Department of Physiology, Faculty of Medicine, Laval University, Quebec, Canada G1K 7P4
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ABSTRACT |
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The mechanisms
regulating leptin secretion were investigated in isolated rat white
adipocytes. Insulin (1-100 nM) linearly stimulated leptin
secretion from incubated adipocytes for at least 2 h. The
adrenergic agonists norepinephrine, isoproterenol (two nonselective
-agonists), or CL-316243 (potent
3) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of
norepinephrine and isoproterenol could be reversed not only by the
nonselective antagonist propranolol but also by the selective antagonists ICI-89406 (
1) or ICI-118551
(
2), the
2-antagonist being less
effective than the
1. Insulin-stimulated leptin
secretion could also be inhibited by a series of agents increasing
intracellular cAMP levels, such as lipolytic hormones (ACTH and
thyrotropin-stimulating hormone), various nonhydrolyzable cAMP
analogs, pertussis toxin, forskolin, methylxanthines (caffeine,
theophylline, IBMX), and specific inhibitors of phosphodiesterase III
(imazodan, milrinone, and amrinone). Significantly, antilipolytic
agents other than insulin (adenosine, nicotinic acid, acipimox, and
orthovanadate) did not mimic the acute stimulatory effects of
insulin on leptin secretion under these conditions. We conclude that
norepinephrine specifically inhibits insulin-stimulated leptin
secretion not only via the low-affinity
3-adrenoceptors
but also via the high-affinity
1/
2-adrenoceptors. Moreover, it is
suggested that 1) activation of phosphodiesterase III by
insulin represents an important metabolic step in stimulation of leptin
secretion, and 2) lipolytic hormones competitively
counterregulate the stimulatory effects of insulin by activating the
adenylate cyclase system.
lipolytic hormones; phosphodiesterases; 1-,
2-, and
3-adrenoceptors
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INTRODUCTION |
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LEPTIN IS A HORMONE encoded by the ob gene and primarily secreted by white adipocytes (for reviews, see Refs. 1, 13, 14, and 38). It stimulates energy expenditure and inhibits food intake by acting via hypothalamic leptin receptors. The expression of leptin in adipocytes and its plasma concentration are both positively correlated with total adiposity. Therefore, it is generally believed that leptin represents a lipostatic factor contributing to the regulation of body weight via a negative feedback loop (10). In addition to total adiposity, plasma leptin concentrations can be acutely modulated by a variety of physiological conditions (starvation-refeeding and cold exposure) and hormonal factors (insulin, catecholamines, glucocorticoids, thyroid hormones, gonadal steroids, etc.) (26). The observations that starvation decreases both plasma insulin and leptin levels and that obesity is strongly associated with hyperinsulinemia and hyperleptinemia have led many researchers to investigate the effects of insulin on leptin secretion. Although several studies found that insulin stimulates leptin expression and secretion in adipocytes in vitro (3, 6, 11, 15, 30), others found little or no effect of insulin (20, 24, 32). The in vivo effects of insulin on leptinemia are also contradictory; some groups reported that insulin increases plasma leptin levels in rodents or humans (16, 21), whereas others found that insulin does not appear to acutely regulate leptin expression or secretion (8, 36).
In addition to starvation, cold exposure represents another
physiological condition known to significantly affect plasma leptin levels, at least in laboratory animals (26). Cold exposure
activates the sympathetic nervous system, increases the levels of
circulating norepinephrine, and decreases plasma insulin and leptin
concentrations (4, 12, 28, 35) as well as leptin gene
expression in adipose tissue (34). The effects of cold
exposure have been mimicked in vivo by administration of the
physiological neurohormone norepinephrine or by treatment with
-agonists in mice (23, 34) and humans (9, 25, 27,
33). However, the nature of the
-adrenoceptor subtypes
(
1,
2, and/or
3) mediating
the effects of norepinephrine on leptin secretion is still not well understood. Although it has been reported that
3-adrenergic agonists inhibit leptin secretion in vivo
and in vitro, at least in rodents (11), few studies have
been performed with selective
-antagonists. One study has claimed
that the high affinity
1/
2-adrenoceptors play essentially no role in mediating norepinephrine effects on leptin
secretion, because it was unaffected by
1/
2-antagonists (11).
However, isoproterenol (a nonselective
-adrenergic agonist) acutely
decreases the levels of circulating leptin in humans and decreases
leptin expression or secretion in cultured adipocytes (9, 27, 30,
33). Because the
3-adrenergic receptor is a
low-affinity receptor for
-agonists such as norepinephrine or
isoproterenol, these observations suggest that norepinephrine might
act, at least partially, via the high-affinity
1/
2-adrenoceptors (17).
Another observation that prompted the present study is that insulin and
catecholamines, the principal hormones acutely regulating energy
metabolism, exert antagonistic effects on lipolysis, leptin expression,
and leptin secretion from adipose tissues, suggesting the presence of
metabolic interactions between insulin activation of phosphodiesterases
and the stimulation of the adenylate cyclase system by catecholamines
(17, 26). Thus the sympathetic nervous system
(catecholamines) and insulin might play a major role in controlling
leptin metabolism in vivo.
On the basis of these observations, we decided to investigate the
nature of -adrenergic pathways regulating insulin stimulation of
leptin secretion in adipocytes isolated from rat epididymal adipose
tissue using selective
-adrenergic agonists/antagonists, lipolytic
hormones, phosphodiesterase inhibitors, hydrolyzable and
nonhydrolyzable cAMP analogs, and other drugs known to affect lipolysis
or the adenylate cyclase complex.
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MATERIALS AND METHODS |
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Chemicals. Fatty acid-free bovine serum albumin, norepinephrine, isoproterenol, dobutamine, procaterol, propranolol, cAMP analogs 8-bromo-cAMP (8-BrcAMP), N6-monobutyryl cAMP (MBcAMP), and N6-dibutyryl cAMP (DBcAMP), IBMX, forskolin, pertussis toxin, adrenocorticotropic hormone, thyrotropin-stimulating hormone (TSH), collagenase (type II, lot 107H8649), caffeine, theophylline, adenosine, N6-(2-phenylisopropyl)adenosine (PIA), and adenosine deaminase were all obtained from Sigma Chemical (St. Louis, MO). Insulin (Humulin R) was purchased from Eli Lilly (Toronto, Canada). ICI-89406 was a generous gift from ICI pharmaceuticals. ICI-118551 was purchased from RBI Sigma-Aldrich (Oakville, Canada). CL-316243 was obtained from American Cyanamid. Imazodan was purchased from Warner-Lambert. Amrinone and milrinone were obtained from Sterling-Winthrop Research Institute.
Animals. Male Wistar rats were obtained from Charles River and were housed in individual cages at 24°C with a 12:12-h light-dark cycle. The rats received standard Purina chow and water ad libitum. The mean body mass of the rats used in the present experiments was 290 ± 15 g.
Adipocyte isolation.
Adipocytes were isolated from epididymal fat pads by a slight
modification of Rodbell's method (29). Briefly, rats were killed by decapitation, and their epididymal fat pads were removed and
placed in Krebs-Ringer bicarbonate (KRB) buffer of the following composition (in mM): 120 NaCl, 4.75 KCl, 2.5 CaCl2, 1.2 KH2PO4, 1.2 MgSO4, 25 NaHCO3, 5.5 glucose, 20 HEPES, and 1% fatty acid-free bovine serum albumin, pH 7.4 (KRB 1%). The minced tissue was incubated in KRB 1% containing 0.5 mg/ml collagenase at 37°C for 15-20
min with a shaking frequency of 150 cycles/min. At the end of
incubation, the cells were filtered through a 500-µm nylon filter
(Nitex) and diluted with 5 ml of KRB 1%. The floating cells were
washed four times with KRB 1% and preincubated at 37°C for 15 min in KRB 1% (shaking frequency of 40 cycles/min) and washed twice with warm
(37°C) KRB containing 4% fatty acid-free bovine serum albumin (KRB
4%). Finally, the cells were incubated under the same conditions for
2 h (unless otherwise specified) in the presence of hormones or
drugs at a concentration of 3-5 × 105 cells/ml
KRB 4%. The adipocytes were then allowed to float, and the
infranatants were frozen at 20°C for leptin and glycerol measurements.
Leptin and glycerol assays. Leptin concentrations were determined by radioimmunoassay using a kit available from Linco Research (St Charles, MO). Glycerol was measured using an enzymatic method (37).
Statistics. The data were analyzed using analysis of variance. Values represent the means ± SE of a number of individual experiments performed on separate occasions (n), as indicated in the text. The responsiveness and sensitivity of adipocytes for the stimulation of leptin secretion or lipolysis (Vmax and EC50) and the half-effective concentration for inhibition of these parameters (IC50) were determined by computer analysis (SigmaPlot program) of concentration-response curves.
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RESULTS |
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Insulin stimulation of leptin secretion.
Concentration-response experiments revealed that insulin approximately
doubled (from 4.1 ± 0.2 to 7.9 ± 0.3 ng
leptin · 106 cells · 2 h
1,
P < 0.01) the basal rates of leptin release from white
adipocytes isolated and incubated as described in MATERIALS AND
METHODS (Fig. 1). Insulin acted
with an EC50 value of 0.7 nM, which is in the physiological
range of plasma insulin concentrations in the rat. Insulin
stimulated leptin secretion in a linear manner for at least 4 h
(Fig. 1, inset). Therefore, all subsequent incubations were
carried out for a 2-h period.
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Inhibition of the stimulatory effects of insulin by -adrenergic
agonists.
Because insulin is a potent antilipolytic hormone, we tested whether
lipolytic agents such as
-adrenergic agonists would reverse the
stimulatory effects of insulin on leptin release. Adipocytes were
incubated in the presence of insulin (added at a concentration of 10 nM
that induces a near-maximal stimulation of leptin release) (see Fig. 1)
and increasing concentrations of
-adrenergic agonists. Extracellular
glycerol (an index of lipolysis) and leptin concentrations were
measured in parallel in the same cellular preparations (Fig.
2, A and B).
Norepinephrine, isoproterenol (two nonselective
-agonists),
dobutamine, procaterol, and CL-316243 (selective
1-,
2-, and
3-agonists, respectively) all
inhibited insulin-stimulated leptin secretion with an order of potency
(IC50 values: CL-316243 = 10 nM > isoproterenol = 56 nM > norepinephrine = 219 nM > dobutamine = 3 µM > procaterol = 14 µM) (Fig. 2)
that was similar to that by which these agents stimulated lipolysis
(EC50 values: CL-316243 = 33 nM > isoproterenol = 47 nM > norepinephrine = 350 nM > dobutamine = 3 µM, procaterol = 19 µM) (Fig. 2). This
provided a first indication that leptin secretion might be
metabolically associated with the stimulation of lipolysis via
cAMP-dependent protein kinases.
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Reversal of the inhibitory effects of adrenergic agonists on
insulin-stimulated leptin secretion by propranolol.
To determine whether the inhibitory effects of norepinephrine,
isoproterenol, and CL-316243 were reversible, we first tested the
effects of propranolol, a potent 1/
2- and
weak
3-antagonist. Adipocytes were incubated in the
presence of insulin (10 nM), norepinephrine (1 µM), isoproterenol
(0.1 µM) or CL-316243 (0.1 µM), and various concentrations of
propranolol. The
-agonists were added at concentrations that nearly
maximally inhibited insulin-stimulated leptin secretion (see Fig. 2).
It can be seen in Fig. 3 that propranolol reversed the effects of norepinephrine and isoproterenol when added at
concentrations that were 1-100 times greater than the agonist
concentrations. However, propranolol only partially reversed the action
of CL-316243, as expected for a weak
3-antagonist.
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Reversal of the inhibitory effects of norepinephrine on
insulin-stimulated leptin secretion by selective 1- and
2-antagonists.
To further assess the contribution of
1-,
2-, and/or
3-adrenoceptors to the
inhibitory effects of norepinephrine, adipocytes were incubated in the
presence of insulin (10 nM), norepinephrine, and various concentrations
of the selective
1-antagonist ICI-89406 or
2-antagonist ICI-118551 (Fig.
4). Norepinephrine was added at a
concentration that nearly totally inhibits insulin (10 nM)-stimulated leptin secretion (Fig. 2), whereas ICI-89406 and ICI-118551 were studied at concentrations that were 1-100 times greater
(1-100 µM) than that of norepinephrine (1 µM). Both
-antagonists partially reversed the inhibitory effects of
norepinephrine on insulin-stimulated leptin release. However, the
1-antagonist ICI-89406 was more effective than the
2-antagonist ICI-118551. These results indicate that
1- and
2-adrenoceptors mediate
norepinephrine action, at least in part. Selective
3-antagonists were not tested because they are not yet
available, at least to our knowledge. However, two observations
strongly indicate that
3-adrenoceptors also mediate
norepinephrine effects: 1) the reversal by
1-
and
2-antagonists was only partial (Fig. 4), and
2) the selective
3-agonist CL-316243 effectively inhibited insulin-stimulated leptin secretion (Fig. 2).
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Reversal of the inhibitory effects of isoproterenol on
insulin-stimulated leptin secretion by selective
1/
2-antagonists.
Experiments similar to those described in Fig. 4 were carried out with
isoproterenol (Fig. 5). This agent is a
potent inhibitor of leptin secretion in humans and acts at much lower
concentrations than norepinephrine (Fig. 2). Comparable results to
those obtained with norepinephrine (1 µM) (Fig. 4) were obtained with
isoproterenol (0.1 µM) but at lower antagonist concentrations (0.1, 1, or 10 µM). The
1/
2-antagonists
completely reversed the effects of isoproterenol, as expected from a
potent
1/
2-agonist.
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Inhibition of the stimulatory effects of insulin by lipolytic
hormones, adenylate cyclase activators, methylxanthines, cAMP analogs,
and phosphodiesterase inhibitors.
The goal of the next experiments was to test whether there is a
cause-effect relationship between the stimulation of lipolysis via the
adenylate cyclase-phosphodiesterase system and inhibition of
extracellular leptin release. If such a relationship exists, then one
should expect that all agents stimulating lipolysis (increasing intracellular cAMP levels) would inhibit insulin stimulation of leptin
secretion. To test this hypothesis, adipocytes were incubated in the
presence of insulin (10 nM) and a variety of agents that increase cAMP
levels via different mechanisms (Figs. 6
and 7). In addition to catecholamines
and adrenergic agents (Figs. 2), we tested a dozen other agents:
1) lipolytic hormones such as ACTH and TSH, which activate
the adenylate cyclase-G protein complex by acting via their specific
membrane receptors, 2) the adenylate cyclase activator
forskolin, 3) pertussis toxin, which is known to inactivate
Gi protein and promote cAMP increment in fat cells, 4) the phosphodiesterase-hydrolyzable analog 8-BrcAMP as
well as the nonhydrolyzable cAMP analogs MBcAMP and DBcAMP,
5) the methylxanthines caffeine, theophyllin, and IBMX,
which inhibit nonspecifically phosphodiesterases, and 6)
specific inhibitors of phosphodiesterase III (imazodan, milrinone, and
amrinone). Each of these agents was tested at a concentration that
maximally stimulates lipolysis and that was determined in preliminary
concentration-response experiments. Comparison of Figs. 6A
and 7A (lipolysis) with Figs. 6B and
7B (leptin secretion) reveals that all agents that maximally stimulated lipolysis totally inhibited insulin-stimulated leptin secretion. Significantly, the hydrolyzable cAMP analog 8-BrcAMP did not
stimulate lipolysis (in the presence of insulin) and did not inhibit
leptin secretion. However, the two cAMP analogs that are resistant to
phosphodiesterase-dependent hydrolysis, MBcAMP and DBcAMP, both
stimulated lipolysis and inhibited leptin secretion. On the whole,
these data show that insulin-stimulated leptin secretion can be totally
inhibited by lipolytic agents known to increase intracellular cAMP
concentration, independently of the mechanisms by which they act.
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Effects of adenosine and other antilipolytic agents on
insulin-stimulated leptin secretion.
We also investigated whether antilipolytic agents other than insulin
would mimic its effects on leptin secretion. We tested several insulin
mimetics and/or antilipolytic agents acting via different mechanisms on
adenylate cyclase: orthovanadate, adenosine, PIA (a nonmetabolizable
analog of adenosine), nicotinic acid, and acipimox, a stable analog of
nicotinic acid. Sodium orthovanadate is an insulin mimetic that
stimulates glucose uptake in isolated adipocytes and inhibits
lipolysis, presumably by the inhibiting protein phosphotyrosine
phosphatases (18). Adenosine, PIA, nicotinic acid, and
acipimox are all antilipolytic Gi-coupled adenylate cyclase
inhibitory agonists (5, 7, 19). Although all these agents
completely inhibited norepinephrine-stimulated lipolysis under the
present experimental conditions, none of them mimicked the stimulatory
effects of insulin on leptin secretion (not shown), at least at short
term (within 2 h of incubation). This suggests that an inhibition
of lipolysis consequent to an intracellular decrease in cAMP levels
does not represent a metabolic event that may, per se, trigger leptin
secretion. However, it has been shown that the antilipolytic agent
neuropeptide Y is able to stimulate leptin secretion after
longer periods of incubation (22 h) (31).
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DISCUSSION |
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The role of 1- and
2-adrenoceptors in
mediating norepinephrine action.
The present study revealed that insulin-stimulated leptin secretion is
mediated not only via the low-affinity
3-adrenoceptors but also via the high-affinity
1/
2-adrenoceptors with
2-adrenoceptors playing a lesser role than
1-adrenoceptors. This conclusion is based on the
following observations: 1) selective
1- and
3-agonists (dobutamine and CL-316143, respectively) and
nonselective agonists (norepinephrine and isoproterenol) all completely
inhibited insulin-stimulated leptin secretion (Fig. 2); 2)
the selective
2-antagonist procaterol, in contrast,
partly inhibited insulin-stimulated leptin secretion and only at high
concentrations (0.1 mM); and 3) the selective
1-antagonist ICI-89406, likewise, reversed more
effectively than the
2-antagonist ICI-118551 the
inhibitory effects of norepinephrine or isoproterenol on
insulin-stimulated leptin secretion (Figs. 4 and 5). Contrary to the
present observations, it has been claimed that the norepinephrine
effects were essentially mediated by
3-adrenoceptors because they were unaffected by selective
1/
2-antagonists (11). However, these results are difficult to interpret because the concentrations of the antagonists were either too low or not specified, as in the case of the
1/
2-blocker
CGP-12177. Furthermore, CGP-12177 may also act as a
3-agonist, depending on its concentration
(22). Another observation that supports a role for
1-adrenoceptors in regulating leptin secretion is the
fact that propranolol inhibited the effects of norepinephrine and
isoproterenol when added at slightly higher concentrations than the two
agonists (Fig. 3). Direct binding studies have demonstrated that the
affinity of propranolol, norepinephrine, and isoproterenol for the
1-adrenoceptors is about 104-105
greater (pKd or pKi
values varying between 8 and 9) than the one for
3-adrenoceptors (pKd or
pKi values varying between 4 and 5). Thus it is
likely that low concentrations of propranolol reverse the effects of
norepinephrine and isoproterenol by competing for the high-affinity
1/
2 binding sites. However, at higher concentrations, propranolol may also affect
3-adrenoceptors. These observations suggest that
circulating catecholamines, levels of which rarely exceed 25 nM, would
regulate leptin secretion mainly via the high-affinity
1-adrenoceptors, whereas the low-affinity
3-adrenoceptors would mainly be activated when
norepinephrine concentrations in the synaptic cleft reached higher
concentrations, such as after cold exposure or other intensive stress
(2).
The role of the adenylate cyclase-phosphodiesterase system.
In addition to -adrenergic agonists, insulin-stimulated leptin
secretion could also be inhibited by a wide variety of agents known to
increase intracellular cAMP levels by stimulating its production at the
cyclase level (ACTH, TSH, pertussis toxin, or forskolin), inhibiting
its degradation by phosphodiesterases (caffeine, theophylline, IBMX,
imazodan, milrinone, or amrinone), or mimicking its action (MBcAMP or
DBcAMP). Without exception, all these agents stimulated lipolysis in
the range of concentrations at which they inhibited insulin-stimulated
leptin secretion. Although cAMP levels were not directly measured in
the present experiments, these results strongly indicate that cAMP
plays a fundamental role in regulating insulin stimulation of leptin
secretion. However, the role of cAMP appears to be merely modulatory
because, in the absence of insulin, all the above lipolytic agents
either did not alter or slightly inhibited basal leptin secretion.
Perspectives
The present study has shown that catecholamines, ![]() |
ACKNOWLEDGEMENTS |
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This work was supported by a grant from the Canadian Institutes of Health Research.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. J. Bukowiecki, Dept. of Physiology, Faculty of Medicine, Laval Univ., Quebec, Canada G1K 7P4 (E-mail: ludwik.bukowiecki{at}phs.ulaval.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published March 6, 2002;10.1152/ajpcell.00033.2002
Received 22 January 2002; accepted in final form 27 February 2002.
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