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Division of Endocrinology, Diabetology and Metabolism (F.P.P., E.C., R.C.G.), Institute of Pharmacology and Toxicology (R.R., B.T.), Service of Internal Medicine B (G.W.) and Department of Surgery (F.M.), University Hospital, 1011 Lausanne, Switzerland
Address all correspondence and requests for reprints to: François P. Pralong, M.D., Division of Endocrinology, Diabetology and Metabolism, Department of Medicine, BH 19707, Centre Universitaire Vaudois, 1011 Lausanne, Switzerland. E-mail: francois.pralong{at}chuv.hospvd.ch
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Abstract |
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Human adrenal glands from kidney transplant donors were dissociated, and isolated primary cells were studied in vitro. These cells were preincubated with recombinant leptin (10-10–10-7 M) for 6 or 24 h, and basal or ACTH-stimulated cortisol secretion was subsequently measured. Basal cortisol secretion was unaffected by leptin, but a significant and dose-dependent inhibition of ACTH-stimulated cortisol secretion was observed [down by 29 ± 0.1% of controls with the highest leptin dose, P < 0.01 vs. CT (unrelated positive control)]. This effect of leptin was also observed in rat primary adrenocortical cells, where leptin inhibited stimulated corticosterone secretion in a dose-dependent manner (down by 46 ± 0.1% of controls with the highest leptin dose, P < 0.001 vs. CT). These effects of leptin in adrenal cells are likely mediated by the long isoform of the leptin receptor (OB-R), because its transcript was found to be expressed in the adrenal tissue and leptin had no inhibitory effect in adrenal glands obtained from db/db mice. Therefore, leptin inhibits directly stimulated cortisol secretion from human and rat adrenal glands, and this may represent an important mechanism to modulate glucocorticoid levels in various metabolic states.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The secreted product of the adipocyte leptin (6) also participates in the regulation of metabolism and food intake, at least partially, by modulating the expression of the hypothalamic orexigenic peptide neuropeptide Y (7). Several other neuroendocrine effects of leptin have been described, including a down-regulation of the fasting-induced activation of the hypothalamo-pituitary-adrenal (HPA) axis (8). Therefore, changes in the nutritional or metabolic status of the organism, as reflected by changes in circulating leptin levels, can ultimately modulate the production of cortisol, a hormone with numerous metabolic functions. These effects are mediated, in part, by the lowering of ACTH secretion induced by leptin (8). However, recent data suggest that leptin could also have direct effects on the endocrine pancreas (9, 10, 11), as well as on ovarian granulosa cells (12, 13). In the present study, we have tested the hypothesis that, in addition to its central nervous system (CNS) effects, leptin may have direct effects in the control of glucocorticoid secretion by the adrenal gland. We have demonstrated that leptin exerts a direct, dose-dependent inhibition of stimulated cortisol secretion by normal human adrenal cells in vitro and that a similar inhibition was also present in normal rat adrenocortical cells in primary culture. This effect is likely mediated by the active isoform of the leptin receptor, OB-Rb (14, 15), because its expression could be demonstrated in human adrenal tissue.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Briefly, adrenals were minced with a scalpel blade, and then subjected to combined enzymatic and mechanical dispersion: tissue fragments were placed in a Bellco flask to allow constant trituration and were incubated for 90 min at 37 C in the presence of Collagenase type I (Sigma, Buchs, Switzerland), followed by Neuraminidase type V (Sigma). After dispersion, cells were resuspended in medium containing 2.5% FCS and plated at a concentration of 1 x 106 cells/well in 6-well plates pretreated with poly-D-lysine (Sigma). Viability was assessed by Trypan blue exclusion and ranged between 60–80%.
Cells were incubated for 48 h at 37 C in 95% O2-5% CO2. Medium was then changed for serum-free medium, and stimulations were performed as described below.
Normal rat and db/db mice adrenal culture
Wistar female rats, weighing 200–250 g, were killed by
decapitation. Adrenals were rapidly removed, and the medulla was
separated from the cortex by squeezing the gland gently after making an
incision through the capsula. In parallel experiments, adult
db/db mice (purchased from Harlan Nederland B. V.,
Horst, The Netherlands) were also killed by decapitation, and
their adrenals were rapidly removed and cut into four pieces.
Db/db mice were used as negative controls, because this
particular strain bears a spontaneous mutation of the leptin receptor,
OB-Rb, rendering it totally devoid of signal transduction capability
(17). Dispersion of rat or mouse glands was performed according to a
similar procedure, as above. Viability was always more than 90%.
Cells were resuspended in medium containing 2.5% FCS and were plated at a concentration of 250,000 cells/well in 24-well plates pretreated with poly-D-lysine. They were incubated for 72 h at 37 C in 95% O2-5% CO2. Medium was then changed for serum-free medium, and stimulations were performed as described below.
Before they were killed, animals were housed in our animal facility under a 12-h light, 12-h dark schedule and were fed ad libitum. All animal care and scientific procedures were carried out in strict accordance with our government directives after formal approval by the State Veterinary Department.
Experimental design
Time course and dose-response experiments were performed in an
identical fashion for both human and rat tissues. Cells were
preincubated for 6 or 24 h in the presence of increasing
concentrations of murine recombinant leptin (purchased from Pepro Tech
EC Ltd, London, UK), ranging from 10-10–10-7
M, in serum-free medium. After this preincubation, medium
was changed and cells were stimulated for 90 min with ACTH
(10-9 M) in the presence of the same leptin
concentration as during the preincubation period. This concentration of
ACTH was previously shown to elicit a half-maximal corticosterone
secretion in our system. Controls consisted of cells preincubated in
serum-free medium containing no leptin and stimulated similarly by ACTH
(10-9 M). In initial experiments, base line
points, consisting of cells preincubated with leptin but not subjected
to ACTH stimulation, were also added. Each condition was performed in
triplicate and repeated in at least 3 (human) or 4 (rat) separate
experiments. At the end of the ACTH stimulation, medium was collected
and immediately frozen until assayed for corticosterone or
cortisol.
Assays and statistical analysis
Corticosterone was measured in duplicate by RIA, as previously
described (18), using our own anticorticosterone rabbit serum. All
samples from a single experiment were always measured in the same
assay, and the intra- and interassay coefficients of variation ranged
between 4 and 7, and 8 and 10%, respectively.
Cortisol was measured by RIA in duplicates using a commercially available kit (Coat-a-Count, DPC, Los Angeles, CA). All samples from a single experiment were also measured in the same assay, and the intra- and interassay coefficients of variation ranged between 3 and 5.1, and 4 and 6.4%, respectively.
Results, expressed as percent of ACTH-stimulated value, to correct for differences in absolute hormone secretion between experiments, are given as means ± SEM. Statistical significance was determined by ANOVA, followed by post hoc testing with the Fisher’s least-significant-difference test to determine individual differences.
Leptin receptor expression
Total RNA was obtained from adrenal tissue, following a slightly
modified version of the method of Chomczynski et al. (19):
volumes have been adapted to small samples, and RNA is routinely
precipitated overnight at -20 C. RNA was then subjected to RT-PCR,
using enzymes and reagents purchased from Perkin-Elmer Europe B. V.
(Rotkreuz, Switzerland) (Gene Amp RNA PCR kit), following the
manufacturer’s recommendations. One microgram of total RNA was
reverse-transcribed using random hexamers and then amplified by PCR in
100 µL, using primers specific for a portion of the intracellular
domain of human OB-Rb (the leptin receptor isoform with full signaling
capability) (15). Amplification was carried out for 35 cycles in a
Perkin Elmer Gene Amp PCR System 9600 thermocycler, using an annealing
temperature of 48 C. Sense primer was 5'-TATCTATTATTTAGGGGTCACC-3' and
antisense primer was 5'-ACCCACAACTATAATCTATTACAC-3'. The PCR product
was subjected to electrophoresis in 2% agarose gel and visualized by
ethidium bromide staining. Molecular weight markers (100-bp ladder)
were purchased from Promega. Two negative controls were always included
with each RT-PCR reaction: a non-reverse transcriptase control in which
the reverse transcriptase is replaced by diethylpyrocarbonate-treated
water, and a blank (B) in which the RNA sample is replaced by
diethylpyrocarbonate-treated water. Furthermore, the identity of the
PCR products was confirmed by sequencing (Microsynth AG, Balgach,
Switzerland).
In addition, this PCR product was purified and, after labeling with 32P by the random hexanucleotide method, used as a probe in a Northern blot analysis of total or messenger RNA from normal human adrenals. Fifteen micrograms of total RNA or 4 µg of messenger RNA were loaded onto a 1% agarose-formaldehyde gel and subjected to size-fractionation by electrophoresis. RNA was then transferred to a nylon membrane (GeneScreen, Biotechnology Systems, NEN Research Products, Boston, MA), fixed by UV cross-linking, and subjected to overnight hybridization at 42 C. After washing, films (Hyperfilm MP, Amersham, Life Sciences) were exposed to the blots for 5 days at -80 C.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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shows cortisol secretion
by human adrenal cells stimulated for 90 min with ACTH
(10-9 M), after preincubation with increasing
concentrations of leptin for 6 h (shaded bars) or
24 h (solid bars). Values are expressed as percent of
ACTH-stimulated cortisol secretion in the absence of leptin (ACTH,
10-9 M). There was no significant effect of
6 h of preincubation with leptin on ACTH-stimulated cortisol
secretion. After 24 h, however, a dose-dependent inhibition of
ACTH-stimulated cortisol secretion was observed: leptin
(10-8 M) decreased cortisol secretion to
75 ± 4% of controls (P < 0.05 vs.
ACTH only), and leptin (10-7 M) decreased it
to 71 ± 5% of controls (P < 0.01 vs.
ACTH only). No effect of leptin was observed on unstimulated cortisol
secretion, either at 6 or 24 h (data not shown).
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represents
corticosterone secretion stimulated by exposure of the cells to ACTH
(10-9 M) for 90 min, after preincubation with
increasing concentrations of leptin for 6 h (shaded
bars) or 24 h (solid bars). Again, results are
expressed as percent of ACTH-stimulated corticosterone secretion in the
absence of leptin. In contrast to the human data, the highest leptin
concentration (10-7 M), after 6 h, was
already found to induce a significant inhibition of stimulated
corticosterone secretion (to 68 ± 6% of controls,
P < 0.01 vs. ACTH only). After 24 h,
leptin induced a dose-dependent inhibition of ACTH-stimulated
corticosterone secretion, to 73 ± 5%, 73 ± 7%, and
54 ± 6% of controls for leptin (10-9 M,
10-8 M, and 10-7 M,
respectively (P < 0.01 for all vs. ACTH
only, P < 0.001 for 10-7 M
leptin vs. ACTH only, P < 0.01 for
10-7 M leptin vs.
10-10 M). Again, there was no effect of leptin
on basal corticosterone secretion, either after 6 or 24 h of
preincubation (data not shown). In sharp contrast to the findings observed with both human and rat tissue, leptin exerted no effect on ACTH-stimulated corticosterone secretion in adrenal cells obtained from db/db mice. After 24 h of exposure to the same graded concentrations of leptin as above, corticosterone secretion was 122 ± 6%, 101 ± 12%, 120 ± 1.5%, and 99 ± 3% of controls for 10-10 M, 10-9 M, 10-8 M, and 10-7 M leptin, respectively (for all, not significant vs. control).
Figure 2 compares the effects of leptin
in both human and rat cells. It represents the same results as above,
after 24 h of preincubation with leptin, expressed as the percent
of inhibition achieved from ACTH-stimulated cortisol (or
corticosterone) secretion. This graph demonstrates the similarity of
the effects of leptin in both the human and the rat models. Statistical
significances are as described above.
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is the photograph of a 2%
agarose gel with ethidium bromide staining. This picture
demonstrates the presence of the expected 380-bp product in human
adrenal. Negative controls (NRT and B) are negative. However, tentative
confirmation of these data by Northern blot analysis of human adrenal
RNA remained negative (data not shown), suggesting a low level of
expression of OB-Rb.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our results are consistent with the recent observation by Bornstein and colleagues (24), who showed a direct inhibition of cortisol secretion from bovine adrenal glands by leptin in vitro. However, unlike these authors, we were unable in our human and rat models to show any long-term effect of leptin on basal cortisol secretion. The reason for this discrepancy is unclear, because the methods used and the experimental paradigms were very similar in both studies. One could speculate that the very low levels of basal cortisol or corticosterone secretion measured in our in vitro system, in the absence of serum, might have prevented us from demonstrating a further decrease of secretion in the presence of leptin.
The mechanism(s) responsible for this inhibition remain unclear:
Bornstein et al. (24) have shown that leptin down-regulates
the expression of the steroidogenic enzyme cytochrome P450 17
, which
is one of the mechanisms through which leptin can inhibit cortisol
production in bovine adrenal cells. However, the rat adrenal gland does
not express this enzyme. Therefore, the effects of leptin reported in
the present study suggest that other steps of the steroidogenic pathway
are likely modulated by leptin in adrenal tissue. The time course of
the effects reported by us, as well as by others (24), with maximum
inhibition occurring after 24 h of exposure to leptin, is fully
consistent with a modulation of adrenal steroidogenesis at the
transcriptional level. This time course is also physiologically
consistent with data dealing with leptin regulation in the human
(25, 26, 27, 28). Most available studies have shown that circulating leptin
levels are not acutely regulated but rather that fluctuations after
nutritional changes take hours to days to take place. In this regard,
it could almost be anticipated that a direct adrenal regulation by
circulating leptin would take some time to fully develop.
Another recent publication has investigated the potential direct effects of leptin on rat adrenocortical cells, showing an acute stimulation of basal corticosterone and aldosterone secretion but no effect on ACTH-stimulated hormone secretion (29). At this point, there is no definitive explanation for this discrepancy between their study (29) and our work, or that of Bornstein et al. (24). The short time course of 1 h, used by these authors (29), might (at least partially) explain this difference, if leptin should turn out to exert biphasic effects. It should also be noted that leptin can probably modulate the activity of the HPA axis at the hypothalamic level, although reports are conflicting: stimulating (30, 31), as well as inhibiting (8, 21), effects have been described, and further studies will be required to clarify this issue.
Although leptin was initially thought to have effects exclusively at the CNS level, there is now accumulating evidence that it has also widespread peripheral actions: it can directly modulate glucose-induced insulin secretion from pancreatic ß-cells (9, 10, 11), and two recent reports have demonstrated its direct action on ovarian granulosa cells to inhibit estradiol production in vitro (12, 13). Thus, although CNS actions of leptin seem to be crucial to modulate food intake (32), as well as different neuroendocrine functions (8), there is an emerging role for leptin to regulate the activity of several endocrine glands, whose function is crucially dependent on the metabolic status of the organism.
Our results strongly suggest that the direct effects of leptin on the adrenal are involving the long isoform of the leptin receptor, OB-Rb (14). Indeed, we were able to demonstrate its expression in human and rat adrenal tissue by RT-PCR, a finding consistent with a report showing the expression of this receptor in the mouse adrenal cortex by in situ hybridization (33). Moreover, leptin had no effect on adrenal cells obtained from db/db mice, which completely lack a functional leptin receptor (17). This latter finding represents an indirect demonstration that OB-Rb is functional in normal rat and human adrenal glands, and therefore may be mediating the effects of leptin in this tissue.
The inhibition of cortisol secretion by leptin may help us to better understand the relationships existing between the metabolism and the response to stress, as well as the crucial role of glucocorticoids in the development of obesity. It is well established that mice lacking a functional leptin (ob/ob mice) exhibit an increased basal production of glucocorticoids throughout life (34) despite normal circulating levels of ACTH (35). Moreover, ob/ob mice subjected to an ether stress show an exaggerated glucocorticoid secretion, in the face of an ACTH response, which is comparable to that of lean controls (35). These two early observations suggest an increased responsiveness of the adrenal of ob/ob mice to ACTH stimulation, compared with normal, and can be explained by the lack of a direct inhibitory action of leptin. Again, these in vivo findings (34, 35) argue strongly in favor of a physiological relevance for the in vitro effects of leptin described here, although this does not exclude the participation of other centrally mediated effects of leptin in its overall modulation of the activity of the HPA axis.
Taken together, the data from Bornstein et al. (24) and the present work demonstrate that the adrenal level is involved in the endocrine loop existing between the adipose tissue and the HPA axis (8, 20, 21): glucocorticoids can stimulate leptin expression and secretion from the adipocyte (36, 37), whereas rising circulating leptin levels can directly down-regulate cortisol synthesis and secretion from adrenal cells. It was demonstrated very recently that circulating glucocorticoids can limit the central effects of leptin on food intake (38), therefore contributing to the leptin resistance syndrome. This leads to the speculation that, by decreasing directly the amount of glucocorticoids produced at the adrenal level, leptin itself can potentiate or prime the hypothalamus to its own effects, by an unknown mechanism involving glucocorticoids. Whether and how this plays a role in the development of the obesity syndrome in humans remains to be evaluated.
In conclusion, we have demonstrated that leptin can directly inhibit cortisol secretion by human adrenal cells, as well as rat adrenal cells in vitro. This effect is probably mediated by OB-Rb, the long isoform of the leptin receptor. This link existing between metabolism and cortisol secretion, via circulating leptin levels, may have profound implications to the understanding of the role of glucocorticoids in obesity, as well as to the response to stress in various conditions of energy balance.
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Acknowledgments |
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Footnotes |
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2 Recipient of a Research Development Carrier Award from the Prof. Dr.
Max Cloëtta Foundation.
3 Recipient of a Research Development Carrier Award from the Swiss
National Science Foundation (No. 32–49673.96).
Received December 1, 1997.
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