were obtained using an iterative nonlinear least
squares routine (Graph Pad Prizm, San Diego, CA), and confidence
intervals were constructed to test specific hypotheses concerning group
differences in agonist potency and efficacy (5). Growth data, serum
characteristics, forskolin-activated AC, and mRNA levels for the
ß3-AR were compared by one-way ANOVA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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illustrates that basal AC
activity was similar in both phenotypes at both ages, but even at 4
weeks the efficacy of epinephrine was higher in lean (52 ± 7 pmol
cAMP/min·mg) than in ob/ob (27 ± 1 pmol
cAMP/min·mg) mice. Over the following 3 weeks, the efficacy of
epinephrine increased substantially (82 ± 3 pmol cAMP/min·mg)
in the lean group, whereas the improvement in adipocyte membranes from
ob/ob mice was modest (43 ± 13) and insignificant
(Fig. 1). Between 4 and 7 weeks of age, the concentration of
epinephrine producing half-maximal cyclase activation
(EC50) decreased in both lean (2.24 to 0.56
µM) and ob/ob (0.31 to 0.04 µM)
mice, but the large SEs attached to these estimates
precluded detection of treatment differences. Given that activation
constants (Kact) of epinephrine for the ß1-
and ß2-ARs are similar and approximately 100-fold higher
than that for ß3-AR (6), these data suggest increases in
the total number of ß1- and ß2-ARs,
particularly in lean mice between 4–7 weeks of age.
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), total ICYP bound by both
ß1- and ß2-ARs was slightly higher in lean
(33.3 ± 0.4 fmol/mg) than ob/ob (26.8 ± 0.5
fmol/mg) mice at 4 weeks (Table 1). Although the high
affinity component of ICYP binding (Fig. 2A), defined previously as
ß1-ARs (16), appeared to account for a greater proportion
of available binding sites in ob/ob mice, the actual number
of ß1-AR-binding sites did not differ between the
phenotypes at this age (Table 1). The second binding component,
ß2-AR, comprised the remaining sites in membranes from
the two phenotypes (Fig. 2A). At 4 weeks of age, there were
approximately 60% more ß2-AR-binding sites in adipocyte
membranes from lean compared to ob/ob mice (Table 1).
Between 4–7 weeks of age (Table 1 and Fig. 2B), total ICYP binding
increased from 33.3 to 60.9 ± 0.5 fmol/mg in lean mice, but was
essentially unchanged over the same period in adipocyte membranes from
ob/ob mice (26.8–33.1 ± 0.5 fmol/mg). A slight
decrease in the proportion of ß1-AR-binding sites in
ob/ob mice translated into an insignificant decrease in the
actual number of ß1-AR sites (Table 1). In contrast, the
total number of ß1-AR-binding sites in lean mice doubled
during this same period (Table 1). The number of
ß2-AR-binding sites increased by 79% between 4 and 7
weeks of age in lean mice, whereas the increase in ob/ob
mice was 51% (Table 1). Thus, the total number of
ß2-AR-binding sites was nearly two-fold greater in
adipocyte membranes from lean compared to ob/ob mice (Table 1).
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). Adrenalectomy of ob/ob mice at 4 weeks of
age prevented the rapid increase in body weight and fat deposition that
normally occurs between 4–5 weeks of age (Table 2). By 7 weeks of age,
ob/ob mice were nearly twice the size of lean mice, and the
epididymal fat pads were 6- to 7-fold larger in the ob/ob
group (Table 2). The adrenalectomized ob/ob mice were
intermediate in size between lean and ob/ob mice at this
age, but were indistinguishable from lean mice with respect to plasma
insulin and glucose concentrations (Table 2). Epididymal fat pads from
7-week-old adrenalectomized ob/ob mice were smaller than fat
pads from ob/ob mice, but were much larger than fat pads
from lean mice (Table 2).
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and 4 illustrate that at 5 weeks of
age, the protected fragments of ß3-AR mRNA were 3-fold
lower in ob/ob compared to lean mice. Figures 3 and 4 also
clearly illustrate that adrenalectomy of ob/ob mice at
weaning (4 weeks of age) fully restored ß3-AR mRNA
expression to the levels observed in lean mice at the same age.
ß3-AR mRNA levels increased over 2-fold between 5–7
weeks of age in lean mice (Fig. 4). In contrast, ß3-AR
mRNA expression decreased slightly between 5–7 weeks of age in
ob/ob mice, such that levels in lean mice were now 13-fold
higher. ß3-AR mRNA increased modestly in adrenalectomized
ob/ob mice between 5–7 weeks of age (Fig. 4) to levels that
were similar to those in lean mice and 10-fold higher than those in
ob/ob mice. These results illustrate that expression of
ß3-AR mRNA increases after weaning in epididymal adipose
tissue from lean mice, but fails to do so in ob/ob mice.
Moreover, adrenalectomy of ob/ob mice at weaning corrected
their deficient ß3-AR mRNA levels and restored the
postweaning development of ß3-AR mRNA expression.
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). BRL37344A failed to produce any
significant activation of AC in adipocyte membranes from
ob/ob mice (Fig. 5A). This lack of a response corresponds to
the low levels of ß3-AR mRNA detected in the
ob/ob group (Figs. 3
and 4). Compared with Fig. 5A, the
small, but significant, activation of AC by epinephrine (Fig. 1) in
ob/ob mice at 4 weeks of age suggests that the response is
due solely to activation of ß1- and ß2-ARs
in this group. The ß3-AR agonist produced a 2.5-fold
activation of AC in membranes from lean mice, and the maximal response
(26.8 ± 3.6 pmol cAMP/min·mg) was noted at 10–100
µM BRL37344A (Fig. 5A). Adrenalectomy of ob/ob
mice at 4 weeks of age completely restored their responsiveness to
BRL37344A (Fig. 5A) with respect to both potency (EC50,
0.54 ± 0.18 µM) and efficacy (36.1 ± 1.3 pmol
cAMP/min·mg).
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). Although
the potency of the agonist was unaffected, maximal activation of AC by
BRL37344A increased to 38.9 ± 3.2 pmol cAMP/min·mg. This
increase in efficacy corresponds roughly with the increase in
ß3-AR mRNA noted during this period (Fig. 4). In
contrast, maximal activation of cyclase by BRL37344A (32.9 ± 1.7
pmol cAMP/min·mg) was essentially unchanged in adrenalectomized
ob/ob mice between 5–7 weeks of age (Fig. 5B), although
there is the suggestion that ß3-AR mRNA levels may have
increased slightly during this period (Fig. 4). Maximal activation of
AC also improved slightly in ob/ob mice between 5–7 weeks
of age (Fig. 5B). However, the difference between estimates of basal
activity (14.6 ± 0.6 pmol cAMP/min·mg) and maximal activity
(20.3 ± 2.0 pmol cAMP/min·mg) indicate that the effect is
modest.
Additional experiments were conducted to determine whether expression
of the catalytic activity of AC was modified by adrenalectomy and
contributed indirectly to differences in efficacy of ß-adrenergic
agonists. Basal AC activity in adipocyte membranes did not differ
between lean and adrenalectomized ob/ob mice at either age,
but was lower in membranes from ob/ob mice at the younger
age (see Fig. 6). However, basal cyclase activity
increased between 5–7 weeks of age in the ob/ob group.
Maximal AC activation by a combination of forskolin and
Mn2+ also did not differ between lean and adrenalectomized
ob/ob mice at either age, although it was lower in
ob/ob mice at the younger age (Fig. 6). Thus, these data
fail to account for group differences in ß-AR-mediated cyclase
activation and suggest that the differences reflect changes in receptor
expression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hypercorticism in the ob/ob mouse has special relevance to adipocyte ß-ARs, as glucocorticoids have been shown to differentially affect ß-AR expression in a number of systems (26, 27). For example, dexamethasone induces reciprocal changes in ß-ARs by increasing the ratio of ß2-AR to ß1-AR expression in cultured adipocytes (13). Thus, the situation in dexamethasone-treated 3T3-F442A adipocytes is similar to the patterns of ß-AR mRNAs in adipocytes from mature ob/ob mice, in that the ß2-AR becomes the predominant receptor subtype (6). In the present study, we evaluated expression of the ß1- and ß2-ARs directly using a high affinity antagonist radioligand (ICYP) and a highly specific ß1-AR antagonist (16). This method provided an estimate of the total ß1- and ß2-AR binding and separated total ICYP binding into the components contributed by each receptor subtype. Using this approach, we found similar numbers of ß1-ARs in adipocyte membranes from lean and ob/ob mice at weaning. However, ß1-ARs increased 2-fold between 4–7 weeks in lean mice, but were unchanged or slightly decreased in ob/ob mice over the same period. In contrast, ß2-ARs increased in both phenotypes between 4 and 7 weeks of age, but at both ages there were nearly twice the number of ß2-ARs in lean compared to ob/ob mice. Thus, the hypercorticism of ob/ob mice appeared to have had little effect on ß2-AR expression. A better case can be made that some aspect of the ob/ob syndrome prevented the postweaning development of ß1-AR expression. Results from experiments with cultured adipocytes are consistent with the expectation that glucocorticoids would decrease ß1-AR expression (13), but it is unclear whether this is actually the same as preventing an increase in ß1-AR expression. In additional experiments with the 7-week-old control and adrenalectomized ob/ob mice (data not shown), we could find no evidence that adrenalectomy altered either ß1- or ß2-AR expression. Thus, we interpret these results to suggest that additional components of the ob/ob syndrome are involved in dysregulating expression patterns of these two receptors. Androgens and thyroid hormones are potential candidates because they are both deficient in ob/ob mice and have been shown to be involved in regulating ß-AR expression (28, 29). Additional experiments will be needed to determine whether either of these endocrine agents contributes significantly to the overall pattern of dysregulation of ß-AR expression in ob/ob mice.
In contrast to the ß1- and ß2-ARs, a stronger case can be made that glucocorticoids impair postweaning development of WAT ß3-AR expression and function in ob/ob mice. The major finding from our study is that adrenalectomy at weaning restores the expression and function of ß3-ARs in WAT of ob/ob mice. The results also indicate that functional coupling of the ß3-AR to AC increases after weaning in lean mice, but fails to follow this developmental pattern in ob/ob mice. Considered together, the data are consistent with the suggestion that excess production of glucocorticoids at weaning prevents the normal postweaning increase in WAT ß3-AR expression. Results from cultured adipocytes support this hypothesis by showing that dexamethasone decreased ß3-AR mRNA and produced a corresponding decrease in activation of AC (7). Moreover, the researchers showed that the effect was transcriptionally mediated (7). Alternative mechanisms are possible, and it should be remembered that insulin produces similar inhibitory effects on ß3-AR expression in 3T3-F442A adipocytes (30). Evidence of hyperinsulinemia is noted as early as 21 days of age in ob/ob mice, and the magnitude of the elevation becomes progressively worse over the following 5–8 weeks (1). In addition, we and others (31) have found that adrenalectomy corrected hyperinsulinemia in ob/ob mice. Thus, the restoration of ß3-AR expression in adrenalectomized ob/ob mice could just as easily be explained by correction of their hyperinsulinemia. The present studies do not distinguish between these possibilities, but illustrate the essential nature of glucocorticoids in several components of this obesity syndrome.
The similarity of insulin and glucocorticoid effects on
ß3-AR expression may arise from common aspects of their
signaling mechanisms in the adipocyte. The ß3-AR is one
of a number of genes whose expression is increased after clonal
expansion ceases and terminal differentiation of adipocytes is
initiated. Transcriptional activation of the ß3-AR and a
number of fat cell-specific genes is regulated in part by
CCAAT/enhancer-binding protein- (C/EBP), a transcription factor
that is itself induced by both insulin and glucocorticoids during the
differentiation process (32, 33). However, recent studies have
shown that insulin and glucocorticoids have the opposite effect in
fully differentiated adipocytes and decrease the expression of C/EBP
(34, 35). Insulin was shown to produce a concomitant decrease in fat
cell-specific gene expression that paralleled the decrease in C/EBP
(35). If the ß3-AR is linked to C/EBP in a similar
manner, this could explain how both insulin and glucocorticoids
increase ß3-AR expression during differentiation, yet
decrease its expression in fully differentiated cells.
The absence of a functional ob gene produces additional endocrine abnormalities that impact ß-adrenergic signaling in adipocytes. This became evident before cloning of the ß3-AR, when it was shown that thyroid hormones produced significant changes in the efficacy of isoproterenol in cultured 3T3-L1 adipocytes (36). Begin-Heick showed that exogenous T4 improved lipolytic efficacy of epinephrine in white adipocytes from ob/ob mice (3). More recently, Fain and colleagues showed that exogenous thyroid hormones increased the level of ß3-AR mRNA in WAT from treated animals (29). Thus, in addition to glucocorticoids and insulin, thyroid hormones appear to represent a third hormonal input into the regulation of ß3-AR expression. The importance of multiple regulatory inputs may be related to our recent demonstration that the ß3-AR inhibits leptin release from isolated white adipocytes (37). Recent studies have confirmed that this system functions in vivo by showing that activation of the ß3-AR rapidly reduces both circulating leptin and leptin mRNA in mouse WAT (38, 39). Considered together, these studies suggest that sympathetic outflow may represent a counterregulatory signal to inhibit leptin expression and release from the adipocyte (37, 38, 39). Thus, modulation of ß3-AR expression could affect both short term mobilization of triglyceride and reset the threshold for leptin release from WAT.
The results of the present study indicate that increased expression of the ß3-AR after weaning in white adipocytes from lean mice increases the ß-adrenergic responsiveness of this tissue. Similar increases in ß3-ARs fail to occur in ob/ob mice during this period, but adrenalectomy of ob/ob mice immediately after weaning restores the expression and function of the ß3-AR. Considered together, the present work suggests that hypercorticism in ob/ob mice represses ß3-AR expression and prevents the normal postweaning development of this signaling system in white adipocytes.
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Acknowledgments |
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Footnotes |
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2 Supported in part by a postdoctoral fellowship from the Medical
University of South Carolina.
Received January 30, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, ß, and 
genes in fully-differentiated 3T3–L1
adipocytes. J Biol Chem 270:647–654 and genes in 3T3–L1 adipocytes
and white adipose tissue. J Biol Chem 269:19041–19047This article has been cited by other articles:
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