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Neuroscience Graduate Program (M.M.N.N., K.L.K.T., S.J.M.) and Department of Psychiatry (M.M.N.N., K.L.K.T., S.J.M., L.Y.M., S.R.G., R.R.S.), University of Cincinnati Medical Center, Cincinnati, Ohio 45237
Address all correspondence and requests for reprints to: Mary M. N. Nguyen or Randall R. Sakai, University of Cincinnati, Building E, ML 0506, 2170 East Galbraith Road, Cincinnati, Ohio 45237-0506. E-mail: mary.nguyen{at}uc.edu; or randall.sakai{at}uc.edu.
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Abstract |
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-dihydrotestosterone (DHT), or cholesterol. Implants maintained constant physiological levels of T. Standard intact, T, and DHT implant colonies formed hierarchies, whereas cholesterol colonies did not. Androgen manipulations significantly altered offensive and defensive behaviors only on the first day of VBS housing. After VBS stress, intact, T, and DHT SUB animals weighed less and lost more adipose and lean tissue than DOM and control males, whereas DOM animals primarily lost adipose tissue. However, on recovery, DHT SUB animals maintained more lean tissue than intact SUB animals. Oral glucose tolerance tests revealed that glucose clears faster in stressed T-implanted males that have increased adipose tissue. Overall, these data suggest that constant androgen concentrations in SUB animals do not prevent weight loss and changes in body composition during stress but do so during recovery. |
Introduction |
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In addition to altering metabolic functioning, stressful situations can impair reproductive axis function by reducing the production of sex hormones (e.g. estradiol and testosterone) (5, 10, 11). Furthermore, sex hormones, particularly androgens, can regulate adipose tissue development (12) and distribution (13, 14), lipid deposition and metabolism, and lean muscle tissue growth (15). Gonadectomy results in increased body weight and adiposity in both males and females as well as obesity-prone animals (16, 17). In addition, age-associated decreases of sex hormones in humans are a risk factor for obesity in the elderly. Taken together, these data suggest that stress and sex hormones are important in influencing the metabolic profile of an organism. With the increased prevalence of stress and obesity in today’s society, determining the causes and mechanisms involved with stress-induced metabolic changes can shed new light on the development of treatments for obesity, diabetes, and the metabolic syndrome.
We use a naturalistic rat model, the visible burrow system (VBS), to study the effects of chronic psychosocial stress. The VBS is an apparatus used to socially house male and female Long-Evans rats in a standard 4:2 ratio, respectively. Within 3 d of VBS housing, the males form a dominant (DOM)/subordinate (SUB) hierarchy. Neuroendocrine, physiological, and behavioral differences are observed between these animals based on their DOM or SUB status, as defined by behavioral observations. For example, DOM and SUB animals display differences in their organ weights, body weight, body composition, and time spent on the outer surface area of the VBS (4, 5, 18). Previous studies demonstrate elevated basal corticosterone concentrations (an indicator of hypothalamic-pituitary-adrenal stress axis activation) in SUB males, compared with DOM males, during VBS housing (4, 10). In contrast, plasma levels of testosterone are decreased in SUB animals, whereas DOM animals have maintained or even elevated levels of testosterone (4). Our past studies demonstrate that DOM males take most of their meals in the open surface area of the VBS. As a result, SUB animals take most of their meals in the smaller chambers to avoid aggressive interactions with the DOM animals (19). Although they all have ad libitum access to food, SUB animals consistently lose 10–15% of their body weight, whereas DOM animals maintain or lose very little body weight during VBS housing (4). The dramatic SUB animal weight loss, partly attributable to decreased food intake, results in loss of adipose tissue along with lean body mass. DOM males, on the other hand, lose adipose tissue while maintaining lean body mass (4). When individually allowed to recover for 21 d from VBS stress, SUB animals regain lost body weight primarily as adipose tissue; however, they never reach DOM or control (CON) weights, even while being hyperphagic. Consistent with increased adiposity during recovery, leptin and insulin levels are also elevated in SUB animals, suggesting that these animals are at risk for developing the metabolic syndrome relative to DOM or CON animals.
Stress alters androgen production, which can affect body weight and body composition. However, the interactions between stress and androgens on body weight and body composition have not been studied in the VBS model, nor have androgen manipulations been performed to determine its affects on physiology and behavior. Therefore, the purpose of this study was to determine whether the reduction of androgens in response to stress exacerbates body weight loss and whether lower androgen levels (in addition to elevated glucocorticoids) contribute to the propensity of regaining lost body weight as adipose tissue during a stress-free recovery period.
Androgens used for this study are testosterone and 5-dihydrotestosterone (DHT). Testosterone primarily acts on androgen receptors; however, testosterone can be aromatized to estradiol in which it exerts its effects by activating estrogen receptors. DHT, on the other hand, is the nonaromatizable, reduced form of testosterone; thus, it acts only on androgen receptors. Therefore, use of testosterone and DHT in this study would help delineate androgenic vs. estrogenic effects.
Androgen levels were maintained via SILASTIC brand implants (Dow Corning Corp., Midland, MI) filled with equivalent amounts of androgens to provide slow, constant release of steroid over prolonged periods of time. It is hypothesized that maintaining constant androgen concentrations in SUB males during stress will prevent body weight loss by maintaining lean body mass. In addition, it is hypothesized that SUB males with constant levels of androgens will exhibit a DOM behavioral and metabolic phenotype.
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Materials and Methods |
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Steroid implants
SILASTIC brand capsule implants (1.98 mm inner diameter, 3.18 mm outer diameter) of 3.2-cm lengths made from Dow Corning Medical SILASTIC tubing were filled with crystalline testosterone (T) (Sigma, St. Louis, MO), DHT (Steraloids, Inc., Newport, RI), or cholesterol (CHOL) (Sigma) and sealed with SILASTIC brand medical adhesive A (Dow Corning) as previously described (20, 21, 22). The hormone release rate was previously found to be 96 and 80 µg/d, respectively, for T and DHT (22, 23).
Experimental design
All procedures were approved by the University of Cincinnati Institutional Animal Care and Use Committee and in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, 1996). One week before experimentation, males were anesthetized with ketamine HCl and acepromazine (75–87 mg/kg per 1.3–2.5 mg/kg), underwent a bilateral gonadectomy, and implanted sc with SILASTIC brand implants filled with T, DHT, or CHOL, depending on the experimental cohort. Each cohort consisted of 12 colonies (four males and two females/colony). Males in the first two cohorts (CHOL and T) received one implant, whereas males in the third cohort (DHT) received two implants per animal to accommodate for the faster conversion of DHT into its metabolite 5-androstanediol (24). Males in a fourth cohort (Intact) served as nonmanipulated controls. After surgery, the males were allowed to recover for 1 wk. After recovery, males and females within each cohort were weight matched to each other by sex. They were then randomly assigned to VBS colonies consisting of the standard four male and two female ratio or to control groups. Control males were singly housed with a female in conventional shoe box cages and underwent the same treatment as their experimental counterparts. Before experimentation, photographs were taken to document each animal’s unique pied fur coat pattern for video identification.
VBS
The VBS, as previously described (4, 6), was constructed from black Plexiglas and consisted of a large outer open surface area connected to two side chambers by a series of clear Plexiglas tunnels (Fig. 1
). The open surface area was kept on a 12-h light,12-h dark cycle via a 15 W light bulb (on: 0600 h), whereas the chambers and tunnels were kept in constant darkness to mimic a natural burrow system. An infrared light source and digital video camera mounted above the burrows recorded colony behavior and animal activity every other day for 6 h during the dark phase starting from lights off (1800 h), a time when the animals were most active. Water and food were available ad libitum in the side chambers and open surface area. All VBS experiments were run in a temperature- and humidity-controlled room.
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Behavioral analysis and dominance determination
Standard criteria were used to determine social status within a colony (4, 6). Dominance was determined by analysis of dyadic agonistic interactions among males. Males that occupied the open surface area, displayed piloerection, and actively attacked conspecifics a majority of the time were assigned DOM status. Males that did not meet these criteria were assigned to the SUB group. The observational data were corroborated by bite number and bite locations (snout and head for the DOM, back and tail for the SUB) and total offensive and total defensive behavioral scores.
Videos recorded during VBS housing were analyzed for specific offensive behaviors (biting, lateral attack, on top of, chasing), defensive behaviors (boxing, on back of, flight), and other behaviors (reproductive mounting, tumbles) beginning at lights-off for the first 15 min of every hour for a total of 6 h on d 0, 2, 6, and 12 (4, 6). Eight colonies from each cohort were behaviorally scored.
Blood sampling
Blood samples were taken before placement in the VBS (pre-VBS, d –1), after VBS exposure (post-VBS, d 13), and after a stress-free recovery period from VBS housing (postrecovery, d 33) for determination of plasma T and corticosterone concentrations. Before the start of each blood sampling, males were left undisturbed for 1 h. Samples were taken in the morning at 1000 h. Males were individually placed into clear Plexiglas restraint tubes (length: 21.5 cm, inner diameter: 6.3 cm), and a blood sample (
200 µl) was quickly acquired via a small tail nick. Total sampling time took less than 5 min, starting from the time the experimenters entered the room to restrain the animals. Post-VBS blood sampling consisted of removing VBS and CON males from group housing and placing them into their individual cages for 1 undisturbed hour before bloods were drawn. All bloods were collected in heparinized tubes, cold centrifuged for plasma collection, and stored at –80 C for further plasma hormone analysis.
Oral glucose tolerance test
Upon the end of VBS housing (d 14) and after the recovery period (d 34), males were individually housed and fasted overnight in clean cages. The next day at 0800 h, all animals were weighed and left undisturbed for 1 h. At 0900 h basal blood samples were acquired at –5 and 0 min, and animals were given an oral gavage of a 20% glucose solution (1.5 g/kg). Blood samples were taken at 15-, 30-, 45-, 60-, and 120-min intervals to determine plasma glucose and insulin levels. This test ascertains the rate of glucose clearance from the blood and the amount of insulin required to clear a glucose load. Area under the curve (AUC) was calculated for the oral glucose tolerance test plots to determine total glucose cleared over time and insulin usage.
Body composition
Whole-body composition was measured before VBS, after VBS, and after recovery to determine body adiposity, lean tissue, and water content using the EchoMRI whole body composition analyzer system (software version 2004; Echo Medical Systems, Houston, TX) (25, 26). Males were individually placed into an adapted plastic restrainer and inserted into the EchoMRI. Scanning took 47 sec with the overall length of time in the restrainer approximately 1 min after which the animals were returned to their appropriate housing. Time in the EchoMRI was minimized to limit stress responses.
Plasma hormone assays
Total plasma testosterone was measured by RIA using a commercial kit, Coat-A-Count total testosterone (Diagnostic Products Corp., Los Angeles, CA), with an analytical sensitivity of 4 ng/dl. The intra- and interassay coefficient of variation is 5 and 6%, respectively.
Total plasma corticosterone was measured by RIA using rabbit antiserum raised against corticosterone (B3-163; Endocrine Sciences, Tarzana, CA) as previously described (27). Assay sensitivity is 0.5 µg per 100 ml (27).
Glucose was measured by exposing plasma samples to glucose oxidase enzyme. Resultant colorimetric changes from the oxidation of glucose were measured as an indication of plasma glucose concentration. Insulin was measured by RIA using guinea pig antiinsulin serum, 125I-labeled insulin (Linco, St. Charles, MO), and a double-antibody separation technique. The minimal detectable concentration in plasma with this assay is 2 pM with intra- and interassay coefficient of variation of 5 and 7%, respectively (28).
Statistical analysis
Data are shown as ± SEM. Behaviors, bites, plasma testosterone, plasma corticosterone, absolute body weights, body compositions, and AUC were analyzed by two-way ANOVA with Status (CON, DOM, SUB) and Implant (Intact, T, DHT, CHOL) as between-subject factors using StatView (SAS Institute Inc., Cary, NC) and/or SigmaStat (Systat Software Inc., Point Richmond, CA) software. AUC was calculated using the trapezoidal method for both glucose and insulin time courses; the data were normalized to baseline. Percent body weights, food intake, and plasma glucose and insulin from the oral glucose tolerance tests were analyzed by three-way ANOVA with Status and Implant as between-subject factors and day (0–35) as a within-subject factor. Significant main effects were further analyzed by Student-Newman-Keuls post hoc test. Significance was set at P < 0.05.
One Intact male was removed from analysis because he became a codominant male. Codominant males were defined as males that occupied the open surface area and displayed piloerection but did not actively attack conspecifics. Eight T animals and five DHT animals that had incompletely filled or punctured implants were removed from analysis. Outliers were detected using the Dixon-Massey method, and when necessary, data were reanalyzed after outlier removal.
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Results |
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There was a main effect of social status on total offensive behaviors (Status, F1,87 = 57.83, P < 0.05) but no main effect of Implant. DOM males in the Intact, T, and DHT cohorts exhibited more offensive behaviors, compared with SUB animals of the same cohort, but there were no offensive differences between cohorts (Table 1). On the other hand, there were no main effects of Status or Implant on total defensive behaviors between cohorts (Table 1). When separated by days, similar trends for offensive and defensive behaviors were observed for d 0, 6, and 12 of VBS housing (Table 1).
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). In contrast, androgen-implanted SUB males exhibited more defensive behaviors on d 0 compared with Intact SUB males (Table 1). Main effects of Status were observed only for d 6 (F1,87 = 17.79, P < 0.05) and d 12 (F1,87 = 45.33, P < 0.05) offensive behaviors in which SUB animals exhibited decreased offensive behaviors, compared with DOM animals of the same cohort.
When offensive and defensive behaviors were broken down into individual components (Table 2), there was a main effect of Status on biting (F1,87 = 15.71, P < 0.05), lateral attack (F1,87 = 39.40, P < 0.05), chase (F1,87 = 39.92, P < 0.05), and tumble (F1,87 = 11.35, P < 0.05) behaviors. Intact, T, and DHT DOM animals exhibited increased biting, lateral attacking, and chasing behaviors, compared with SUB animals within the same cohorts, whereas increased tumbles were observed only in the DOM animals of the Intact and T cohorts. Additionally, a main effect if Implant was observed for biting (F2,87 = 3.16, P < 0.05) and tumble (F2,87 = 6.02, P < 0.05); however, post hoc analysis did not result in significant differences between Implant groups.
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), whereas SUB animals received a higher percentage of bites localized to the body and tail (Table 3). DOM males tended to have wounds centered primarily on the face and neck, whereas SUB males had bites located mostly on their back and rear. These bite patterns are indicative of DOM and SUB attack behaviors. There was also a main effect of Implant on percent body and tail bites (F2,107= 3.40, P < 0.05). Specifically, there were no differences in DOM bite patterns and percentages between cohorts, but DHT SUB males had an overall increase in tail bites and a corresponding decrease in body bites, compared with the Intact SUB animals, suggesting that the males may be differentially attacking specific body regions. In contrast, CHOL males did not receive any bites while being housed in the burrows (data not shown).
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). All of the T concentrations were within the physiological range in this study.
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). Additionally, there was a main effect between Intact pre- and post-VBS colonies (F1,112 = 9.32, P < 0.05) in which SUB males experienced a significant drop in post-VBS T concentrations, compared with their pre-VBS levels. This demonstrates that SUB males experienced a drop in testosterone levels at the end of VBS housing, compared with their levels before VBS housing.
During recovery, Intact SUB T concentrations returned to DOM and CON levels (data not shown), and there were no main Status or Implant effects. CHOL males had no detectable levels of T throughout the study (Fig. 2, A and B).
Plasma concentrations of basal corticosterone did not differ significantly within each cohort before (data not shown) or after VBS housing (Fig. 3).
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, A–D, and the insets, all CON animals, irrespective of experimental condition, gained weight throughout VBS housing and recovery periods. In the Intact cohort, there was a main effect of Status (F2,471 = 40.05, P < 0.05). Intact DOM males had similar body weights, compared with CON, whereas SUB males lost a significant amount of body weight immediately on entering the VBS. They maintained this lower body weight throughout the 2-wk stress period, but once in recovery, Intact SUB animals regained their lost body weight back to CON levels (Fig. 4A).
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, B and C). T and DHT DOM males weighed less than their CON animals while in the VBS, but they steadily gained weight throughout the VBS housing period. During the recovery period, DOM body weights caught up to CON weights. T and DHT SUB animals showed similar body weight loss as the Intact SUB animals; however, unlike the other cohorts, DHT SUB weight percentages did not reach CON levels during the recovery period, albeit having equivalent ending absolute weights (main effect of Status for DHT recovery, F2,278 = 8.93, P < 0.05) (Fig. 4C).
There was a main Status effect (F1,471 = 6.28, P < 0.05) during VBS housing for the CHOL colonies. Although they did not form hierarchies, the CHOL colonies had lower body weights, compared with their controls, despite continuing to gain weight throughout VBS housing (Fig. 4D). Once in recovery, there were no differences between VBS-housed and CON groups.
Overall, during the recovery phase, Intact and CHOL males gained approximately 10–15% of their original body weights, whereas the androgen-implanted colonies (T and DHT) gained approximately 20–30% of their original body weights.
Body composition
After 14 d of VBS housing, there was a main Status effect (F2,49 = 51.35, P < 0.05) for percent adipose tissue in which DOM and SUB males in the Intact, T, and DHT colonies lost a significant percentage of adipose tissue, compared with their corresponding CON animals (Fig. 5A). Similarly, there was a main effect of Status (F2,49 = 31.71, P < 0.05) on percent lean tissue, in which both DOM and SUB males in the T and DHT cohort had higher percentages of lean body mass, compared with their CON, whereas only the SUB animals in the Intact group exhibited increased lean (Fig. 5B). CHOL animals did not have adipose or lean tissue differences after burrow housing (Fig. 5, A and B).
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, A and B). However, there was an overall main Implant effect (F2,49 = 32.99, P < 0.05) for percent recovery adipose in which an increase in percent adipose was observed in the T implant cohort, compared with Intact and DHT groups (Fig. 6A). There was also a main effect of Implant for percent recovery lean (F2,49 = 70.31, P < 0.05). In contrast to the recovery adipose, lean tissue was increased in only the DHT group, compared with the Intact and T colonies (Fig. 6, A and B). After recovery, no adipose or lean tissue differences were found in the CHOL animals (Fig. 6, A and B).
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, A–D).
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, A–D). There was a main effect of Implant (F2,45= 9.02, P < 0.05) on glucose AUC in which DHT SUB males had a higher AUC, compared with Intact and T SUB animals (Fig. 8E). No main effects of Status or Implant were observed in plasma insulin or AUC for both post-VBS and postrecovery. However, there was a trend for DHT SUB animals to release less insulin, compared with their DOM and CON counterparts (Fig. 9, A–E).
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Discussion |
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We confirmed past VBS studies (10), in that a DOM/SUB social hierarchy quickly developed in the Intact colonies, and SUB males had decreased T levels, compared with DOM and CON animals. A social hierarchy also formed in both the T and DHT cohorts. Using well-established criteria for determining dominance hierarchies (4, 6), both T- and DHT-implanted colonies established a DOM/SUB hierarchy irrespective of the fact that they had equivalent levels of androgens before entering and throughout burrow housing. In contrast, CHOL colonies did not form dominance hierarchies.
Behavior
Consistent with the observed hierarchies, DOM males exhibited more offensive behaviors, which lasted throughout VBS housing, compared with their SUB counterparts (Fig. 2). DOM males, who were more offensive, received higher percentages of attacks localized to the head, whereas SUB males, who exhibited more flight behavior, received a higher percentage of attacks localized to the body. CHOL males exhibited very few offensive behaviors. Offensive attack patterns and number of attacks also reflect the lack of hierarchal behavior. The lack of a hierarchy in the CHOL animals parallel studies showing decreased aggression, offensive behaviors, and agonistic activity seen in gonadectomized males (29, 30).
Although the T and DHT groups had different concentrations of T before and after VBS, compared with Intact colonies, the overall social behaviors did not differ between these cohorts except during the early stages of hierarchy formation (d 0). DHT males exhibited more offensive and defensive behaviors, compared with Intact males, suggesting that activation of androgen receptors early in hierarchy formation may result in different colony-forming behaviors or strategies. This difference in behavior is also indirectly revealed through attack patterns. DHT SUB males received fewer attacks to the body and more attacks to the hind quarters, suggesting that DHT may produce different attacking strategies in the DOM animals or different defensive strategies in the SUB animals.
Plasma hormones
The implants were designed to release constant levels of T. Even though the concentrations of testosterone in the T cohort were lower than anticipated, they still released physiological concentrations of T that were similar to Intact DOM concentrations. More importantly, the implants prevented the post-VBS SUB drop in T observed in the Intact SUB males, thus demonstrating that T was consistently maintained in the T-implanted animals. Plasma T levels were detected in the DHT animals despite gonadectomy (Fig. 4, A and B). Given that DHT cannot be converted to T, the presence of T could be attributed to adrenal androgen production.
Even though the T and DHT implant groups received different androgen treatments, there was not an effect of androgens on hierarchy formation. Overall, these data suggest that the presence of androgens (either T or DHT) are necessary for hierarchy formation and status determination within cohorts. However, these findings further emphasize that differing concentrations of circulating androgens do not predict social status and dominance.
Basal plasma corticosterone did not differ within animals after VBS housing. This was an unexpected finding in light of past VBS studies. Similarly, Hardy et al. (10) did not observe elevated CORT by the end of 2 wk of VBS housing. However, elevated corticosterone levels were observed on d 4 and 7 of VBS housing (10). It is possible that during the 2-wk period, burrow-housed SUB males habituate to the social stress. Even so, SUB animals from this study still manifest phenotypes consistent with exposure to chronic stress as evidenced by the drastic body weight loss. A lack of increased basal corticosterone does not preclude a history of elevated basal corticosterone and stress experience.
Body weight and body composition
Consistent with previous reports from our laboratory (4), within a day of being socially housed, SUB animals from all cohorts (Intact, T, and DHT) lost a considerable amount of body weight, compared with their corresponding DOM and CON animals. SUB animals maintained this lower body weight throughout the 2-wk VBS housing period. DOM males from all cohorts also lost body weight during the initial days of VBS housing; however, by d 3, they proceeded to steadily gain weight. DOM males also exhibited a decrease in body weight, compared with CON males. This weight loss can be attributed to an increase in activity and exercise within the VBS because the CHOL animals (which did not form a hierarchy) also lost body weight, compared with CON animals. This suggests that the larger housing area of the VBS might endow these animals with more activity space.
All CON animals steadily gained weight throughout the VBS and recovery periods. During the recovery period, body weights of DOM rats increased and were similar to that of CON weights. DHT SUB animals were hyperphagic and gained weight during the recovery phase, but their percent body weight still remained lower than that of their appropriate controls. This suggests that while recovering from stress, DHT-treated animals were unable to increase recovery body weights back to CON levels. This also implies that there might be a disassociation between androgen and estrogen actions in regards to regaining lost body weight after a bout of stress because the DHT cohort did not fully regain their body weight.
After VBS housing, all DOM and SUB animals in the Intact, T, and DHT colonies lost a significant percentage and absolute amount (data not shown) of adipose tissue, compared with their controls. Additionally, Intact and DHT SUB animals lost absolute lean body mass (data not shown), even though percent lean body mass was increased in all the SUB animals. Considering that the SUB animals have lost such a significant amount of body weight and adipose tissue, the increase in SUB percent lean (because it takes into account the body weight of an animal) might be an artifact of the calculations. However, DOM percentages are not similarly affected because they did not lose such a significant amount of weight. From these data, the VBS stress-induced weight loss experienced by the SUB males was attributable to a loss of both adipose and lean body mass, whereas DOM males lost only adipose tissue. This further replicates and extends our past VBS findings (4).
Contrary to the body compositional differences observed during VBS housing, the recovery profile was quite different. Because of the anabolic effects of androgens, we expected that lean/somatic tissue would be increased in the androgen-implanted cohorts, compared with the Intact and CHOL cohorts during recovery. Interestingly, only the DHT cohort demonstrated a higher percentage of lean body mass, compared with the T and Intact colonies. However, what the T cohorts lacked in lean, they gained as adipose. The T cohort gained body weight preferentially as adipose tissue despite being similarly hyperphagic and gaining 20–30% of their original body weight, whereas the DHT cohort had equivalent amounts of adipose, compared with the Intact animals. Even though the androgen-implanted groups were similar in their extra 20–30% body weight gain, compared with the VBS-standard colonies, they had very different end body compositions. These data suggest that the constant presence of T or DHT in the implanted animals caused them to distribute their weight differently, and this difference might be mediated by the conversion of T to estradiol. Future studies will include analysis of plasma and adipocyte estradiol concentrations and differences in fat pad size and adipose accumulation.
Glucose clearance
Glucose is normally used in the body as a source of energy. The availability of glucose to tissues is controlled by insulin. Because of the differences in adipose and lean body mass observed in VBS males, it is possible glucose clearance and insulin secretion may be disturbed by social stress. Therefore, an oral glucose tolerance test was administered to the VBS males. This test ascertained the rate of glucose clearance from the blood and the amount of insulin required to clear a glucose load.
There were no differences in the oral glucose tolerance test time course or AUC between or within groups after VBS housing (data not shown). Similarly, no differences were observed in the glucose and insulin time course during recovery, although DHT SUB animals exhibited a greater AUC glucose value than Intact or T SUB. These data suggests that DHT SUB males had a difficult time clearing a glucose load. It is possible that DHT interferes with glucose clearance only after a bout of stress and is not dependent on body composition. Because DHT SUB males have increased lean tissue and lower body weights, it is also possible that these qualities can interfere with the clearance of a glucose load. Future studies will address these issues. Similar to the decreased glucose uptake, there was a trend for DHT SUB animals to release less insulin during the glucose challenge, although there were no differences in insulin AUC values. It is feasible that stress and increased activation of the androgen receptor impairs insulin secretion, which would in turn result in impaired glucose uptake in the DHT SUB animals.
In summary, this study suggests that the presence of androgens is necessary for hierarchy formation. Androgens helped maintain lean body mass during VBS housing. Only DHT treatment prevented the gain in adipose tissue and promoted lean tissue during recovery. All socially housed animals were hyperphagic during recovery. Even while hyperphagic, DHT SUB animals did not attain CON or DOM weights. Contrary to our initial hypothesis, during times of stress, it seems that maintaining constant androgen levels are not sufficient to rescue the SUB phenotype. The data suggest that during times of recovery from stress, maintaining higher levels of DHT may promote lean body mass and diminish the gain of body adiposity through the activation of the androgen receptors.
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Acknowledgments |
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Footnotes |
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The material contained in this manuscript was used for the partial fulfillment of a Ph.D. dissertation at the University of Cincinnati for M.M.N.N.
Disclosure Statement: The authors have nothing to disclose.
First Published Online September 20, 2007
Abbreviations: AUC, Area under the curve; CHOL, cholesterol; CON, control; DHT, 5-dihydrotestosterone; DOM, dominant; SUB, subordinate; T, testosterone; VBS, visible burrow system.
Received April 12, 2007.
Accepted for publication September 12, 2007.
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References |
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4–5-reductase and 3-hydroxysteroid dehydrogenase. Endocrinology 109:1225–1233 reduced androgens by various tissues of the male rat. J Androl 11:161–167
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