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Endocrine Care |
University Research Centre for Neuroendocrinology (D.S.J., D.F., S.L.L.), University of Bristol, Bristol, United Kingdom BS2–8HW; and Department of Physiology (M.F.D.), University of California, San Francisco, California 94143
Address all correspondence and requests for reprints to: David Jessop, University Research Center for Neuroendocrinology, University of Bristol, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, United Kingdom. E-mail: David.Jessop{at}bris.ac.uk
Abstract
Increased hypothalamo-pituitary-adrenal axis drive has been reported in obese subjects but with paradoxically low or normal levels of plasma cortisol. Our current study was designed to investigate whether glucocorticoid feedback was altered in obesity, both under basal and stressed conditions. Plasma ACTH and cortisol concentrations in male control or obese subjects (age range 20–50 yr) were measured at frequent intervals over 24 h during infusion of saline or hydrocortisone at two physiological doses (7.5 and 15 mg/d) designed to occupy predominantly mineralocorticoid rather than glucocorticoid receptors. The same subjects then underwent insulin-induced hypoglycemia either in the morning or the evening. Obese subjects had significantly higher basal ACTH and lower cortisol concentrations throughout the 24 h infusion period, compared with controls (P < 0.05, two-way ANOVA followed by Newman-Keuls posthoc analysis). Basal plasma ACTH was decreased in obese groups given low- or high-dose hydrocortisone during the day (P < 0.05) but not during the night, unlike controls who responded to hydrocortisone both during the day and at night (P < 0.05). Obese subjects also showed resistance to steroid-induced inhibition of the ACTH response to hypoglycemia, compared with controls (P < 0.05). These data clearly show that obesity is associated with a relative insensitivity to glucocorticoid feedback, which is most marked during the night, and suggest that this condition is characterized by a decreased mineralocorticoid receptor response to circulating corticosteroids.
HOMEOSTATIC MECHANISMS THAT regulate appropriate plasma levels of glucocorticoid hormones are essential for the maintenance of many physiological functions. These include both the metabolic processes of lipogenesis and gluconeogenesis (1) and the modulation of expression of several hypothalamic neuropeptides that are involved in appetite control, including CRH and neuropeptide Y (2). Defects in hypothalamo-pituitary-adrenal (HPA) axis function would therefore be expected to result in changes in energy metabolism, which could contribute to alterations in total body fat mass. Altered HPA axis activity in obesity has been widely reported (3, 4, 5), although there is considerable variance within the literature as to whether obesity is associated with elevated (6), normal (7, 8, 9, 10, 11), or decreased (12, 13, 14) plasma cortisol. In addition, the primary site of HPA axis dysfunction is unclear.
Although a defect in cortisol feedback on HPA axis activity was proposed in an elegant study two decades ago (12), there has been no empirical consensus as to whether obese patients exhibit altered feedback sensitivity of the HPA axis (15, 16, 17). One reason for the discrepant results in the literature could be the common use of the glucocorticoid dexamethasone as a synthetic agent to study the integrity of HPA axis feedback mechanisms (18). Dexamethasone is poorly suited to this type of study for two reasons. First, even at low doses, it interacts with the low-affinity type 2 GR and not the high-affinity type 1 MR. Second, in contrast to hydrocortisone, dexamethasone has limited access to GR in the brain (19). This is the first study to use the endogenous corticosteroid, hydrocortisone (or cortisol), to investigate glucocorticoid feedback both in normal and obese subjects using 24-h low-dose infusions designed to increase MR occupancy during the nadir of ACTH and cortisol secretion at night while having little effect during the day.
Another feature of the published literature on the effects of stress or glucocorticoid feedback on HPA axis activity is that most studies have been performed in the morning. It is now clear that the response to stress or to glucocorticoid feedback is not of equal magnitude around the clock but that windows of sensitivity exist. In rat and man, the centrally mediated stress response is greater during the trough of the circadian cycle than at the peak (20). This is also true for sensitivity to glucocorticoid feedback. For many years glucocorticoid feedback has presented a most puzzling paradox whereby, although circulating glucocorticoids are elevated during the trough of the diurnal rhythm in chronically stressed rats, an intact or even enhanced response to acute stress is retained (21), and there is resistance to exogenously administered glucocorticoids (22).
We have now studied this phenomenon in detail in human volunteers. Basal and stress-stimulated HPA axis activities were measured in obese subjects and controls of normal weight at both the morning and evening periods of the circadian cycle. The effects of glucocorticoid feedback on ACTH and cortisol were determined following daytime or nocturnal hydrocortisone infusion.
Subjects and Methods
Study design
Ethical approval for this study was obtained from the Research Ethics Committee, United Bristol Healthcare NHS Trust, Bristol (project E. 2969), and informed consent was obtained from all subjects. Control subjects were white male volunteers (age range 20–50 yr) with a body mass index (BMI) less than 25 kg/m2. White male subjects selected from within the same age range were conventionally obese (BMI 30–40 kg/m2). Obese subjects had no cardiovascular disorders, history of epilepsy, anemia, or renal dysfunction. All subjects were admitted to the Metabolic Unit, Bristol Royal Infirmary, on three occasions for saline or hydrocortisone (7.5 or 15 mg/24 h) infusion and their three treatment protocols were given in randomized order. Seven controls and seven obese subjects were given morning insulin tests (group A) on three separate occasions at least 1 wk apart, and new subjects were recruited for evening tests (group B). All tests were randomized, double-blind studies. All participants were given standard meals of identical protein, fat, carbohydrate, and calorific value at predetermined times and were allowed water ad libitum. An iv cannula was inserted into each arm at 0900 h (group A) and at 2100 h (group B) for the iv infusion of 1) isotonic saline (control), 2) 7.5 mg hydrocortisone over 24 h, or 3) 15 mg hydrocortisone over 24 h. These doses were selected on the basis of a report that as little as 10 mg hydrocortisone per day can alter ACTH secretion (23). After 11 h of hydrocortisone infusion, an additional cannula was inserted contralaterally. One hour after cannulation, blood sampling commenced and samples (4 ml) were taken every 30 min over a 12-h period for cortisol and ACTH measurement. After 24 h of saline or hydrocortisone infusion, subjects were given a single iv dose of insulin (0.15 IU/kg, Actrapid, Novo Nordisk, Copenhagen, Denmark) and 4-ml blood samples were taken every 15 min for an additional 2 h. During this period, patients had capillary blood samples taken every 10 min for blood sugar estimation using a glucometer. Group A subjects fasted overnight before injection of insulin at 0900 h, and group B subjects fasted for 5 h before injection of insulin at 2100 h.
RIAs
Blood was collected into lithium-heparin–coated plastic tubes on ice, centrifuged, and plasma stored at -20 C for ACTH and cortisol measurements. Total cortisol was measured directly in plasma by in-house RIA using antisera raised in rabbits to cortisol-3-(O-carboxymethyl) oxime (Bioclinical Services Ltd., Cardiff, Wales). Tracer was cortisol-3-(O-carboxymethyl) oximino-(2-[125I]iodohistamine (Amersham Pharmacia Biotech Ltd., Little Chalfont, Bucks, UK). Intra- and interassay coefficients of variation for cortisol were 5 and 8–12%, respectively. ACTH was measured by in-house RIA following extraction on Sep-Pak C18 cartridges (Waters Corp., Milford, MA) as previously described (24). Intra- and interassay coefficients of variation for ACTH were 5–7.5 and 10–14%, respectively.
Statistics
Data were first analyzed by three-way ANOVA, corrected for repeated measures in the dimension of time. The analyses were performed separately for basal and insulin tolerance test concentrations of plasma ACTH and cortisol. The main factors of the analysis were: morning/evening (with morning and evening designated as the time of day at which insulin was given; df = 1), infusion (the amount of hydrocortisone infused over 24 h; df = 2), and whether the subjects were normal or obese (df = 1). We had specific expectations about the feedback efficacy of hydrocortisone infusions in normal subjects. Therefore, when there were main effects and interactions that were significant at P less than 0.l among the main effects, two-way ANOVA was performed to distinguish posthoc (Newman-Keuls) significance within normal or obese groups.
Results
Basal ACTH and cortisol concentrations
Regular blood sampling at 30-min intervals revealed significant
daily rhythms in ACTH and cortisol in both control and obese groups
infused with saline (Fig. 1
). However,
mean basal ACTH concentrations were higher and mean basal cortisol
concentrations were lower in obese, compared with normal, subjects
during both daytime and nocturnal 12-h periods (Figs. 1 and 2). Mean plasma ACTH concentrations over
both 0900 h-2100 h and 2100 h-0900 h averaged 30–35
pM/liter in obese subjects, compared with 15–20
pM/liter in the normal subjects (Fig. 2a). Mean nocturnal
and daily concentrations of cortisol were around 50% lower in obese
subjects, compared with controls (Fig. 2b).
|
|
). Mean
ACTH concentrations were inhibited to an equal extent by both doses
when infused during the night but were inhibited in a dose-related
fashion during the day (Fig. 2). Unlike controls, ACTH concentrations
in obese subjects were insensitive to hydrocortisone infusions during
the night but were inhibited by cortisol infused during the day (Fig. 2). The patterns of ACTH and cortisol concentrations during the two
infusion periods are shown in Fig. 3. The
major effect of hydrocortisone infusions at both periods appears to be
inhibition of many of the pulsatile secretory episodes of ACTH observed
in the vehicle infusion experiments. Hydrocortisone infusion throughout
a 24-h period did not significantly increase mean plasma cortisol
concentrations in either obese subjects or controls (Fig. 3), showing
that the endogenous adrenocortical axis could compensate for the extra
cortisol (i.e., hydrocortisone) infused into the
circulation.
|
Blood glucose levels fell below 2.2 mmol/liter in all subjects
following injection of insulin either at 0900 h or 2100 h.
The anticipated increases in ACTH and cortisol were observed in
response to insulin in both control and obese groups, compared with
preinsulin controls (data not shown). The magnitude of ACTH responses
to insulin at 0900 h and 2100 h was significantly greater in
obese subjects, compared with controls (Fig. 4a). Conversely, the cortisol response to
insulin administered in the morning or evening was lower in obese
subjects (Fig. 4b).
|
). Neither dose of
hydrocortisone infusion reduced plasma ACTH responses to insulin at
either time of day in obese subjects.
The cortisol response to insulin injected at 0900 h in controls
was significantly greater than the response following injection at
2100 h (Fig. 4b). Cortisol responses in obese subjects were
significantly lower than in controls when given insulin at 0900 h,
and evening responses to insulin were similar in control and obese
groups.
Discussion
We have demonstrated significant differences in basal and hypoglycemia-stimulated HPA axis activity between normal and obese subjects. A circadian rhythm was observed for plasma cortisol in both obese and control groups, with a high daytime and low nocturnal pattern. Daytime and nocturnal plasma concentrations of cortisol were significantly lower in the obese group. These data confirm the original observations of decreased plasma cortisol in obesity (12), and the weight of evidence now supports this concept of hypocortisolemia in obesity. Other groups have reported normal or even elevated plasma concentrations of cortisol in obesity (6, 7, 8, 9, 10, 11), but the majority of these observations were made from blood samples taken at one or two time points from subjects with massive obesity. Our 24-h frequent sampling schedule provides compelling evidence for significantly decreased plasma concentrations of cortisol in subjects with conventional obesity. In the one comparative study of obese males and females (12), 24-h mean cortisol concentrations were decreased in obese women but not in men. The reasons for this sex discrepancy between this study and ours are not clear, and future studies should take into account possible sex and BMI effects.
Plasma cortisol was decreased, and ACTH was elevated, during both daytime and nocturnal periods in our obese subjects, compared with controls. Paradoxically, the elevated ACTH in our obese subjects did not result in increased plasma cortisol, in either basal or insulin-stimulated conditions. These data clearly point to a relative adrenal insensitivity to ACTH, resulting in decreased cortisol secretion. One consequence of lower circulating levels of cortisol in obesity will be increased HPA axis drive. The disparity between plasma levels of ACTH and cortisol in obesity suggests that the HPA axis must be reset at a higher level of activity than in normal subjects to maintain adequate cortisol secretion in the presence of elevated plasma ACTH.
It is possible that the hormone leptin that is synthesized in fat cells and is raised in obesity (25) could be inhibiting the release of cortisol. Leptin has a circadian rhythm that is inversely related to that of cortisol (26, 27), and it has been proposed that leptin inhibits HPA activity in obesity (28, 29) The corticosterone response to chronic stress was decreased in obese rats (30) in which leptin is elevated (31), and leptin reversed the increase in anterior pituitary POMC mRNA observed in obese mice (32). However, there is no evidence for a direct effect of leptin on cortisol secretion in primates (33). Another explanation for decreased plasma cortisol in obese subjects is that there is an increased peripheral degradation of cortisol by catabolic enzymes (11, 34) and consequent enhanced metabolic clearance rate (12) with higher levels of urinary cortisol metabolites (35). Impaired activity of 11ß-hydroxysteroid dehydrogenase-1 has been reported in the liver of obese men (36), resulting in a shift toward cortisone production and a consequent decrease in plasma cortisol.
In addition to our findings of raised plasma ACTH and lower plasma cortisol levels in obese subjects, we have also been able to demonstrate differences in glucocorticoid feedback. Although 7.5- and 15-mg doses of hydrocortisone over 24 h might appear to be very small, they were carefully chosen as physiological doses designed to predominantly occupy MR whose affinity is 10-fold higher than GR for cortisol (37). In detailed studies in the rat (37, 38), MR occupancy was found to be about 90% at both morning and evening time points during the diurnal rhythm. In our study, MR occupancy would predictably be lower during the night when cortisol levels have fallen to their nadir. During this period, the low doses of hydrocortisone that we used would bind to MR without significantly binding to GR. This is apparent because the blood cortisol levels in the groups infused with hydrocortisone are not significantly greater than endogenous levels in the group infused with saline. Very high concentrations of corticosterone (the rodent equivalent to cortisol) were required before significant occupancy of GRs occurred (37, 38). In nonstressed rats with basal plasma corticosterone concentrations around 50nmol/liter, MR occupancy was 78–85% and GR was 30% (38). A majority of GR was occupied only in response to a 20-fold increase in corticosterone following stress. Basal nocturnal cortisol levels in our human study were therefore in the range sufficient to occupy predominantly MR with little effect on GR.
Both infusion rates of cortisol were sufficient to inhibit plasma ACTH levels in normal subjects during the day and night, although during the day there was a dose-response effect with the higher dose of hydrocortisone having a greater inhibitory effect. At night both doses of hydrocortisone had an equivalent effect and at both times of day the higher dose reduced ACTH to the same minimal level in control subjects. Obese subjects, on the other hand, showed an inhibitory effect of the hydrocortisone infusions only during the day and have completely lost their sensitivity to feedback from physiological doses of hydrocortisone during the night.
Obese and control subjects also displayed differential responses to insulin-induced hypoglycemia. ACTH responses to hypoglycemia were greater in obese subjects, compared with controls, whether insulin was given during the morning, confirming a previous study (8), or in the evening. On the other hand, cortisol responses to insulin administered in the morning were significantly lower in the obese subjects than in controls. Thus the pattern of paradoxically decreased cortisol and increased ACTH that we have observed in obese subjects under basal conditions also occurs during HPA axis activation. The cortisol response to insulin in obese subjects has not previously been observed to differ from controls (6, 8, 39), but these studies were performed in women. The marked 50% decrease in response to cortisol that we observed in our obese male subjects may be due to a sex difference in sensitivity to hypoglycemia. Kopelman et al. (6) reported an impaired cortisol response to insulin in massively obese women but only when the obesity had developed at an early age. Subjects with late-onset obesity had a normal cortisol response (40), suggesting that HPA axis dysfunction in obesity may be affected by developmental factors.
Hydrocortisone infusions of 7.5 and 15 mg over 24 h inhibited the ACTH response to insulin administered during the morning but not during the evening, and obese subjects failed to show any effect of the hydrocortisone on the ACTH response to hypoglycemia at either time of day. There is therefore impaired glucocorticoid feedback on basal ACTH secretion at night and on hypoglycemia induced ACTH secretion in the morning in obese subjects. This observation confirms the original proposal that the cortisol-ACTH feedback system is defective in obesity (12). The low doses of hydrocortisone used in our study were designed to bind to MR during the night, when endogenous cortisol is low and MRs are not saturated. The failure of hydrocortisone infusion to reduce plasma ACTH in obese subjects during the night, and the failure to affect the ACTH response to morning injection of insulin, is compelling evidence that resistance to glucocorticoid feedback in obesity is primarily an MR- mediated defect.
The central nervous system site most likely to be involved in MR-mediated feedback is the hippocampus, which has been strongly implicated in the negative feedback control of the HPA axis (41). Although GRs are distributed widely in the brain including the hippocampus and the paraventricular nucleus of the hypothalamus, MRs are more specifically localized within the hippocampus (42). Deficiencies in GR feedback regulation in obesity have previously been proposed on the basis of resistance to dexamethasone (43), and polymorphic mutations in the GR gene in obese subjects have been reported (44), but the results of therapeutic intervention using a GR antagonist have been disappointing (45). Our data may provide a possible explanation for this, in that although we agree glucocorticoid feedback is impaired in obesity, our evidence is that the deficiency is likely to be one of MR, not GR, insensitivity. The biochemistry underlying impaired MR sensitivity remains unknown. Access to MRs and GRs can be differentially modulated by compounds such as corticosteroid-binding globulin or 11ß-hydroxysteroid dehydrogenase, but the former is not found in the healthy brain, and there is no evidence that the latter affects access of low levels of glucocorticoids to the hippocampus (46).
In conclusion, we have demonstrated basal and stress-stimulated HPA axis dysfunction in male subjects with obesity. These subjects have lost feedback inhibition in response to low doses of hydrocortisone, suggesting they have glucocorticoid feedback insensitivity, probably through a centrally mediated MR mechanism. MR antagonists such as spironolactone should be employed to increase HPA axis drive and restore circulating glucocorticoid levels to determine whether these antagonists are useful in the treatment of obesity.
Acknowledgments
We are grateful for the assistance of Moira Hunt and Caroline Matthews throughout the project.
Footnotes
This work was supported by a grant from the Sir Jules Thorn Charitable Trust. M.F.D. was supported by NIH Grant DK28172.
Abbreviations: BMI, Body mass index; HPA, hypothalamo-pituitary-adrenal.
Received November 8, 2000.
Accepted May 14, 2001.
References
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