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Endocrinology Vol. 142, No. 7 2796-2804
Copyright © 2001 by The Endocrine Society

ARTICLES

Sucrose Ingestion Normalizes Central Expression of Corticotropin-Releasing-Factor Messenger Ribonucleic Acid and Energy Balance in Adrenalectomized Rats: A Glucocorticoid-Metabolic-Brain Axis?1

K. D. Laugero2, M. E. Bell, S. Bhatnagar, L. Soriano and M. F. Dallman

Department of Physiology (K.D.L., M.E.B., M.F.D.), University of California San Francisco, San Francisco, California 94143-0444; Department of Psychology (S.B.), University of Michigan, Ann Arbor, Michigan 48109-1109; and AGY Therapeutics (L.S.), South San Francisco, California 94080

Address all correspondence and requests for reprints to: Mary F. Dallman, Department of Physiology, Box 0444, University of California San Francisco, San Francisco, California 94143-0444.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Both CRF and norepinephrine (NE) inhibit food intake and stimulate ACTH secretion and sympathetic outflow. CRF also increases anxiety; NE increases attention and cortical arousal. Adrenalectomy (ADX) changes CRF and NE activity in brain, increases ACTH secretion and sympathetic outflow and reduces food intake and weight gain; all of these effects are corrected by administration of adrenal steroids. Unexpectedly, we recently found that ADX rats drinking sucrose, but not saccharin, also have normal caloric intake, metabolism, and ACTH. Here, we show that ADX (but not sham-ADX) rats prefer to consume significantly more sucrose than saccharin. Voluntary ingestion of sucrose restores CRF and dopamine-ß-hydroxylase messenger RNA expression in brain, food intake, and caloric efficiency and fat deposition, circulating triglyceride, leptin, and insulin to normal. Our results suggest that the brains of ADX rats, cued by sucrose energy (but not by nonnutritive saccharin) maintain normal activity in systems that regulate neuroendocrine (hypothalamic-pituitary-adrenal), behavioral (feeding), and metabolic functions (fat deposition). We conclude that because sucrose ingestion, like glucocorticoid replacement, normalizes energetic and neuromodulatory effects of ADX, many of the actions of the steroids on the central nervous system under basal conditions may be indirect and mediated by signals that result from the metabolic effects of adrenal steroids.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ADRENALECTOMY (ADX) alters CRF, ACTH secretion, sympathetic outflow, and energy balance (1, 2, 3). These effects result from the loss of glucocorticoids because replacement with the adrenal steroid corrects these deficiencies (1, 2, 3, 4). However, and unexpectedly, we have found that, like corticosteroid replacement, voluntary ingestion of sucrose also corrects increased ACTH secretion, sympathetic outflow, and energy balance in ADX rats (4). Furthermore, whereas intact rats normally like equally sweet but nonnutritive saccharin to drink, ADX rats consume very little saccharin, and these rats exhibit the normal imbalances that accompany ADX (1). These results suggest that ADX rats develop a preference for calorically rich sucrose compared with nonnutritive saccharin, and that this behavioral expression is critical to the restoration of normal metabolic, neuroendocrine, and autonomic function. The results also suggest that the postingestive (energetic) effects of sucrose alter systems in the central nervous system (CNS) that control neuroendocrine, autonomic, and behavioral expression in the absence of adrenal steroids.

As with stress, many of the behavioral, neuroendocrine, and autonomic effects of ADX may be mediated by changes in central CRF. CRF administered to the brain mimics (5, 6, 7) and mediates (8, 9, 10, 11) stress-induced changes in behavior, caloric intake and storage, autonomic outflow, and hypothalamic-pituitary-adrenal (HPA) activity. Glucocorticoids modulate central CRF under both stressed and basal conditions, and the expression of this neuropeptide in the paraventricular nuclei (PVN) of the hypothalamus is inhibited in strict relationship to the systemically provided dose of corticosterone (6, 12, 13). CRF messenger RNA (mRNA) and content in the central nucleus of the amygdala (CeA) is also responsive to ADX and glucocorticoids (3, 14, 15, 16), and the PVN and CeA are integral to an anatomical and functional circuit that mediates neuroendocrine, autonomic, and metabolic function (17). Furthermore, CRF in both sites is responsive to the state of feeding (18, 19), and it is well known that the HPA and autonomic responses to stress depend on the nutritional state of the animal (20, 21). Therefore, sucrose ingestion in the ADX rat may alter these central CRF systems.

Finally, brain stem catecholaminergic systems project to these central CRF cell groups (22, 23), and ADX alters norepinephrine turnover and concentration in various brain sites (e.g. (2)]. Norepinephrine also stimulates activity in the hypothalamic PVN after both stress and ADX (24, 25). Moreover, glucocorticoids and ADX specifically influence catecholaminergic activity in the brain stem medulla and pons (26, 27, 28). Catecholaminergic cell groups in A2/C2 and locus coeruleus (LC) respond to metabolic cues from the periphery and innervate CRF-expressing neurons in the PVN (23) and the forebrain (29), where norepinephrine is important for learning, arousal, and attention (29, 30, 31).

In these studies, we asked whether ADX induces a preference for sucrose, a metabolically useful substrate. Although our previous results (1, 4) suggested an ADX- induced preference for sucrose, rats in those studies were not given a choice between the two sweet drinks. Here we examine consummatory behavior in ADX and control rats allowed choice between the two sweet drinks and saline, in a three-bottle test. To determine the effects of drinking sucrose on the central nervous system, we measured the expression of CRF mRNA in hypothalamus and amygdala, and dopamine-ß-hydroxylase (DBH) in A2/C2 and locus coeruleus in ADX and control (sham-ADX) rats drinking saline ± saccharin or sucrose. We also examined the effects of sucrose consumption on circulating metabolites (e.g. glucose) and metabolic hormones (e.g. leptin). These metabolic variables are known to convey information of energy use and storage to the CNS, and thus might mediate the metabolic effects of sucrose on brain.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
In all experiments, male rats (Sprague Dawley from Bantin and Kingman, Gilroy, CA) weighing 190 ± 10 g were individually caged in a temperature-controlled (21–23 C) and light-controlled (lights on 0700–1900 h) room. Rats were allowed to adapt to their new environment for at least 2 days before studies were begun. All studies were approved by the University of California San Francisco Institution Animal Care and Use Committee.

Bilateral ADX or sham-ADX was performed under isoflurane anesthesia by the dorsal approach. Skin incisions were clipped. All rats were provided with access to rat chow to eat (Purina no. 5008) and 0.5% NaCl to drink ad libitum. Body weights as well as food, saline, sucrose and saccharin intakes were measured daily. For experiments that tested the effects of sucrose ingestion on neuropeptide mRNA expression, energy balance, and hormones, rats were decapitated under basal conditions, brains were removed, and trunk blood was collected between 0800–0830 h. Brains and plasma were stored at -80 C and -20 C, respectively. Plasma corticosterone, leptin, and insulin concentrations were analyzed by RIA (ICN Biomedicals, Inc., Orangeburg, NY, and Linco Research, Inc., St. Charles MO, respectively). Enzyme (colorimetric) assays were used to determine plasma concentrations of glucose, triglyceride (both Sigma Diagnostics, St. Louis, MO) and FFA (Wako Chemicals USA Inc., Richmond, VA), and selected fat pads were also collected and weighed (18). Brain sections (14 µm), from a 1 in 8 series of fixed and acetylated coronal slices encompassing the rostral-caudal extent of each nucleus, were hybridized, in situ, with an antisense riboprobe to CRF mRNA (Dr. Kelly Mayo, Northwestern University, Evanston, IL) or DBH mRNA (Dr. Dona Wong, Stanford University, Stanford, CA). Hybridizations for each experiment were carried out in a single lot followed by analysis of the signal on x-ray films (14-day experiment) or emulsion (5-day experiment), guided by cresyl violet staining of adjacent sections (n = 4–7 rats/group). In situ hybridization and semiquantitative analyses were carried out as previously described by Viau et al. (16).

Experiments
1) We tested whether ADX induces a preference for sucrose compared with saccharin. ADX and sham-ADX rats were provided with an ad libitum three-bottle choice among 1 M sucrose, 2 mM saccharin, and 0.5% saline immediately following surgery and for the next 5 days. Daily intakes were measured, and bottles were rotated each day to minimize any positional effects. 2) Previously, in a 14-day experiment, we had tested in ADX rats the effects of corticosterone and/or 9 days of drinking either sucrose or saccharin on energy balance and hormones (1, 4). Here, we measured in the brains of those rats the effects of sucrose or saccharin ingestion on CRF and DBH mRNA expression. 3) In a second experiment of 5 days duration, we measured the brain neuropeptide mRNA expression, energetic, and hormonal effects of continuous access to sucrose or saccharin in ADX or sham-ADX rats. Five groups were studied: sham-ADX, sham-ADX + sucrose, ADX + saline, ADX + saline and sucrose, and ADX + saline and saccharin. All drinks were provided immediately following the adrenal surgery, which initiated the experiment.

Statistical analyses
Data were analyzed by one-way ANOVA. Comparison of the results from ADX rats drinking only saline, and those allowed saccharin as well, showed that saccharin had no effect on any variable; therefore, the results from the two groups were pooled (saline ± saccharin) for further analysis and presentation of all data. A significant (P <= 0.05) global effect of ANOVA was followed by posthoc tests of individual group differences (Fisher’s PLSD). Simple linear regression analyses were performed to determine the possible relationship between some variables. ANOVA was used to test the null hypothesis that slopes did not significantly differ from 0 (P <= 0.05).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Sucrose preference in ADX rats
In all experiments to date, our results have shown that ADX consistently and substantially curbs saccharin drinking compared with that of sucrose. While those results suggested that ADX rats prefer sucrose to the equally sweet saccharin, we tested this hypothesis directly by providing rats with a three-bottle choice (saline, saccharin, and sucrose). The results definitively showed that ADX rats prefer sucrose to saccharin, whereas sham-ADX rats ingested equal amounts of both solutions (Fig. 1Go, P <= 0.01). Sham-ADX rats drank a total volume of 129 ± 23 ml sucrose, 123 ± 18 ml saccharin and 118 ± 42 ml saline in 5 days; ADX rats drank a total volume of 56 ± 11 ml sucrose, 13 ± 1 ml saccharin and 209 ± 22 ml saline in 5 days. Thus, despite the distinct preference shown by the ADX rats for sucrose, they drank only 43% as much sucrose solution as sham-ADX rats (P < 0.001), as shown previously (4).



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  		Figure 1. Adrenalectomized rats prefer sucrose (1 M) to saccharin (2 mM), when given a choice between these two equally sweet drinks. Shams like the sweet drinks equally. Rats were given a three-bottle choice between sucrose, saccharin, and 0.5% saline. Drinks were provided ad libitum and bottles were rotated daily to avoid positional effects. The percentage of sucrose consumed = the cumulative amount of sucrose drunk over the 5-day study divided by the cumulative consumptions of sucrose + saccharin, with the result multiplied by 100. See Results for absolute intake of sucrose and saccharin. *, Groups are significantly different (P <= 0.05). Bars, Group means ± SEM (n = 7 ADX, 5 sham-ADX rats).

 
Changes in metabolism provided by sucrose
Sucrose consumption by ADX rats maintained normal energy balance during the 5-day study (Fig. 2Go). Body weight gain (2A), caloric intake (2B), caloric efficiency (2C), and fat stores (2D) were normal compared with sham-ADX controls, and all variables were significantly greater in ADX rats drinking sucrose than those in ADX rats drinking saline ± saccharin (P <= 0.05). Sucrose ingestion also significantly (P <= 0.05) prevented the ADX-induced decrease in circulating leptin and triglycerides (TG), but not insulin (Table 1Go). Insulin was, however, 40% higher (P <= 0.10) in sucrose-drinking ADX rats compared with ADX rats drinking saline ± saccharin and did not differ significantly from sham-ADX controls. There were no differences in basal circulating glucose but FFA concentrations were increased in sham-ADX rats drinking sucrose. We cannot explain the significant increase in free-fatty acids in the sham-ADX group drinking sucrose compared with all other groups; however, we do know that this finding is not consistent across several sets of subsequent experiments.



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  		Figure 2. Sucrose (ADX-S) consumption by ADX rats restored: A, total body weight gain (g); B, caloric intake (kcal); C, caloric efficiency (mg body weight gain/kcal intake); and, D, relative mesenteric white adipose tissue (mWAT) weight to normal. All variables represent the net quantity over 5 days. All data were analyzed by one-way ANOVA and, when significant, posthoc analyses were performed (Fisher’s PLSD). Groups with different letters differ significantly (P <= 0.05). Bars, Group means ± SEM (n = 5–11/group). In this, and subsequent figures, SHAM, sham ADX; SHAM + S, sham ADX rats drinking sucrose; ADX, ADX rats drinking saline ± saccharin; ADX + S, ADX rats drinking sucrose.

 

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  		Table 1. Effect of sucrose ingestion on circulating metabolic hormones and metabolites

 
CRF mRNA in the PVN
In the 14-day experiment, CRF mRNA expression in the paraventricular nuclei PVN was elevated, as expected in the ADX rats drinking saline ± saccharin (Fig. 3Go). By contrast, in the rats which had been ADX for 14 days and drinking sucrose, CRF mRNA expression in PVN was not different from the levels in sham-ADX rats that drank saline ± sucrose (Fig. 3Go; ANOVA: F3,17 = 32.9, P < 0.0001).



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  		Figure 3. CRF mRNA expression in the hypothalamic PVN was increased by ADX, but sucrose ingestion completely prevented this ADX effect in the 14-day study (ADX+ S). Groups with different letters differ significantly (P <= 0.05). Bars, Group means ± SEM (n = 5–6/group).

 
In the 5-day experiment, CRF mRNA levels in the PVN were not significantly reduced by allowing ADX rats sucrose to drink (Fig. 4AGo; ANOVA:F3,24 = 4.4, P = 0.014); however, the variance in this group was unusually high. Linear regression of the relationship of CRF on sucrose (Fig. 4Go, B and C) explains why the overall mean CRF mRNA (Fig. 4AGo) was not significantly reduced in sucrose-drinking adrenalectomized rats. Essentially the entire variance (97%) of CRF in the PVN of the ADX rats drinking sucrose was explained by the quantity of sucrose ingested during the last day of the experiment. In the 14-day study, the level of CRF mRNA in the PVN did not correlate with sucrose ingested during the last day (not shown).



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  		Figure 4. As expected, ADX increased CRF mRNA expression in the PVN relative to shams (SHAM). Although the mean CRF mRNA expression in ADX, sucrose-drinking rats (ADX + S) was not different from that of ADX rats drinking saline ± saccharin in the 5-day study (A), the variance was essentially explained by the amount of sucrose drunk over the last 24 h in ADX rats (B, C). Groups with different letters differ significantly (P <= 0.05). Bars, Group means ± SEM (n = 5–11/group).

 
CRF mRNA in the CeA
In both the 14-day and 5-day studies, CRF mRNA expression in the amygdala (CeA) of ADX rats drinking saline ± saccharin was significantly reduced, compared with sham-ADX (Fig. 5Go; 5-day ANOVA: F3,22 = 3.2, P = 0.045, 14-day ANOVA: F3,17 =5.4, P = 0.009). In contrast to ADX rats drinking saline ± saccharin, CRF mRNA expression in the CeA of ADX rats drinking saline and sucrose was not different from values observed in sham-ADX rats in either study. Only on day 5, sham-ADX rats drinking saline and sucrose had significantly decreased CRF mRNA expression in the CeA compared with sham-ADX rats drinking saline (Fig. 5BGo). These changes in CRF expression in both PVN and CeA were specific, because there were neither ADX- nor sucrose-induced changes in CRF expression in the bed nuclei of the stria terminalis (not shown).



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  		Figure 5. As expected, ADX decreased CRF mRNA expression in the amygdala (CeA) compared with shams (SHAM), and this did not occur when the ADX rats drank sucrose. A = 14 day (n = 5–6/group); B = 5 day (n = 5–11/group); C = an example from each group in the 5-day experiment. Groups with different letters differ significantly (P <= 0.05). Bars, Group means ± SEM.

 
DBH in A2/C2 and in LC
At 5 days (n = 3–6/group), DBH expression in the locus coeruleus was increased by ADX rats drinking saline ± saccharin, compared with ADX rats drinking sucrose (5-day ANOVA: F2,11 = 4.7, P = 0.034). By 14 days, the overall effect of sucrose was not significant (P = 0.22), although there was still a significant difference between ADX rats drinking sucrose compared with those drinking saline ± saccharin. DBH expression in ADX rats drinking sucrose was not different from sham-ADX rats (Fig. 6Go, A and B). In the medulla (Fig. 6Go, C and D) at 5 days there was a clear effect of ADX on DBH mRNA content in A2/C2 with and without sucrose (Fig. 6CGo; ANOVA: F3,15 = 3.5, P = 0.042). However, by 14 days after ADX, there were no differences in DBH mRNA content in the A2/C2 cell groups in any group (Fig. 6DGo). Consistent with the increased metabolic water load of animals drinking sucrose, DBH expression in the basolateral medullary cell groups (A1/C1), which preferentially innervate magnocellular AVP-expressing neurons in the PVN (23), was markedly reduced in both groups drinking sucrose compared with groups given only saline (P <= 0.01; not shown).



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  		Figure 6. Compared with ADX rats drinking only saline, DBH mRNA expression in both locus coeruleus (LC; A, B, n = 3–7/group) and medullary (A2/C2; C, D, n = 3–8/group) cell groups was decreased in ADX rats drinking sucrose (A and C). Sham-saline rats are missing in panel A because sections were lost. Although there was no overall treatment effect (ANOVA, P >= 0.20) on DBH expression in the 14-day study, when only ADX rats were compared, sucrose significantly lowered DBH expression in the LC (B; * = significanty different by t test). Groups with different letters differ significantly (P <= 0.05). Bars, Group means ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Glucocorticoids have profound effects on the brain that alter the physiology and behavior of the organism. These adrenal steroids influence neural systems that control learning and memory (31, 32, 33), feeding (1, 34), drinking sweet solutions (1, 4), autonomic output (1, 4, 35) and activity of the hypothalamic-pituitary-adrenal axis (36). Evidence of the importance of glucocorticoids on these variables is demonstrated by the classic studies of glucocorticoid removal through ADX and steroid replacement. ADX changes CRF and NE activity in brain (2, 3), increases ACTH secretion, sympathetic outflow (1, 4), and disrupts behavior [e.g. feeding (1, 34), wheel running (37, 38) and drinking sweet solutions (1, 4)]; all are corrected by treatment with adrenal steroids. Our results demonstrate that, like the effects of glucocorticoid replacement, when adrenalectomized rats drink sufficient sucrose energy balance, and expression of CRF in hypothalamus and amygdala are normal. Furthermore, sucrose ingestion may prevent enhanced catecholaminergic activity in medullary and LC cell groups, as suggested by the normal levels of expression of DBH mRNA. Finally, the loss of glucocorticoids alters ingestion of sweet solutions so that a preference for sucrose is developed, and access to this metabolically useful substrate, but not saccharin, induces normal caloric intake. Together, our results suggest that: 1) the metabolic effects of sucrose ingestion induce signals (metabolic and/or hormonal) in the periphery that alter expression of central CRF; 2) the preference for sucrose to the equally palatable saccharin drink in ADX rats develops as a consequence of the postingestive energy that follows sucrose ingestion; 3) the signals that arise from restored metabolism may be transmitted, at least in part, via catecholaminergic pathways that are known to innervate central CRF neurons; and finally, 4) the normal action of glucocorticoids on CRF, under basal conditions, is mediated by effects of the steroid on metabolism rather than a direct effect on brain (summarized in Fig. 7Go).



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  		Figure 7. Schematic view of the proposed glucocorticoid-metabolic-brain feedback axis. Under basal conditions, the metabolic effects of glucocorticoids may mediate the steroid’s effects on central CRF expression. Signals resulting from restored feeding (e.g. insulin secretion) and metabolism (possibly fat metabolism) may act directly on brain and/or through brain stem mechanisms. Signals to the brain may be transmitted neurally (through the vagus), through metabolites or humorally. It is easy to imagine how carbohydrate ingestion might modulate the effects of stress on CRF and catecholamines in the brain under conditions of chronic stress.

 
CRF in the PVN
The results of studies in ADX rats have suggested that corticosterone acts directly on brain to inhibit expression of CRF in the PVN, and consequently, the downstream activity in the HPA axis. Replacement of ADX rats with corticosterone maintains normal CRF expression (3, 12, 13, 39), and CRF expression in the PVN is inhibited in strict relationship to the systemically provided dose of corticosterone. However, whereas the brain mediates the feedback effects of the adrenal steroid, the site(s) of glucocorticoid action under basal conditions have yet to be identified. Various brain lesions have been shown to alter activity in the HPA axis (40, 41, 42, 43), and implants of corticosterone in amygdala, the preoptic area and in the prefrontal cortex have been shown to inhibit stress-induced ACTH secretion [e.g. (44, 45, 46)]. However, attempts to determine a specific site of action in brain of corticosterone feedback on basal HPA activity have been generally unsuccessful (47, 48) with one exception.

Corticosterone implants were shown to inhibit basal ACTH concentrations in ADX rats after implantation into the hippocampus, amygdala and lateral septum, but not PVN (49). Those results were obtained in rats with chronic implants, and the feedback efficacy of the steroid may have been mediated by implant-induced changes in metabolism. Here, we show that sucrose ingestion, independently of glucocorticoids, restores CRF mRNA expression in the parvocellular region of the PVN of ADX rats. The decrease in CRF mRNA suggests that sucrose ingestion inhibits drive to the CRF neuron. CRF cell bodies in the PVN send axons to the median eminence and secrete CRF into the pituitary portal vasculature to stimulate ACTH. The sucrose-induced reduction in CRF mRNA in the 14-day ADX rats probably was reflected by reduced CRF peptide secretion, because, unlike the ADX group drinking saccharin (1) circulating ACTH concentrations were not significantly elevated in the ADX group drinking sucrose compared with sham-ADX (4). Thus, sucrose ingestion is capable of supplanting the negative feedback function of glucocorticoids in the hypothalamic-pituitary-adrenal axis.

CRF in the CeA
As in the PVN, our results demonstrate a glucocorticoid-independent effect of sucrose ingestion on CRF mRNA expression in the CeA of ADX rats. Several lines of evidence suggest that high concentrations of glucocorticoids also increase CRF expression in the CeA. Corticosterone pellets implanted over the dorsal margin of the CeA increases CRF mRNA expression in intact rats (15). Systemic administration of high concentrations of corticosterone also increases CRF mRNA expression in the CeA and parallel elevations in median eminence CRF peptide have been shown to occur following treatment with the steroid (3, 14). However, these studies, which exposed the CeA to high (stress) concentrations of corticosterone, do not prove that low to average glucocorticoid concentrations act directly on brain to maintain basal CRF expression in ADX rats. After adrenalectomy, CRF mRNA expression in the CeA decreases; this change, and its reversal by corticosterone, is blocked by lesions of the PVN (39). These results suggest strongly that the ADX- induced decrease in CRF expression in CeA is not directly glucocorticoid-dependent. Although high glucocorticoid concentrations clearly increase CRF expression in the CeA in intact rats, they also increase CRF mRNA in the bed nuclei of the stria terminalis (3, 14), although CRF in the BNST does not change after ADX (this study and Refs. 3, 50). There is no evidence, to our knowledge, that demonstrates a direct restorative effect of centrally administered glucocortcoids on CRF expression in the CeA of ADX rats. Therefore, it seems unlikely that glucocorticoids normally act directly on brain to sustain basal levels of CRF expression in the amygdala.

Sucrose on energy and brain pathways
In addition to the effects of sucrose ingestion on brain CRF, we have shown that, like glucocorticoid replacement, sucrose consumption also normalizes energy balance in ADX rats (4). These effects of sucrose on energy balance in ADX rats (1, 4) were confirmed here in the 5-day study. Thus, glucocorticoid replacement and sucrose ingestion in ADX rats appears to induce a common effect (e.g. on metabolism) that consequently alters activity in the same, or a closely parallel pathway. The effect of corticosterone on CRF mRNA expression in the PVN and/or the amygdala of ADX rats appears to be a consequence of the steroid’s effects on metabolism rather than a direct effect on brain (see Fig. 7Go). In addition to our results showing parallel effects of sucrose ingestion and corticosterone on central CRF and energy balance, the neuroanatomical and functional substrates for a glucocorticoid-metabolic-brain axis are well described (51).

The amygdala and PVN receive information about metabolic function (22), control autonomic outflow (17), and affect energy balance (51, 52). Bilateral lesions of the amygdala result in fat rats, and it has been suggested that CeA-regulated sympathetic outflow is important to the normal maintenance of fat stores (53, 54, 55). Feeding also increases CRF release in the CeA of rats (19). ADX reduces food intake, enhances sympathetic outflow and depresses lipogenesis, whereas sucrose ingestion restores these metabolic variables to normal, as demonstrated by normal uncoupling protein content in thermogenic brown adipose tissue, fat stores and triglyceride production in the ADX, sucrose-drinking rats (4). Like the amygdala, the hypothalamic PVN is also implicated as an important integrator and regulator of food intake and energy balance. Lesions of the PVN result in a food intake-dependent obesity (56), and glucocorticoids are required for expression of this obesity (57) as well as the obese phenotype in fa/fa rats (58). Furthermore, the hypothalamic-pituitary-adrenal response to stress depends on the caloric status of the rat (20). Clearly, both of these CRF-rich nuclei are affected by signals related to energy balance.

Brain stem catecholaminergic pathways
Brain stem catecholaminergic systems project to central CRF cell groups (22) and are influenced by glucocorticoids (26, 28, 59). Furthermore, there are studies suggesting that an intact catecholaminergic system is required for glucocorticoid feedback on the CRF neuron (reviewed in Ref. 60). The medullary catecholaminergic systems are major viscerosensory pathways in the brain (22) and relay to hypothalamic and extrahypothalamic nuclei signals related to cardiovascular, respiratory, and metabolic (e.g. glucose, lipogenesis) states.

Sucrose ingestion affected DBH expression in the A2/C2 and locus coeruleus (LC) cell groups of ADX rats in the 5-day study, suggesting altered catecholaminergic activity in these neurons. Catecholaminergic fibers from A2/C2 and LC project to PVN and amygdala, and are believed to transmit to these CRF-rich nuclei signals of metabolic origin. Norepinephrine stimulates CRF secretion in the PVN (61), and ipsilateral transection of ascending medullary catecholaminergic fibers reduces basal CRF immunostaining in the PVN (62, 63), suggesting that this pathway tonically stimulates CRF expression. Therefore, it is possible that sucrose ingestion induces metabolic signals that are transmitted from body to brain via catecholaminergic brain stem nuclei. In line with this metabolic effect of sucrose on catecholaminergic cells, it has been shown that the alterations in lower brain stem nuclei (e.g. in medullary neurons throughout the rostral- caudal extent of the NTS) resulting from sucrose ingestion are predominantly due to postingestive effects. A significant proportion of these sucrose-induced effects is likely to be mediated by afferent vagal fibers from liver to brain stem (64, 65).

As well as innervating the amygdala, the locus coeruleus, is innervated and activated by CRF fibers from the CeA and PVN (66, 67); the altered DBH mRNA expression in LC induced by sucrose drinking in ADX rats could be mediated by the restored CRF mRNA, and presumably CRF peptide in the CeA. These effects of sucrose and adrenalectomy on DBH mRNA are transient in both the LC and in the medullary A2/C2; clearly, further exploration of enzyme expression and activity will be required to interpret accurately the effects of drinking sucrose on tonic changes in catecholaminergic activity in brain stem. Others have also shown (27) that ADX-induced changes in the activity of medullary catecholaminergic neurons are temporally related to the time of ADX, and are transient. The largest effect of ADX on metabolism occurs within the first week; thereafter, rats appear to reach a new energetic steady-state, perhaps explaining the transient response of the medullary catecholamine group. The LC is believed to play a role in heightened awareness of and focus on emotional or affective states (68). Signals of importance to the survival of the individual may be integrated and stored for determining future responses by both LC and CeA; the altered catecholamine and CRF expression persists for weeks when the effect of sucrose is compared in ADX rats. These signals need not be aversive; feeding, like restraint stress, provokes CRF secretion in the CeA. It has been suggested that the CRF and NE systems serve to draw attention to significant biological cues or events, such as those of food availability (19), or, as in the case of the ADX rat, the metabolic benefits of ingesting calories as sucrose.

In addition to transmitting visceral information, brain stem nuclei also relay gustatory information to the CeA (69, 70). Thus, the effects of sucrose on the CNS in the present study probably result from either the metabolic actions of sucrose alone or the combined gustatory and metabolic actions of this sweet drink. It appears that, regardless of the gustatory effects of sucrose, there is importance placed on the nutritive value of the sweet drink in the ADX rat.

How are the metabolic effects of sucrose transmitted to the brain?
Several possibilities exist, and the answer probably will be through a combination of many signals and pathways. However, we favor a lipogenic signal in our ADX rat model. ADX did not appear to affect circulating glucose, but it did significantly depress circulating triglycerides and fat stores. Because ADX rats have reduced caloric intake and reduced fat stores due to the loss of corticosterone (34), we believe that sucrose induces restoration of this metabolic pathway in the major lipogenic tissues (liver and fat); indices of lipogenesis or lipolysis then would provide either neural (vagal) or humoral signals that indicate the favorable nutritional effects of sucrose ingestion.

It is also possible that metabolic hormones, such as leptin and insulin, act as mediators of the sucrose-induced changes in metabolic state. These hormones are especially regarded as signals of adiposity, which probably act at the CNS (71). We showed that circulating leptin and insulin are restored to normal in ADX rats drinking sucrose. In addition, there is a strong negative correlation between circulating leptin and mesenteric fat mass and CRF mRNA in the PVN of sucrose-drinking ADX rats (not shown). Leptin may also act at the brain stem (e.g. NTS), or at additional hypothalamic cell groups that are known to influence feeding behavior, autonomic output, and overall energy balance. While we are aware of a possible direct fat depot to brain neural pathway (72), sympathetic innervation of adipose tissue is believed to primarily function as an efferent regulator of lipid mobilization. Its afferent, sensory function is uncertain, and leptin (and probably insulin) appears to be the means by which adiposity is signaled to the brain because leptin deficiency or leptin resistance alone causes hyperphagia and obesity in the ob/ob, db/db, and fa/fa rodent models and in humans (71).

General implications
Although these studies deal with the restorative effects of sucrose on deficits induced by ADX under basal conditions, the results also have major implications for understanding the panoply of responses to chronic stress and depression. Under conditions of chronic stress, glucocorticoids are elevated and food intake, insulin and body weights are reduced in rats (73). However, if increased feeding also occurs, more insulin is secreted and, in conjunction with elevated glucocorticoids, calories are stored as fat (74). Carbohydrate feeding is important to behavioral responses to stressors because rats drinking glucose after inescapable shock exhibit neither the body weight loss nor learned helplessness behavior normally induced by such shock (75, 76). Similarly, rats allowed a high caloric diet and/or carbohydrate to drink during a period of sustained stress have reduced adrenocortical responses to stress (77, 78). Furthermore, sucrose, but not saccharin reduces the quantity of morphine rats self-administer in a pain/tolerance paradigm (79) and this effect is not a consequence of shifts in protein or micronutrient intake (80). In man, provision of a high carbohydrate diet before experimental stress also inhibits cortisol and feelings of depression after the stressor (81). Thus, stress responses can be modulated by experimental provision of carbohydrate in both rats and man. Therefore, in addition to the major effects of sucrose ingestion in the absence of corticosterone, it appears that there may be equally, or more, marked effects in the presence of stress and high glucocorticoid concentrations.

Self-treatment, by increasing carbohydrate and overall intake, may occur in stressed or depressed individuals. Patients who have night-eating syndrome are anorexic in the morning and then exhibit evening hyperphagia and insomnia; the syndrome occurs during periods of life stress and is alleviated when stress is reduced (82). Night eaters ingest more than 50% of their daily calories after dinner, 70% as carbohydrate. They also hypersecrete cortisol and have significantly lower mood scores that decrease further as the evening progresses after dinner time (83). Some patients with unipolar depression overeat, sleep more and are apathetic, rather than being anorexic, insomnic and anxious. From our results, increased carbohydrate intake would be expected to reduce the drive to CRF and norepinephrine in both night eaters and depressed people. Thus, it is plausible to speculate that some stressed and depressed individuals find that it feels better (84) to ingest carbohydrate, to reduce the degree of insomnia, mental anxiety and agitation imposed by chronic stress and melancholic depression.

Brain CRF, particularly in the amygdala, and noradrenergic (NE) systems, particularly in the locus coeruleus, are extensively interconnected (10) and are implicated in chronic stress responses and the etiology of major depression (10, 85). We demonstrate here that sucrose ingestion in ADX rats dramatically alters these glucocorticoid-sensitive neurotransmitters, and that these effects are probably caused by the metabolic changes that result from the consumption of sucrose. Thus, fluctuations in body energy status modulate brain neurotransmitters that cause anxiety, autonomic activity and arousal, and these findings suggest a neural basis for reports that manifestations of chronic stress (76, 77, 78, 81) [and possibly depression (83, 86)] are regulated by metabolic signals from body to brain.


   Footnotes
 
1 This work was supported, in part, by NIH Grant DK-28172. Back

2 Supported by Grant DK-07418 Back

Received January 25, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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