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Endocrinology Vol. 143, No. 2 403-410
Copyright © 2002 by The Endocrine Society

NEUROENDOCRINOLOGY

Glucose Relays Information Regarding Nutritional Status to the Neural Circuits That Control the Somatotropic, Corticotropic, and Gonadotropic Axes in Adult Male Rhesus Macaques

Joaquin Lado-Abeal, Johannes D. Veldhuis and Reid L. Norman

Cell Biology and Biochemistry (J.L.-A., R.L.N.), Texas Tech University Health Sciences Center, Lubbock, Texas 79430; and Department of Medicine and NSF Center for Biological Timing (J.D.V.), University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Reid L. Norman, Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, Texas 79430. E-mail: reid.norman{at}ttmc.ttuhsc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In male mammals, the neuroendocrine responses to fasting include increased GH and cortisol secretion and suppressed LH and T levels. Because blood glucose levels fall during fasting, we hypothesized that this modest, but consistent, change in blood glucose was a metabolic signal for the neuroendocrine adjustments of reproductive and metabolic hormones. Glucose (D-dextrose, 480 kcal/d) was infused into fasted (48 h) adult male rhesus macaques; and LH, cortisol, and GH were measured in plasma from samples collected at 15-min intervals for the last 15 h of the fast. We analyzed hormone secretion by deconvolution analysis, and the orderliness of release patterns by the approximate entropy statistic. Circulating blood glucose was 76 ± 7 mg/dl in the fed control group, significantly higher (P < 0.01) than the level of 56 ± 3 mg/dl in the fasted group. The increase in GH pulsatility and the 2-fold elevation in cortisol levels observed in the fasted male macaques were prevented by parenteral glucose delivery. The suppression of LH in fasted animals was not relieved by glucose infusions but seemed to be partially prevented in three of the animals. These findings are consistent with the hypothesis that glucose serves as a signal of nutritional status controlling adaptive neuroendocrine responses to fasting in the primate.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN ADULT MALE rhesus monkeys, short-term fasting inhibits the gonadotropic axis and activates both the corticotropic and the somatotropic axes (1, 2). These neuroendocrine responses are directed, in part, to conserve energy and to mobilize stored energy, thereby maintaining vital physiological functions (3).

The mechanisms that trigger the neuroendocrine adaptive response to fasting are poorly understood. Undue psychological stress (4) and changes in insulin ( 5) and endogenous opioids (6) have been dismissed as the proximate causes of fasting-induced suppression of gonadotropin and T secretion. Fasting elevates circulating cortisol, and high levels of cortisol can block gonadotropin secretion (7), but several weeks of high cortisol levels are required for this effect to emerge (8). Elevated glucocorticoid production is most likely attributable to increased CRH-induced ACTH release acting through the pituitary CRH receptor 1 (9). CRH can inhibit GnRH secretion (10), possibly through a direct action on GnRH neurons (11). However, CRH-deficient mice continue to show repression of LH and T secretion during fasting (12), indicating that, in this species, CRH action is not obligatory for inhibition of gonadotropin secretion associated with fasting.

Circulating leptin levels fall rapidly during short-term fasting, and a role for leptin as a signal relaying nutritional status to the brain has been proposed (13). In rodents, leptin administration during fasting prevented the suppression of the thyrotropic, gonadotropic, and somatotropic axes and blunted the activation of adrenal axis (13). In pubertal male macaques, leptin infusion prevented the fasting-induced suppression of LH and FSH secretion (14). However, in fasted adult male macaques, infusion of physiological doses of recombinant rhesus monkey leptin did not prevent the inhibition of LH and T secretion or the increase in cortisol secretion and GH pulsatility (2).

The mechanisms that trigger the reductions in gonadotropin output during fasting are energy dependent. In a series of elegant experiments in adult male rhesus monkeys, Cameron et al. (4, 15) have shown that overfeeding animals on the day before fasting or direct intragastric infusion of nutrients during fasting reversed inhibition of LH secretion. The authors concluded that neither of these maneuvers relieved the psychological stress of food withdrawal. Therefore, a neural or nutritional signal, arising from the gastrointestinal tract, was proposed to mediate the restoration of LH secretion during refeeding (15).

In the present study, we examined the effect of iv glucose infusion, during short-term fasting, on LH, cortisol, and GH secretion in adult male rhesus monkeys. This study was based on the fact that the primary fuel for central nervous system neurons is glucose and that the supposition that decreased energy availability elicits neuroendocrine adjustments that conserve energy. Therefore, replacing glucose in fasted animals should prevent the neuroendocrine responses to fasting. Our hypothesis is that, in fasted animals, the fall in blood glucose can elicit neuroendocrine adjustments that conserve energy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental animals
Four adult male rhesus macaques (Macaca mulatta), 6–8 kg in weight (5–6 yr old) were housed in individual cages, in the same room, under temperature (23 ± 2 C)- and light-controlled conditions (lights on, 0600–1800 h). Animals were maintained on a diet of monkey chow and fresh fruit, with tap water available ad libitum. Routine daily animal care and maintenance consisted of cage cleaning at 0800 h, feeding at 0900 h, and an afternoon feeding at 1300 h, where the food that was not eaten was left in the cage until the following morning. Fresh fruit was provided three times a week. Entry into the primate room was restricted to the animal caretakers and personnel involved in the research project. The animal studies were approved by the Institutional Animal Care and Use Committee at Texas Tech Health Sciences Center.

Experimental protocol
Each animal was studied on 3 separate days, between 0700–2200 h, with blood samples (1.0 ml) collected from a remote site at 15-min intervals on each occasion. Because these animals were young, the first study was the fed control, and it served to establish that they exhibited adult patterns of LH, cortisol, and GH. In the other two studies, we analyzed the secretion of these hormones during fasting, with and without glucose infusion. When fasted, not all animals show a suppression of LH secretion at the same time after the initiation of the fast. Therefore, the second experiment was the fasted control to document that LH secretion was significantly suppressed. In these experiments, three of the animals were not fed for 48 h before blood sampling began. However, one animal (no. 7494) had to be fasted for 80 h before there was a clear reduction in LH levels. Both the fasted studies were conducted after an 80-h fast in this animal. In all animals, food restriction was extended until the end of the 15-h sampling period. In the fasting with glucose studies, a 50% glucose solution (D-dextrose) was infused at the rate of 10 ml/h (20 kcal/h), beginning at 0700 h (the time of the first missed meal). With the glucose infusions, the animals received 480 kcal of energy each day. This is less than the 734 kcal the animals are fed each day but more than the established energy requirements of 40–50 kcal/kg/d for adult animals of this species (16, 17).

Collection of blood samples from tethered animals was accomplished as previously described (18). The samples were centrifuged at the end of the study, and the plasma was withdrawn and stored frozen at -20 C in polypropylene vials until hormone assays were conducted. Glucose levels were measured in fresh blood samples at hourly intervals in control and fasted experiments. However, because the same catheter was used for glucose infusion and collection of blood samples, we could not monitor glucose levels during the trials when glucose was infused. In these studies, circulating glucose levels were measured in blood samples taken from the saphenous vein at the end of the sampling period.

Hormone assays
Plasma concentrations of LH were measured in duplicate, in 5- or 10-µl plasma aliquots, with a mouse Leydig cell bioassay (19); and results were expressed as nanograms of NICHHD rhesus LH RP-1 (WDP-XV-20)/ml. Sensitivity of the assay was 0.1 ng LH with 10 µl plasma. Only an occasional sample fell below this level, and those points are plotted directly on the abscissa in the figures. T (25-µl plasma and 10-µl Leydig cell medium aliquots), cortisol (2.5-µl plasma aliquots), and GH (50-µl plasma aliquots) were measured by solid-phase RIA (T and cortisol, Diagnostic Products, Los Angeles, CA; GH, Diagnostic Systems Laboratories, Inc., Webster, TX). Intra- and interassay coefficients of variation were 12% and 15%, respectively, for LH; 6% and 10% for cortisol; and 2% and 14% for GH. Venous blood glucose was measured with an Accu-Chek Simplicity glucometer (Roche Molecular Biochemicals, Indianapolis, IN).

Data analysis
Approximate entropy (ApEn).
ApEn was used as a scale- and model- independent statistic to quantify the serial orderliness or regularity of hormone release. Normalized ApEn parameters of m = 1 and r = 20% of the intraseries SD were used, as previously described (20, 21). For this parameter set, ApEn is designated ApEn (1.20%). ApEn quantifies the regularity of subordinate (nonpulsatile) patterns in the data; and, as such, yields information complementary to peak analysis. Higher absolute ApEn values denote greater disorderliness or irregularity of neurohormone release, as observed in Cushing’s disease (20); the aging LH (22) and GH ( 21) axes; and for the GH axis in women, compared with men (23).

Deconvolution analysis.
Deconvolution analysis is a mathematical technique applied to a pulsatile serum hormone concentration vs. time series, to estimate subject-specific measures of pulsatile hormone secretion and half-life (24, 25, 26). The hormone production rate was computed as the product of secretory burst frequency and the mean mass of hormone released per secretory pulse. Based on earlier validation studies (27, 28), deconvolution analysis was carried out at 95% joint statistical confidence intervals for all calculated hormone secretory burst amplitudes, with the technician blinded to the order of the studies.

Statistical analyses.
Differences in glucose levels between groups in Fig. 1Go were analyzed by split-plot ANOVA with repeated measures. Statistical differences in the data for each hormone after deconvolution analyses were assessed by ANOVA. The results of these analyses (see Fig. 5Go) are presented as the mean ± SEM. Statistical significance was accepted for P less than 0.05.



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  		Figure 1. Blood glucose concentrations (mean ± SEM) are shown at hourly intervals in animals either fed a normal diet (control studies) or fasted for 2 d.

 


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  		Figure 5. Deconvolution analysis of LH, GH, and cortisol secretion in control, fasted, and fasted + glucose studies. Data included secretory burst frequency (number of events), amplitude (ng/ml·min for LH and T; µg/dl·min for cortisol), and mass (concentration units) and mean (ng/ml for LH and T; µg/dl for cortisol). Results are shown as mean ± SEM. Significant differences between groups are indicated by different letters.

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Hourly blood glucose concentrations in the control and fasted animals are shown in Fig. 1Go. The average glucose level in the fed control group was 76 ± 7 mg/dl, which was significantly higher (P < 0.01) than the level observed (56 ± 3 mg/dl) in the fasted group. In the samples taken from the saphenous vein at the end of each study in the fasted group infused with glucose, the circulating glucose level averaged 151 ± 39 mg/dl.

Figure 2Go shows repetitively sampled plasma LH concentrations in each of the three trials in all four animals. LH pulse patterns typical of those observed in adult male macaques were observed in three of the animals, and a pattern more reminiscent of a pubertal animal was observed in no. 5698. There was a clear, significant suppression of mean LH levels in both the fasted controls (1.7 ± 0.6 ng/ml) and the fasted animals infused with glucose (3.8 ± 1.4 ng/ml), compared with controls (10.8 ± 3.3 ng/ml). This suppression was attributable primarily to the calculated amount (mass) of LH released during each pulse. In all except one animal (no. 5698), LH seemed to be more pulsatile in the fasted animals treated with glucose than in the fasted controls. However, neither the number of LH pulses nor the mass of LH release was different between these two groups (see Fig. 5Go). In contrast both fasted groups had fewer LH pulses than did fed controls.



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  		Figure 2. Bioactive plasma LH concentrations in four adult male rhesus macaques that were fed a normal diet (control), fasted, or fasted and infused iv with glucose (480 kcal/d). Blood samples were collected from each animal at 15-min intervals for 15 h. In the fasting studies, blood samples were collected during the last 15 h of the fast. In Figs. 2–4GoGoGo, the abscissa is unscaled. Each graph shows the three studies from the same animal.

 
Clear, distinct pulses of GH, with interpulse levels that were nearly undetectable, was the pattern characteristic of GH secretion in fed controls (Fig. 3Go). There was a 2-fold increase in the number of GH pulses in fasted animals (13.8 ± 2 pulses/15 h), compared with fed controls (6.8 ± 0.8 pulses/15 h). GH pulses were less distinct in the fasted animals, and interpulse levels remained elevated. Glucose-infused fasted animals had the same mean number of pulses (6 ± 0.4 pulses/15 h) as fed controls (see Fig. 5Go), and the profiles of GH secretion were more similar to those of fed controls than fasted animals. There was no difference in mean levels of GH among the groups.



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  		Figure 3. Plasma GH concentrations in four adult male rhesus macaques that were fed a normal diet (control), fasted, or fasted and infused iv with glucose (480 kcal/d). Blood samples were collected from each animal at 15-min intervals for 15 h. In the fasting studies, blood samples were collected during the last 15 h of the fast.

 
Cortisol profiles in fed animals in nearly all trials were high in the morning and lower in the afternoon and evening, reflecting the diurnal changes characteristic of the secretory pattern of this hormone. In the fasted animals, there was a consistent robust cortisol peak, just after the time of the expected morning meal, that was not obvious in the other two groups (Fig. 4Go). The only statistical difference in cortisol secretion was a nearly 2-fold increase in mean levels of this hormone in fasted animals (33.2 ± 4.1 µg/dl), compared with fed controls (18.5 ± 3.9 µg/dl). Glucose infusions (12.2 ± 3.3 µg/dl) completely prevented the increase in cortisol in fasted animals (Fig. 5Go).



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  		Figure 4. Plasma cortisol concentrations in four adult male rhesus macaques that were fed a normal diet (control), fasted, or fasted and infused iv with glucose (480 kcal/d). Blood samples were collected from each animal at 15-min intervals for 15 h. In the fasting studies, blood samples were collected during the last 15 h of the fast.

 
The ApEn of LH and cortisol secretion was not different among the groups (Table 1Go). ApEn of GH secretion increased significantly during fasting (P < 0.01), denoting highly disordered GH release, and this was prevented by parenteral glucose infusion (Table 1Go). ApEn is a measure of the regularity of pulsatile hormone secretion, wherein lower values indicate more regular hormone secretion.


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  		Table 1. ApEn statistics for LH, GH, and cortisol secretion

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we confirmed our previous observation (2) that 2 d of fasting in male rhesus monkeys triggers neuroendocrine responses similar to those observed in healthy men. Mean LH levels were suppressed in fasting animals because of a decrease in both the mass of LH released per secretory burst and number of LH pulses. As also observed in humans, fasting elevated serum cortisol levels because of an increase in the mass of cortisol released per secretory burst without a change in the number of pulses (29). The GH response to fasting in male macaques was different from that observed in humans. In both species, fasting increased GH pulse frequency (30); but in macaques, mean secretory burst mass and mean serum GH levels did not change significantly. Consistent with our previous result (2) and that in the human, the ApEn statistic showed that GH secretion was more disorderly in the fasted group, compared with controls.

The provision of 480 kcal/d, by continuous iv infusion of glucose, prevented the cortisol and GH changes in response to fasting and partially alleviated the suppression of LH and T in three of the animals. The increase in irregularity of pulsatile GH secretion observed in fasting animals was blocked by parenteral glucose administration; whereas, in our previous studies, leptin infusions had no effect on fasting-induced changes in GH secretion (2).

The diurnal pattern of cortisol secretion in fasted males with the robust midmorning peak associated with omission of the first meal of the day is more typical of the pattern observed in female macaques (31) and in orchidectomized male macaques treated with E2 and progesterone implants (32). One cause for this cortisol peak in fasted males could be anxiety as a result of not receiving the morning meal. Remarkably, when the same animals were fasted and given glucose, this elevation in cortisol was absent in three animals, suggesting that the animals did not experience the same anxiety when given glucose or that anxiety was not the inciting factor. However, T levels (not shown) were lower in the fasted group, compared with the fed controls or the fasted group given glucose, allowing for an alternative interpretation that this pattern of cortisol secretion is modulated by changes in gonadal steroids.

The present results are not consistent with the notion that a signal from the gastrointestinal tract primarily serves to mediate the neuroendocrine responses to short-term food restriction, at least for the somatotropic and corticotropic axes. However, the fasting-induced suppression of LH secretion in the present study was not completely blocked by iv infusion of dextrose but was fully overcome in fasted male macaques given intragastric infusions of dextrose (33). Therefore, stimulation of a gastrointestinal signal in response to ingestion of a meal may be involved in the regulation of the neuroendocrine axis controlling gonadotropin release (15).

The present data do not exclude the possibility that other signals arising from outside the central nervous system might mediate these neuroendocrine responses to fasting. Among the many physiological changes during fasting is a decrease in circulating insulin (34). Although glucose transport into brain cells is considered to be an insulin-independent process, insulin receptors are expressed in neurons (35), and mice with a neuron-specific disruption of the insulin receptor have reduced fertility of hypothalamic origin (36). However, suppression of insulin output with diazoxide does not reduce LH secretion in fed macaques, an observation that argues against insulin as the predominant signal to the neuroendocrine circuits that control GnRH release (5). Conversely, GH secretion was not suppressed during an euglycemic hyperinsulinemic clamp in humans (37), suggesting that increased plasma insulin levels during glucose infusion are probably not the cause of the normalization of GH secretion. Last, there is no apparent role for circulating insulin per se in mediating other tissue responses to glucose counterregulation (38).

Blood glucose levels showed an expected decrease (average 26%) during the present fasting studies; but this is a modest, gradual decline in blood glucose, compared with that induced by insulin. However, the ability of parenteral glucose to prevent the GH and cortisol responses to fasting is consistent with the notion that this nutrient is an important metabolic signal that allows the central nervous system to adjust to acute reductions in energy availability. Both the liver (39) and central nervous system ( 40) have glucose sensors that trigger a counterregulatory hormone response to glucopenia. Central nervous system glucose receptors are located in the IV ventricle (41) and in the ventromedial hypothalamic nucleus (40). Brain glucose sensors mediate the increase in cortisol levels observed during neuroglucopenia in dogs and sheep (42, 43), and the change in cortisol in the present study are most likely mediated by changes in hypothalamic CRH release in response to changes in blood glucose (44). Regarding the control of the gonadotropic axis, our present understanding of this system is that glucose sensors in the hindbrain mediate the physiological adjustment to circulating changes in this nutrient. Hypoglycemia-induced inhibition of GnRH pulse generator activity in the rat was prevented by removal of the area postrema in the hindbrain (45); and in sheep, infusion of 2-deoxy-D-glucose, an inhibitor of intracellular glucose oxidation, into the IV ventricle suppressed pulsatile LH release (43). These findings are consistent with the idea that neuroendocrine responses to glucopenia are mediated through hindbrain glucose sensors and neuroglial oxidation.

GH release during hypoglycemia has been related to an inhibition of somatostatin release in the hypothalamus (23). Conversely, an acute oral load of glucose suppresses basal and GHRH-induced GH secretion (46), most likely by stimulating hypothalamic somatostatin outflow (47). Taken together, available data point to glucose sensors in the central nervous system as mediators of the glucose counterregulatory response. Our finding that glucose replenishment restrains the GH response to fasting is consistent with this idea.

The present data also support the premise that the neuroendocrine adjustments to fasting are a response to changes in available energy (glucose) rather than to signals from stored energy (leptin). Our data are consistent with the observations that pulsatile LH secretion resumes within a short time after refeeding in fasted rats (48), swine ( 49), and monkeys (15, 33). However, the observation that administration of leptin to fasted peripubertal male monkeys can restore suppressed gonadotropin secretion (14) suggests that signals from stored energy also relay information regarding nutritional status to the central nervous system during the peripubertal period in this species. Notwithstanding the lack of any significant changes in circulating leptin levels during the pubertal transition in male macaques (50, 51), it is possible that this peptide has a unique physiological role during the pubertal transition in primates.

Because suppression of LH secretion was only partially prevented in fasted animals given glucose, the present data are consistent with the observation that nutrients other than glucose are important for adult patterns of LH secretion (33). The metabolic response to a 48-h fast in male monkeys includes lipolysis and ketogenesis, resulting in elevated ketone levels in the urine (Lado-Abeal, J., and R. L. Norman, unpublished observations). Both GH and cortisol stimulate lipolysis (52), and the fasting-induced changes in secretion patterns of these hormones were prevented by parenteral glucose administration. Increased insulin secretion, as a result of elevated blood glucose in the animals infused with glucose, would also inhibit lipolysis and stimulate lipogenesis. Therefore, it is likely that lipolysis and ketogenesis were suppressed in animals infused with glucose. If this were the case, fasted animals given glucose would be deprived of FFA both from dietary sources and from lipolysis, leaving glucose as the only source of energy. These findings, together with those showing that LH secretion is restored in fasted animals given nutrients that do not return blood glucose to control levels (33), indicate that glucose alone is not sufficient to maintain patterns of LH secretion typical of adult male animals.

In summary, the present study shows that the somatotropic and corticotropic neuroendocrine responses in animals exhibiting a moderate reduction in blood glucose as a result of short-term fasting can be prevented by parenteral administration of glucose. In addition, the suppression of LH secretion in some animals can be alleviated with glucose administration. These findings suggest that glucose can serve as a signal of acute changes in nutritional status to the neural circuits controlling neuroendocrine responses that govern GH and cortisol release but that other nutrients are necessary to restore LH secretion to control levels.


   Acknowledgments
 
We thank Qian Xu Ping, Corey Hough, and Lisa Adams for excellent technical assistance. The National Hormone and Pituitary Program at NIDDK and A. F. Parlow supplied the rhesus LH standard.


   Footnotes
 
This work was supported by NIH Grants HD-18591 (to R.L.N.) and HD-28934-NIH U54 Specialized Cooperative Center for Reproductive Research (to J.D.V.).

Abbreviation: ApEn, Approximate entropy.

Received June 5, 2001.

Accepted for publication October 11, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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