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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 6 2138-2142
Copyright © 1998 by The Endocrine Society

Original Studies

Relationship between Plasma Adrenocorticotropin, Hypothalamic Opioid Tone, and Plasma Leptin1

Gary S. Wand and Henry Schumann

Departments of Medicine and Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Gary S. Wand, M.D., The Johns Hopkins University School of Medicine, Ross Research Building, Room 850, 720 Rutland Avenue, Baltimore, Maryland 21205. E-mail: gwand{at}welchlink.welch.jhu.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The purpose of the present study was to further the understanding of the relationship between plasma leptin concentrations, hypothalamic opioid tone, and plasma ACTH secretory dynamics. ACTH(1–24) challenges (250 µg) produced the expected increase in plasma cortisol levels but did not alter plasma leptin levels. Activation of the entire hypothalamic-pituitary-adrenal (HPA) axis was induced by employing the opioid receptor antagonist, naloxone. By blocking opioidergic inhibitory input to hypothalamic CRH neurons, naloxone induced the expected increase in plasma ACTH and cortisol. Plasma ACTH levels peaked 30 min after naloxone administration, whereas plasma cortisol levels peaked 60 min after opioid receptor blockade. Once again, plasma leptin concentrations were not altered by this manipulation. However, there was a positive correlation between fasting, integrated plasma leptin concentrations, and plasma ACTH responses to naloxone (peak r = 0.822, P < 0.0001; and area under curve r = 0.832, P < 0.0001). The correlation was stronger when leptin was normalized to body mass index and expressed as the leptin/body mass index ratio (peak r = 0.878, P < 0.00001; and area under curve r = 0.882, P < 0.00001). In summary, these findings indicate that activation of the HPA axis does not acutely alter plasma leptin concentrations. However, plasma leptin levels may influence hypothalamic opioidergic tone and thus modulate the magnitude of CRH release. The acute interaction of the HPA axis and leptin is unidirectional.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THERE IS a strong association between nutritional status and the activity of the hypothalamic-pituitary-adrenal (HPA) axis (1, 2). Obesity (3, 4, 5), as well as calorie deprivation (6), modify the functioning of the HPA axis. Leptin, a newly discovered adipostatic hormone (7), inhibits appetite and also has an inhibitory effect on the HPA axis (8, 9, 10). For example, administration of leptin to fasting rodents (9) or to rodents stressed by immobilization (10) inhibits plasma ACTH and corticosterone levels. Administration of leptin reduces corticosterone levels in the genetically obese, ob/ob mice (11). Leptin also inhibits hypoglycemia-induced CRH secretion from isolated, perifused rat hypothalami (10). More evidence supporting inhibitory actions of leptin on the HPA axis includes studies showing a reciprocal relationship between plasma leptin and plasma corticosterone concentrations (9). Leptin may modulate the diurnal rhythm of corticosterone secretion.

The mechanism(s) through which leptin inhibits HPA axis activity remains unknown. A clue to this mechanism may be the interaction of leptin and opioidergic (POMC) neurons of the arcuate nucleus. Recent studies have shown that leptin’s action is, in part, mediated through release of melanocortin from arcuate nucleus POMC neurons (12). These studies indicate that leptin-induced melanocortin release reduces food intake via signaling through the melanocortin-4 (MC4) receptor (12). The arcuate nucleus POMC neurons also have another function. This opioidergic system inhibits CRH neuron activity through ß-endorphin release (13, 14, 15, 16, 17). Because plasma leptin levels stimulate arcuate nucleus POMC activity and, in turn, POMC neurons (through ß-endorphin) inhibit CRH release, it is plausible that ambient plasma leptin concentrations may influence HPA axis secretory dynamics through acute and chronic effects on this opioidergic pathway.

Although there is mounting evidence that leptin has an inhibitory effect on the HPA axis in rodents and humans, the nature of the reciprocal relationship is uncertain. A recent study showed no change in plasma leptin levels after the administration of CRH (18). However, it remains unclear whether activation of the HPA axis by other means will alter plasma leptin levels. Therefore, the first aim of the study was to determine whether activation of the HPA axis would acutely alter plasma leptin levels. To this end, plasma leptin levels were monitored at baseline and for 120 min after activation of the HPA axis after administration of ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) or naloxone. The second aim of the study was to determine whether there was an association between plasma leptin levels and hypothalamic opioid activity. Our hypothesis was that plasma leptin concentrations would correlate with peak plasma ACTH levels induced by opioid receptor blockade. The hypothesis was tested by comparing the magnitudes of plasma ACTH release, in response to opioid receptor blockade, as a function of an individual’s integrated plasma leptin level.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Sixteen healthy, nonobese volunteers (9 women and 7 men), 18–25 yr old, were recruited by newspaper advertisement. All subjects gave informed consent. General health status was assessed by medical history, physical examination, and standard laboratory tests (complete blood cell counts, electrolytes, liver and renal function tests, and glucose). To control for hormonal fluctuations, female subjects were studied only during the follicular phase of the menstrual cycle. Exclusion criteria were: 1) meeting Diagnostic and Statistical Manual-IV criteria for any psychoactive substance use disorder, including nicotine dependence; 2) meeting Diagnostic and Statistical Manual-IV criteria for a major axis I disorder and being in need of, or currently undergoing, pharmacotherapy; 3) being pregnant; 4) experiencing a serious medical condition; 5) having abnormal liver functions; 6) having central nervous system or endocrine disorders; and 7) being treated within the last 10 yr with:antidepressants, neuroleptics, mood stabilizers, sedative hypnotic medications, isoniazid, glucocorticoids, or psychostimulant appetite suppressants.

Neuroendocrine protocol

Subjects reported for sessions at 1230 h, having fasted since 0900 h breakfast. At each session, an iv catheter was inserted into a forearm vein at 1300 h. One hour after IV line placement, naloxone (125 µg/kg), ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) (250 µg) dissolved in 0.9% saline or Placebo (0.9% saline), was administered over 1 min as a bolus dose. Baseline blood samples were obtained 15 min before, and immediately before drug administration. After naloxone, ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24), or Placebo administration, blood samples were drawn at 15, 30, 45, 60, 90, and 120 min. Sessions were administered (double-blind) in randomized order. Study days were separated by at least 48 h.

Hormone assays

Plasma concentrations of cortisol were measured by RIA (Diagnostic Products Corporation, Inc.; Los Angeles, CA). Intraassay and interassay coefficients of variation were 5.2% and 8.0%, respectively. Plasma concentrations of ACTH were measured by 2-site immunoradiometric assay (Nichols, San Capistrano, CA); intraassay and interassay coefficients of variance were 9% and 10%, respectively. Plasma concentrations of Leptin were measured by RIA (Linco Research, St. Charles, MO); intraassay and interassay coefficients of variance were 5% and 7%, respectively.

Statistical analyses

Hormone response was measured by two indicators: 1) Peak response was defined as the highest value after stimulation; and 2) Area under the cortisol-time curve was calculated over the 2-h time interval using the trapezoidal rule. Means plus and minus SEM are reported. The effect of naloxone, cortrosyn, and placebo were analyzed by repeated-measures ANOVA with time of sampling as a within-subject factor. Correlation analysis between leptin and ACTH was performed by linear regression. Significance was accepted at P < 0.05.

Each subject was assigned a plasma leptin concentration. Leptin concentrations were determined by two methods: 1) Leptin levels were expressed as the mean time 0 value (before injection), determined by averaging time 0 leptin concentrations recorded for each session (mean of time 0 placebo, naloxone, and cortrosyn); 2) Leptin levels were also expressed as 2-h integrated values, determined by taking the average leptin concentration measured during the 120-min placebo session or naloxone session or cortrosyn session. Tables 1Go and 2Go indicate that for each subject, plasma leptin concentrations were extremely stable within and between sessions. Integrated placebo leptin concentrations were used for linear regression studies.


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  		Table 1. Mean fasting plasma leptin concentrations

 

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  		Table 2. Stability of plasma leptin concentrations

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
To determine whether direct adrenal activation of cortisol secretion is sufficient to acutely alter plasma leptin levels, ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) challenges were performed. Figure 1Go shows that ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) produced the expected increase in plasma cortisol levels but did not alter the plasma leptin concentration. Plasma leptin levels were identical throughout placebo and ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) sessions. Activation of the entire HPA axis was induced by employing the opioid receptor antagonist, naloxone. By blocking hypothalamic opioidergic inhibitory input to CRH-secreting neurons, naloxone induced the expected increase in plasma ACTH and cortisol (Fig. 2AGo). Plasma ACTH levels peaked 30 min after naloxone administration. Plasma cortisol levels peaked 60 min after the naloxone challenge. Once again, plasma leptin concentrations were not altered by this manipulation (Fig. 2BGo).



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  		Figure 1. Mean ± SE plasma cortisol (A) and leptin (B) responses to ACTH(1–24) or to placebo in seven normal men and nine normal women.

 


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  		Figure 2. Mean ± SE plasma ACTH (A), cortisol (A), and leptin (B) responses to naloxone (125 µg/kg) or to placebo in seven normal men and nine normal women.

 
As indicated in Tables 1Go and 2Go, subjects had no significant within-session or between-session changes in plasma leptin levels. Linear regression was performed to test whether there is an association between hypothalamic opioid activity and integrated plasma leptin levels. There was a positive correlation between the 2-h integrated plasma leptin concentrations and plasma ACTH response to naloxone (peak r = 0.822, P < 0.0001; and area under curve r = 0.832, P < 0.0001) (Fig. 3Go, A and C). The correlation was stronger when leptin was normalized to body mass index (BMI) and expressed as leptin/BMI ratio (Fig. 3Go, B and D) (peak r = 0.878, P < 0.00001; and area under curve r = 0.882, P < 0.00001). The mean BMI was 25 ± 1 kg/m2 (men, 27 ± 1.2; women, 24 ± 1.2). The correlations held true when women and men were analyzed separately. There was no correlation between baseline ACTH levels and leptin, nor was there a correlation between peak ACTH levels and BMI.



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  		Figure 3. Correlation of plasma leptin and naloxone-stimulated plasma ACTH levels. A, Peak ACTH vs. leptin (peak r = 0.822, P < 0.0001); B, peak ACTH vs. leptin/BMI (peak r = 0.878, P < 0.00001); C, AUC ACTH vs. leptin (AUC r = 0.832, P < 0.0001); D, AUC ACTH vs. leptin/BMI (AUC r = 0.882, P < 0.00001).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Leptin decreases food intake and increases metabolism (19, 20, 21). This signaling peptide is synthesized and secreted by adipose cells with circulating levels reflecting total body white adipose tissue (20). Several leptin receptor splice variants have been identified in hypothalamus and in other tissues (22, 23, 24, 25, 26). The principal action of leptin is to reduce appetite through an action on the hypothalamus (27). Leptin’s hypothalamic actions involve signaling through opioidergic, CRH, and neuropeptide Y pathways (11, 28).

In addition to modulating food intake and energy expenditure, leptin interacts with a number of endocrine systems (29, 30, 31, 32, 33, 34), including the HPA axis (9, 35). Most studies indicate that leptin restrains and inhibits HPA axis activity. The current study was performed to determine whether activation of the HPA axis would acutely alter plasma leptin levels and to determine whether there was an association between hypothalamic opioid tone and integrated plasma leptin levels. Our results firmly demonstrate that activation of the HPA axis does not acutely effect plasma leptin concentrations. Thus, the acute interaction of the HPA axis and leptin is unidirectional. Because we did not measure plasma leptin levels beyond 2 h after naloxone or ACTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) administration, it is possible that plasma leptin levels increased or decreased at later time points. In fact, a recent study showed that plasma leptin levels were greater 24 h after receiving 1 mg dexamethasone than before taking the corticosteroid (36). Additionally, our small sample size increases the possibility for type II error and the unequivocal acceptance of the null hypothesis. However, if the HPA axis does alter plasma leptin levels over this 2-h interval, it is a very minor effect and probably would have no physiological relevance.

Interestingly, there was a strong positive correlation between integrated fasting plasma leptin levels and the magnitude of plasma ACTH release after opioid receptor blockade with naloxone. The higher the leptin concentration, the greater the ACTH response to naloxone stimulation. This finding cannot be attributed to differences in BMI, for two reasons. First, there was no correlation between BMI and the ACTH response; second, the association between plasma leptin and stimulated ACTH release was even stronger when leptin levels were normalized to each subject’s BMI. This observation suggests that ambient leptin concentrations are associated with, and perhaps influence, the magnitude of ACTH release, at least when ACTH secretion is provoked by modulating the opioid system. How might this come about? The hypothalamic POMC system in the arcuate nucleus is implicated in energy homeostasis. Recent studies have shown that leptin-induced reductions in food intake are mediated through the opioidergic pathway (37). For example, agonists of the MC4 receptor reduce food intake (37), and targeted mutation of the MC4 receptor causes obesity (38). There are high levels of leptin receptor expression on POMC neurons in the arcuate nucleus (39). In addition to being involved in appetite control, arcuate nucleus opioidergic neurons impose inhibitory constraint on CRH neurons of the paraventricular nucleus (14). The greater the opioid tone, the greater the inhibition of the CRH neuron. The observation that the hypothalamic POMC system is one mediator of leptin’s action is interesting because recent findings show that human obesity and hyperleptinemia are linked to a segment of chromosome 2 near the POMC gene locus (40). It is plausible that plasma leptin concentrations alter opioidergic activity in the arcuate nucleus, which then, in turn, influences CRH-ACTH interactions. We speculate that individuals with higher plasma leptin concentrations have higher hypothalamic opioid tone. The effect of plasma leptin concentrations on opioidergic tone is unmasked during opioid receptor blockade (Fig. 4Go).



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  		Figure 4. Proposed model for how plasma leptin concentration may influence the secretory dynamics of the HPA axis. Plasma leptin modulates arcuate nucleus opioidergic activity by signaling through leptin receptors on POMC neurons. Acute action: We speculate that an acute rise in plasma leptin induces melanocortin release, which (in conjunction with neuropeptide Y) inhibits appetite. Simultaneously, leptin induces ß-endorphin release, which inhibits CRH secretion. Chronic action: Whereas acute leptin exposure increases melanocortin and ß-endorphin release, we speculate that chronic leptin exposure modulates POMC gene expression and/or biosynthesis and thereby modulates opioid tone. The greater an individual’s plasma leptin concentration, the greater the hypothalamic opioid activity. The greater the opioid activity, the greater the tonic restraint on the CRH neuron. Therefore, the magnitude of plasma ACTH response to opioid receptor blockade with naloxone positively correlates with the amount of opioid activity.

 
In summary, these findings indicate that activation of the HPA axis does not acutely alter plasma leptin concentrations. However, plasma leptin levels may influence central nervous system opioidergic tone and thus modulate the magnitude of CRH release.


   Acknowledgments
 
We thank Dr. Daniel Berkowitz for thoughtful discussions on this topic, and June Dameron for preparation of the manuscript.


   Footnotes
 
1 This work was supported by NIH Grant RO1-AA-09000 (to G.S.W.), The Alcohol Medical Research Foundation (to G.S.W.), and a generous gift from The Kenneth Lattman Foundation (to G.S.W.). Back

Received February 17, 1998.

Revised March 12, 1998.

Accepted March 17, 1998.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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