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Department of Nutritional Sciences and * Department of Animal Sciences, Rutgers University, New Brunswick, NJ
3To whom correspondence should be addressed. E-mail: Shapses{at}aesop.rutgers.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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46% weight from baseline, EnR rats maintained their weight throughout the study. Energy restriction was associated with lower Ca absorption (5-d measurement, 45Ca radioisotope) and Ca balance in lower EA but not higher EA rats. Similarly, Ca absorption was correlated with both serum E2 (r = 0.68, P < 0.05) and body weight (r = 0.72, P < 0.05) in rats with lower EA but not in those with higher EA. Finally, 24-h corticosterone excretion was higher in EnR than in CTL rats, a response that was blunted in the higher EA rats. Our findings suggest that decreases in estrogen and hyperadrenocorticism with energy restriction play an important role in the regulation of Ca absorption and balance.
KEY WORDS: • absorption • calcium • estrogen • corticosterone • weight loss
Weight loss has been associated with loss of bone mass in numerous studies in animals (1,2), in epidemiological cohort studies (3,4), and in most controlled intervention trials (5–12). However, the mechanism driving bone loss during weight reduction has not yet been elucidated. In a previous report of premenopausal women from our laboratory (13), we did not observe bone loss with weight reduction, and a possible explanation for this discrepancy may involve the higher estrogen levels in the heavier population of premenopausal women in that study (13) compared to that of the leaner and/or older individuals from other reports (5–8,10–12). This possibility is supported by findings that energy restriction induces a greater hypoestrogenic state in lean than in obese rats (14) and may imply that leaner individuals who lose weight are at greater risk of hypoestrogenism and thus bone loss.
We observed that decreases in serum estradiol (E2)4 tend to be associated with decreases in Ca absorption (14), suggesting that the 2 events may act in conjunction to affect the Ca balance. This is supported by the presence of estrogen receptors in the intestinal mucosa and by evidence of a direct effect of estrogen promoting intestinal Ca absorption (15,16). To the best of our knowledge, the relationship between estrogen decline and the reduction in Ca absorption during weight loss has not been studied. We hypothesized that an energy restriction–induced decrease in estrogen is a major mechanism for inducing a decrease in Ca absorption in mature rats and that a higher estrogen status during energy restriction would prevent the decrease in Ca absorption.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Diets. Throughout the study, rats had free access to tap water. Three semipurified diets (Table 1) containing 0.5% Ca and 0.3% phosphorus (17) were provided (Research Diets). Between 4 and 6 mo of age, rats ate a diet for growth, based on AIN-93G (18), ad libitum (Table 1). After 6 mo of age, rats were divided into 2 weight-matched groups that were assigned to either a control diet (for mature rats), based on AIN-93M (18) (Table 1), or a 40% energy-restricted diet. This was accomplished by pair-feeding the energy-restricted rats with their weight-matched control (CTL-M) and reducing the carbohydrate content of the energy-restricted diet. Daily intakes of protein, fat, fiber, vitamins, and minerals were the same in both diet groups.
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At 6 mo of age, all rats were ovariectomized under xylazine and ketamine anesthesia, administered via intraperitoneal injection. Ninety day–release 1.7-mg 17ß-E2 pellets (0.02 mg/d) (Innovative Research of America) were implanted subcutaneously at this time to maintain serum E2 at low physiological levels. Three weeks were allowed for recovery from surgery and adaptation to the E2 implants. Rats were then divided into 2 weight-matched groups, which were assigned to either control (CTL group; with ad libitum access to food) or 40% energy-restricted diet (EnR group; given daily between 800 and 900 h). This dietary treatment continued for 10 wk, after which 24-h urine was obtained and a 5-d Ca balance was performed. Rats were killed at 9 mo of age by decapitation after CO2 inhalation in the early afternoon between 1200 and 1400 h and blood, uteri, and parametrial fat pads were collected.
Biochemical analyses.
Concentrations of E2, 25-hydroxyvitamin D [25(OH)D], and 1,25-hydroxyvitamin D [1,25(OH)D] were measured in acetonitrile-extracted serum using an RIA [double antibody, DPC, for E2; and DiaSorin for 25(OH)D and 1,25(OH)D]. Intact bioactive serum parathyroid hormone (PTH) was measured using a rat-specific RIA (Immutopics). Corticosterone was analyzed in 24-h urine samples using a rat-specific RIA kit (ICN Biomedicals). Urinary creatinine (No. 555, Sigma Diagnostics) was measured on a spectrophotometer (Microplate autoreader EL311, BioTek Instruments, 
= 575). All CV were <15%, as reported by the manufacturers.
Uterus and parametrial fat pad weights. Uteri were dissected and weighed in a balance scale at the time of killing to be used as an indicator of estrogenic activity (EA) during chronic energy restriction. Parametrial fat pads were dissected and weighed.
Bone turnover. Bone resorption was assessed in 24-h urine by total urinary pyridinium crosslinks [pyridinoline (PYD) and deoxypyridinoline (DPD)], which were measured by HPLC after hydrolyzed samples were subjected to a prefractionation procedure (19). Peaks were detected by fluorescence (20) and quantitated by external standards. Values are expressed as 24-h excretions (CV of 8 and 13% for PYD and DPD, respectively). Bone formation was assessed in serum using rat-specific osteocalcin (OC) with an enzyme-linked immunoassay (Biomedical Technologies) with a CV of <8%.
Intestinal Ca absorption. Calcium absorption and intestinal Ca metabolism (intestinal Ca secretion, endogenous and total fecal Ca) were measured according to O’Loughlin and Morris (16) as previously described (14). Briefly, rats were placed in individual metabolic cages and administered 2 MBq (0.054 mCi) of 45Ca i.m. to monitor the secretion of endogenous Ca into the gut. Ca balance was determined over 5 d, with daily food consumption recorded and all urine and feces collected. Fecal and urinary 45Ca were determined by liquid scintillation counting. Fecal and urinary total Ca content was determined using atomic absorption spectrometry. Calcium balance, endogenous fecal Ca, and Ca absorption were calculated using equations described previously (14).
Statistical analysis.
The effects of energy restriction and estrogenic status (see below) were evaluated using 2-way ANOVA and significant effects were further analyzed by Tukey’s post hoc comparison tests. For body weight values measured serially over time, a 3-way ANOVA with repeated measures over time was performed. Pearson’s correlation coefficient was used to evaluate correlations between dependent variables. Differences with P values 
0.05 were considered significant. Data are means ± SD unless otherwise indicated. All analyses were conducted using the SAS statistical package (SAS Institute, version 8.2).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Slow-release 17ß E2 pellets were implanted immediately after ovariectomy. Based on uterine weights, it was apparent that the E2 pellets (90 d–release pellet) dissolved faster than anticipated in this 90-d study, but only in some of the rats. Nevertheless, because we used uterine weights to determine group assignment, our hypothesis remained unchanged (rats with normal uterine weights would maintain calcium absorption during semistarvation). Because uterine weights are an excellent indicator of the chronic estrogenic milieu (21) and weights ranged from 127 to 700 mg, rats were separated into groups based on higher and lower estrogenic status at study conclusion. Uterine weight was examined in a dichotomous manner (lower and higher EA) because the linear model in its continuous form is inappropriate due to a positive skewness at upper ranges of weights. Hence, the median of 228 mg was used as the cutoff, yielding 2 groups with uteri weights of 177 ± 24 ("lower EA," n = 12) and 370 ± 125 mg ("higher EA," n = 12) (P < 0.0001). Uterine weights in the lower EA group are consistent with those in mature ovariectomized rats treated with low doses of E2 (0.015 µg/d) (22) and with mature energy-restricted intact rats in our previous studies (14). The higher estrogen group had uterine weights similar to that of mature rats (23) and to that of mature ovariectomized rats treated with E2 (0.05–1.5 µg/d) (22,24) and, as expected, uteri were smaller than in rats treated with supraphysiological doses of E2 (2–25 µg/d) with uterine weights ranging from 500 to 800 mg (14,15,25,26). Overall, the advantage of the data in our rats is that there are 2 levels of estrogen status being compared, and the larger uteri could be considered a physiological rather than a pharmacological estrogen replacement, whereas the smaller uteri reflect a very low estrogen status.
Uteri weights were not affected by energy restriction in either the lower EA (179 ± 140 and 175 ± 32 mg for CTL and EnR, respectively) or the higher EA group (378 ± 164 and 361 ± 86 mg for CTL and EnR, respectively).
Energy restriction with lower and higher estrogenic activity
Body weight and food intake. Body weights did not differ between groups (Table 2, Fig. 1) at 6 mo of age before energy restriction began. While consuming 40% less energy than CTL rats (P < 0.0001), EnR rats ate the same amount of Ca (Table 2). EnR rats had lower body weights than CTL rats throughout the intervention period (Table 2, Fig. 1). Rather than achieving weight loss, EnR rats maintained their weight (1.3 ± 9.1% change) whereas CTL rats gained 46.0 ± 14.4% body weight (Fig. 1). EnR rats had less parametrial fat and excreted less creatinine (an indicator of muscle mass) (Table 2) than CTL rats. Body weights, parametrial fat pad weights, and creatinine excretion did not differ between rats with lower and higher EA.
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0.07) for an interaction between estrogenic status and diet, with EnR rats having a smaller secretion in lower EA rats in contrast to the larger secretion in higher EA rats, compared with their respective controls (Table 3). Ca absorption measurements were not available for 3 rats due to an error in fecal collection during the 5-d balance.
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Bone turnover. Urinary crosslinks were not affected by 10 wk of energy restriction or estrogen status. Serum OC was lower in EnR than in CTL rats, regardless of the estrogen status.
Correlation analyses.
Correlations of body weight in rats separated by estrogenic status were determined (Table 4). Parametrial fat pad weight was correlated with OC (r = 0.48, P < 0.05) and excretion of PYD (r = 0.43, P < 0.05) and DPD (r = 0.55, P < 0.01). Uterine weights were correlated with E2 levels (r = 0.68, P 0.01) and 1,25(OH)D (r = 0.66, P 0.02) in the higher EA group, but not in the lower EA group (r < 0.35, P < 0.28). Among rats with higher uterine weights, 25(OH)D was directly associated with TFCA (r = 0.74, P < 0.01), net absorption (r = 0.72, P < 0.05), Ca balance (r = 0.69, P < 0.05), and intestinal secretion (r = 0.70, P < 0.05) and negatively associated with fecal Ca (r = –0.66, P < 0.05). Serum 1,25(OH)D did not correlate with these variables in either the lower or the higher EA rats. Rats with lower EA showed a significant correlation between TFCA and both serum E2 (r = 0.68, P < 0.05) and weight (r = 0.72, P < 0.02). Estradiol concentrations correlated with fat pad weights (r = 0.69, P < 0.05) and inversely with corticosterone (r = –0.66, P < 0.05). These associations were not present in rats with higher uterine weights.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Previously, researchers observed that energy restriction decreases estrogen levels in otherwise healthy rats (1,2,14) and humans (10,28) and has a negative impact on intestinal Ca absorption in rats (14). Estrogen deficiency impairs intestinal Ca absorption in mice (15,16,23,29) and new evidence shows the direct effect of estrogen on intestinal Ca transporters that is independent of vitamin D (30). In addition, Ca absorption is reduced in estrogen-deficient women (31), whereas treatment with E2 has been shown to stimulate Ca absorption (15,16,32). We hypothesized that estrogen replacement during energy restriction would prevent the decrease in Ca absorption and Ca balance previously observed (14). Consistent with our hypothesis, rats with higher estrogen status showed no significant impact of energy restriction on Ca absorption compared with rats with lower E2 levels. We found that low, but still detectable serum E2 levels did not induce hyperphagia and/or increase body weight compared with rats with higher E2 levels. Our lower EA group may be a good model of the postmenopausal woman who has minimal, yet detectable levels of estrogen due to the extraovarian production that has been shown to influence bone health (33,34).
In light of the findings by the Women’s Health Initiative, which showed increased health risks with the use of estrogen plus progestin protocols (35) despite a reduction in fracture risk, alternatives to continuous hormone replacement therapy are being explored. Importantly, the correlation between serum E2 and TFCA, only within the group with low estrogenic status, suggests that these limiting E2 levels are critical in the regulation of Ca absorption and balance and provide evidence that low physiological levels of estrogen status are important in regulating bone health (33). Cyclical estrogen levels are typical in premenopausal women, yet the effect of cyclical estrogen replacement during energy restriction remains to be evaluated.
We found that energy restriction was associated with decreased serum E2 and that lower body weights correlated with lower serum E2, but only in rats with lower EA. Ovaries are the main source of estrogens in intact animals and premenopausal women; however, the activity of the enzyme aromatase in adipose tissue makes this tissue an additional source of E2. Interestingly, in rats with lower EA, serum E2 was directly correlated with parametrial fat pad weights, suggesting that fat was an additional relevant source of estrogen, and fat loss during weight reduction had an impact on E2 levels. This is consistent with our previous clinical weight loss trials in postmenopausal women (10), which showed good correlation between fat loss and decreased serum estrone during weight loss. In addition, Hui et al. (36) showed that the decrease in estrogen levels in women between the ages of 31 and 50 can be prevented by weight gain. Furthermore, we showed that energy restriction causes a greater estrogen deficiency in lean compared with obese rats (14). Local synthesis of estrogen in the excess adipose tissue of obese women may preserve serum E2 levels and protect against the deleterious effects of weight reduction on Ca metabolism and bone.
Serum 25(OH)D levels were not affected by energy restriction or estrogenic status. Higher vitamin D status, however, was a predictor of higher TFCA and Ca balance, but only in rats with higher estrogenic status. This finding is interesting in light of observations from clinical studies. For example, the direct relationship between Ca absorption and serum vitamin D present in estrogen-replete premenopausal women is not observed in estrogen-deficient postmenopausal women (27). In addition, when 1,25(OH)D is administered to estrogen-deficient women there is a smaller increase in Ca absorption than in women with estrogen replacement (37). A possible mechanism for the vitamin D resistance in hypoestrogenic states (27,37) may be related to the ability of estrogen to directly increase intestinal vitamin D receptors and/or their responsiveness to vitamin D in the intestine (38).
Energy restriction was associated with increased corticosterone excretion, consistent with previous findings (14,39,40). Interestingly, elevated corticosterone levels in energy-restricted rats were only present in rats with lower E2 levels. Not only was this rise in corticosterone dramatic (more than 100% higher than controls), but also the inverse association between corticosterone and serum E2 suggests a potential relationship between these 2 hormones that may be relevant during energy restriction. However, the cause-and-effect relationship between the increase in corticosterone and the decrease in estrogen is not clear. It is possible that the energy restriction–induced rise in corticosterone contributed to the decrease in E2 in the rats with lower estrogen activity (41,42). On the other hand, these data show that within an estrogen-sufficient state, the rise in corticosterone is prevented, possibly showing a protective effect of estrogen. Estrogens and phytoestrogens have been shown to decrease adrenal steroid synthesis (43–45) and estrogen replacement lowers the corticosterone response to stress in ovariectomized rats (46). We suggest that the decreased Ca absorption and balance during energy restriction in the group with lower estrogen status may have been a consequence of both low E2 (16) and increased corticosterone (47). Whether the effects are the sum of the 2 events or whether the hormones act synergistically remains to be elucidated. Furthermore, it is well documented that elevated levels of glucocorticoids (48,49) and/or low levels of sex hormones (50) will promote bone loss. Consistent with this, our data show a decrease in bone formation relative to bone resorption. The combined effects of low estrogen and high corticosterone may be important in mediating the negative effects of weight reduction on Ca and bone metabolism. Clarification of the role of corticosteroids in a future energy restriction study is indicated.
A limitation of this study could be that the E2 pellets did not increase estrogen levels as high as anticipated in all of the rats. However, we suggest that the more physiological range of E2 levels in this study is particularly relevant to the new lower levels of estrogen replacement that are currently being examined for use in postmenopausal women. In addition, because laboratory analysis of the variables was performed in a manner blind to group assignment, investigator bias was avoided. Furthermore, to avoid the risk of Type II errors in the interpretation of the data, results that were only trends were not further analyzed or emphasized in this paper.
In summary, the decrease in intestinal Ca absorption and the low Ca balance due to energy restriction in rats was prevented by maintaining estrogenic status. These findings strongly suggest that the susceptibility of Ca metabolism to energy restriction in mature rats may be mediated by decreased EA and possibly by hyperadrenocorticism. It is suggested that estrogen mitigates an energy restriction–induced increase in corticosterone. Studies of the mechanisms involved, including the role of estrogen metabolism in adipose tissue during weight loss, in addition to levels and responsiveness of intestinal vitamin D receptors, calbindin-D(9k) and TRPV6, are necessary to further understand these findings. The clinical implications in manipulating estrogen levels to prevent the adverse effects of weight reduction on bone remain to be evaluated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Current address: Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.
4 Abbreviations used: CTL, control group; DPD, deoxypyridinoline; E2, estradiol; EA, estrogenic activity; EnR, energy-restricted group; OC, osteocalcin; 1,25(OH)D, 1,25-hydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone; PYD, pyridinoline; TFCA, true fractional Ca absorption.
Manuscript received 24 February 2004. Initial review completed 29 March 2004. Revision accepted 29 April 2004.
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