Obesity is a major risk factor for the development of type 2 diabetes and cardiovascular disease (10,17). In males, obesity is associated with the occurrence of several metabolic abnormalities, such as dyslipidemia, hypertension, hyperglycemia, as well as hypogonadism (8). Hypogonadism, as indicated by decreased levels of total and free testosterone, plays an important role in the overall metabolic syndrome and also results in erectile dysfunction and other disorders in obese males (31–33).
Previous studies reported that concentrations of total and free testosterone were inversely correlated to total obesity (as indicated by body mass index) and abdominal obesity (as indicated by waist circumference) in males (20,21,28). Compared to males without metabolic syndrome, males with metabolic syndrome had significantly lower levels of testosterone (1,2). Moreover, hypogonadism was related to visceral adiposity, indicating a possible link between impaired Leydig cell function and intra-abdominal fatness (4,25). Obesity-related hypogonadism was also reported in animal studies, such as those conducted in dietary induced or genetically obese rodents (19,38).
There are several mechanisms by which obesity may result in lower testosterone production in males. These mechanisms include an inhibition of luteinizing hormone (LH)/human chorionic gonadotropin–stimulated testosterone production by leptin, an increase in adipose tissue aromatization of testosterone, a reduction in testosterone production controlled by insulin resistance, or inflammatory inhibition of testicular steroid production in obesity (14). Several protein/cytokines are indicators of local adipose tissue and systemic inflammation, which are related to the metabolic syndrome related to obesity (12). For example, monocyte chemotactic protein 1 (MCP-1) is an indicator of macrophage infiltration into local tissue and a biomarker of chronic inflammation; adiponectin is an anti-inflammatory protein mainly released by adipose tissue and the release of this protein from adipose tissue is inversely related to obesity and severity of metabolic syndrome; leptin is an adipose tissue-derived hormone that is closely linked with obesity and energy metabolism (12). Therefore, these adipose tissue-derived proteins or hormones may also play important roles in the mechanisms of obesity-related hypogonadism.
Inappropriate diet and physical inactivity are causes for obesity-related metabolic dysfunction and increase the risk for clinical diseases and disorders (24). The effects of exercise training alone on metabolic syndrome have been well studied (36). In human studies, aerobic and resistance exercise training lowered the amount of lipids, glucose, and markers of chronic inflammation and improved the symptoms of metabolic syndrome (5,6,9,11,36). In rodent studies, aerobic exercise also reversed metabolic syndrome in high-fat diet–induced obese rats (30). Recent animal studies reported that 12 wk of high-intensity, but not low- or moderate-intensity treadmill exercise, lowered testosterone levels in lean rats (7). In addition, 12 wk of increasing physical activity by wheel running, but not food restriction, increased testosterone levels in mildly obese Otsuka Long Evans Tokushima Fatty (OLETF) rats (13).
Previous studies reported various findings regarding the effects of aerobic exercise training on testosterone levels and have not answered if lean and obese animals respond differently to exercise training and if exercise training can prevent genetically severe obesity-related hypogonadism. Therefore, this study hypothesized that chronic aerobic exercise would increase testosterone levels in obese, but not lean, Zucker rats. In addition, we conducted preliminary analyses to investigate the relationship between testosterone levels and other hormones/inflammatory factors and to clarify the possible mechanisms of its changes in response to obesity and aerobic exercise.
Male Zucker rats, lean (Fa/Fa) and obese (fa/fa), age 4–5 wk were purchased from Harlan Laboratories (Indianapolis, IN). The rats were housed one lean and one obese per cage in the animal facility at the University at Buffalo with a 12:12-h light–dark cycle and constant temperature (22°C–24°C). The rats were provided with water and lab chow ad libitum. Immediately after being received, all rats had an Avid microchip (Avid Identification Systems, Inc., Norco, CA) inserted subcutaneously in their upper dorsal region for identification purposes. The protocol of this study was approved by the Animal Care and Use Committees at the State University of New York at Buffalo and the University of Massachusetts Boston and adhered to the American College of Sports Medicine animal care standards.
This study was a randomized controlled study with an 8-wk intervention period. The animals were acclimated to animal facilities for 2 wk before being randomized into either sedentary or exercise training groups. Therefore, there were four groups at the beginning of the study as follows: lean sedentary, lean exercise, obese sedentary, and obese exercise, with n = 7–8 each group. The exercise groups walked on a rodent treadmill during the 8-wk intervention period. After this intervention, all groups underwent euthanasia and sample collection. Body weight was recorded weekly and also on the day of euthanasia.
The exercise groups were placed on a custom-built rodent treadmill, with one animal per lane. The training protocol was similar to those reported by previous studies (22,23). The training began with the rats exercising for 20 min·d−1 (including 15 min at a prescribed speed and a 5-min warm-up/cool-down), 5 d·wk−1 for the first week, and then gradually built up to 60 min·d−1 (including 45 min at a prescribed speed and a 15-min warm-up/cool-down) per day, 5 d·wk−1 during the next 7 wk. Over this duration, the speed gradually increased from 10 to 20 m·min−1 at 0% grade, as tolerated by the rats. To ensure that the animals remain on the treadmill, pressurized bursts of air was used. All exercising rats completed the planned exercise training with no adverse events or major injuries. Animals in the sedentary groups were also handled and put on the running cage for 5–10 min each time, five times per week during this intervention period.
Euthanasia and specimen procedures were processed in the morning after an 8-h fast. Specifically, for the exercise animals, all procedures were processed 48–72 h after the last bout of exercise. Four animals were euthanized each round, including one animal randomly chosen from each of the four groups. The animals were first anesthetized with a 75/10-mg/kg ketamine/xylazine injection. Sample collection began immediately after bilateral absence of a withdrawal reflex. Animals were sacrificed by cardiac puncture with the blood collected used for all blood marker analyses. After euthanasia, intra-abdominal (retroperitoneal, epididymal, and mesenteric) white adipose tissue were removed and weighed. The inguinal (from the subcutaneous areas surrounding the torso by the hind leg) and epididymal (from intra-abdominal areas surrounding the epididymis and testis) white adipose tissue from the right side were collected and processed for MCP-1 release. The testes were collected, weighed, and frozen at −80°C for determination of intratesticular testosterone concentrations. In addition, skeletal muscles (vastus intermedius) from the right hind limbs were collected and frozen at −80°C to determine citrate synthase activity.
Fasting whole blood samples were centrifuged at a speed of 3000 rpm for 20 min, and serum samples were collected and stored at −80°C for analyses. Serum total cholesterol and glucose levels were measured by Kaleida Health Laboratory Services (Kaleida Health, Buffalo, NY). Concentrations of insulin (sensitivity = 0.1 ng·mL−1, intra-assay coefficient of variation [CV] = 9.0%) and adiponectin (sensitivity = 1 ng·mL−1, CV = 4.1%) were measured by radioimmunoassay (RIA) using kits from Millipore (St. Charles, MO). Concentrations of total testosterone (sensitivity = 0.08 ng·mL−1, CV = 8.5%) and free testosterone (sensitivity = 0.18 pg·mL−1, CV = 6.2%) were also determined by RIA using kits from Beckman Coulter (Brea, CA). Concentrations of LH (sensitivity = 4.9 pg·mL−1, CV = 6.8%), FSH (sensitivity = 47.7 pg·mL−1, CV = 4.3%), and MCP-1 (sensitivity = 3.8 pg·mL−1, CV = 8.2%) were determined by using Milliplex immunoassay (Millipore). Concentrations of leptin (sensitivity = 20 pg·mL−1, CV = 5.5%) and estradiol (sensitivity = 6.6 pg·mL−1, CV = 3.2%) were measured by ELISA using kits from Invitrogen (Carlsbad, CA) and Cayman Chemical (Ann Arbor, MI), separately. Concentrations of blood variables were measured in duplicate. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated with the formula, fasting plasma insulin (ng·mL−1) × fasting glucose (mg·mL−1)/16.2, which was based on the following: fasting plasma insulin (μU·mL−1) × fasting plasma glucose (mmol·L−1)/22.5 (16).
Muscle citrate synthase
Citrate synthase activity in hindlimb skeletal muscles was measured in all animals to confirm that the training protocol was effective. Approximately 20 mg of muscle samples was homogenized on ice in 0.1 mol·L−1 Tris buffer containing 0.1 Triton X-100, pH 8.35. The homogenates were processed using a citrate synthase assay kit (Sigma-Aldrich, St. Louis, MO) according to the manufacturer’s instructions. The readings were taken by using a microplate reader (Bio-Rad, Hercules, CA). The solubilized protein extracts of the homogenates were quantified by using bicinchoninic acid reagents (sensitivity = 5 μg·mL−1, CV = 5.2%; Pierce, Rockford, IL). The citrate synthase activity was normalized to total protein concentrations. All samples were measured in duplicate.
Intratesticular testosterone was measured as previously described in literature (15,26) with slight modifications. First, testosterone in tissue was extracted by using diethyl ether. Testicular tissue (100 mg) was homogenized in 500 μL of Tris–HCl buffer (0.01 mol·L−1, pH 7.4). The mixture was then mixed and vortexed with 1000 μL of diethyl ether. The aqueous phase of the mixture was quickly frozen by dry ice, and the unfrozen portion of the mixture was poured into a collection tube. The aqueous phase of the mixture was again mixed and vortexed with 1000 μL of diethyl ether and then quickly frozen, and the unfrozen portion was combined with the above collected solution. The combined ether-extracted hormone solution was air-dried overnight in a hood to evaporate the diethyl ether. The sample was resuspended in 100 μL ethanol and 1000 μL of Tris–HCl buffer and frozen at −80°C until analysis. Concentrations of testosterone were measured in duplicate by using RIA (Beckman Coulter).
Adipose tissue MCP-1 release
Adipose tissue MCP-1 secretion was processed as previously described (37). Minced fresh adipose tissue fragments (5–10 mg each, total of 200 mg) were placed in 2 mL of medium 199 (Invitrogen) containing 1% albumin (Serologicals, Norcross, GA), pH 7.4, and incubated in a shaking water bath at 60 rpm, 37°C under an atmosphere of 95% O2/5% CO2 for 3 h. At the end of the incubation, samples of the incubation medium were collected and frozen at −80°C until analysis. Release levels of MCP-1 from adipose tissue were measured in duplicate by using the Milliplex immunoassay (Millipore).
Statistical analyses were performed using JMP 10 for Windows (SAS, Cary, NC) and IBM SPSS Statistics 20 (IBM, Armonk, New York). First, two-way ANOVA tests were used to determine any main effects of obesity, main effects of exercise, and obese-by-exercise interactions. Once an obese-by-exercise interaction was identified, LSD post hoc tests were used to compare individual group differences. For variables that were not normally distributed, the logarithm of each variable was used for these analyses. Second, Pearson correlation coefficients were used to determine the relationship between hormones and inflammatory variables. All data are presented as mean ± SE, and the level of significance was set at P < 0.05 for all analyses.
General conditions of lean and obese Zucker rats during interventions
Of the 31 animals that were assigned into the four groups, 29 were included in data analyses (lean sedentary, n = 7; lean exercise, n = 8; obese sedentary, n = 7; obese exercise, n = 7). Two animals were excluded because of inadequate sample or a minor tail injury at the time of sample collection.
Body weight changes of animals in all four groups during the 8-wk intervention period are shown in Figure 1. Compared to lean animals, obese animals had significantly higher body weight at each week (all P < 0.001). Compared to sedentary animals, exercise animals had lower body weight at weeks 4, 5, 6, 7, and 8 (P < 0.01 to P < 0.001). There were no obesity-by-exercise interactions on body weight at any time point.
Hindlimb muscle citrate synthase activities of animals in the four groups after the 8-wk intervention are shown in Figure 2. Muscle citrate synthase activity was higher in the exercise group than in the sedentary groups (P < 0.001), indicating that this exercise protocol was effective in changing the metabolic properties in these animals. There was not a main effect of obesity or an obesity-by-exercise interaction on muscle citrate synthase activity.
Effects of obesity status and exercise training on body composition and metabolic risk factors in Zucker rats
As shown in Table 1, compared to the lean animals, obese animals had significantly higher body weight, visceral fat weight, total cholesterol, glucose, insulin, and HOMA-IR (all P < 0.001). However, there was no difference in testicular weight between the lean and obese animals. Compared to sedentary animals, exercise animals had significantly lower body weight and visceral fat weight (P < 0.001 and P < 0.05, respectively). There were no differences between sedentary and exercise animals on other body composition and metabolic risk factors.
Effects of obesity status and exercise training on sex hormone concentrations in Zucker rats
As shown in Figure 3, there were significant obesity-by-exercise interactions on serum and testicular concentrations of testosterone (all P < 0.05). Compared to lean sedentary rats, obese sedentary rats had lower serum and testicular testosterone concentrations (0.72- to 0.74-fold, all P < 0.001). There were no group differences between lean sedentary and lean exercise rats on serum and testicular testosterone concentrations. However, compared to the obese sedentary group, the obese exercise group had significantly higher serum and testicular testosterone concentrations (1.37- to 1.47-fold, all P < 0.05).
As shown in Figure 3, there were no main effects of obesity or main effects of exercise, or obesity-by-exercise interactions on estradiol and LH concentrations. A significant obesity-by-exercise interaction was detected on serum FSH concentrations (P < 0.05). There were no differences in serum FSH concentrations between lean sedentary and obese sedentary rats and between lean sedentary and lean exercise rats. However, obese exercise rats had higher serum FSH concentrations than lean exercise rats (0.32-fold, P < 0.05).
Effects of obesity status and exercise training on adipose tissue-derived hormones/inflammatory factors in Zucker rats
Serum leptin (lean sedentary = 1.63 ± 0.26 ng·mL−1, lean exercise = 1.59 ± 0.38 ng·mL−1, obese sedentary = 84.51 ± 5.85 ng·mL−1, obese exercise = 82.31 ± 4.02 ng·mL−1) and adiponectin (lean sedentary = 3.64 ± 0.21 μg·mL−1, lean exercise = 3.66 ± 0.24 μg·mL−1, obese sedentary = 5.64 ± 0.32 μg·mL−1, obese exercise = 6.37 ± 0.47 μg·mL−1) concentrations indicated that there were significant effects of obesity (both P < 0.001). There were no main effects of exercise or obesity-by-exercise interactions on serum leptin and adiponectin concentrations.
As shown in Figure 4, there were significant obesity-by-exercise interactions on serum and epididymal adipose tissue MCP-1 release (P < 0.05). Compared to lean sedentary rats, obese sedentary rats had higher serum and epididymal adipose tissue MCP-1 release (1.01-fold, P < 0.01 and 0.77-fold, P < 0.05, respectively). There were no group differences between lean sedentary and lean exercise rats on serum and epididymal adipose tissue MCP-1. However, compared to the obese sedentary group, the obese exercise group had significantly lower serum and epididymal MCP-1 (0.29-fold, P < 0.05 and 0.36-fold, P < 0.05, respectively). Compared to lean animals, obese animals had higher inguinal adipose tissue MCP-1 release (P < 0.01). There were no main effects of exercise or obesity-by-exercise interactions on inguinal adipose tissue MCP-1 release.
As shown in Figure 5, in the whole cohort, serum and testicular concentrations of testosterone were negatively related to epididymal adipose tissue MCP-1 release (all P < 0.05). Although there was a similar trend on the relationships between testosterone concentrations and serum MCP-1 concentrations (vs serum total testosterone [r = −0.27] vs serum-free testosterone [r = −0.17] vs testicular testosterone [r = −0.22]) or inguinal adipose tissue MCP-1 release (vs serum total testosterone [r = −0.33] vs serum-free testosterone [r = −0.19] vs testicular testosterone [r = −0.22]), these correlations were not statistically significant.
This study investigated whether aerobic exercise training differently affects testosterone concentrations in lean and obese Zucker rats. Our findings indicated that, compared to lean sedentary animals, obese sedentary animals had significantly lower serum and testicular testosterone concentrations, and exercise-trained obese rats had significantly higher testosterone concentrations than sedentary obese rats. Thus, aerobic exercise training improved hypogonadism in genetically obese rats in the current study. In addition, the testosterone concentrations were inversely related to epididymal, but not inguinal adipose tissue MCP-1 secretion. To our knowledge, this is the first study to report that aerobic exercise training attenuates hypogonadism in severely obese rats, and this effect is related to regional adipose tissue inflammation.
Our results support findings by previous studies showing that serum concentrations of testosterone were lower, and concentrations of LH and FSH were not different between lean and obese male Zucker rats (38). The difference in FSH concentrations between lean exercise and obese exercise animals in the current study indicated that obesity status only affected FSH concentrations in exercise animals. Previous findings indicated that the Leydig cells of the obese rats were hypertrophied and showed decreased signs of active hormone synthesis (38). Therefore, it appears that the genetically obese male Zucker rat has a defect in testicular testosterone production. In addition, there are several factors that can indirectly decrease testosterone concentrations through an inhibition of the function of the hypothalamic–pituitary–gonadal axis, such as insulin, leptin, adiponectin, and inflammatory cytokines (14). In the current study, obese animals had significantly higher concentrations of insulin, leptin, adiponectin, and MCP-1. Obese Zucker rat is a genetically obese rat model with elevated concentrations of insulin and several adipose-derived hormones because of the much higher fat mass (fourfold to fivefold) in obese animals compared to that of lean animals (12,18). In the current study, obesity had no effects on the concentrations of LH, FSH, and estradiol. The unaltered pituitary hormones could appear with hypogonadism even in hypogonadotropic hypogonadism. More accurate assessments include measuring LH response to GnRH during stimulation tests, in addition to testing the absolute levels of pituitary hormones. Lastly, an increased adipose tissue aromatization of testosterone would increase estradiol concentrations in obesity. In this study, we did not observe a significant difference in estradiol concentrations between lean and obese animals. However, it is possible that increased aromatization has occurred but that it was masked by the low concentrations of testosterone in obese animals. Considering the similar patterns of changes in circulating and testicular testosterone concentrations in obese rats, it is likely that the sex organ is a major site involved in the mechanism of obesity-related hypogonadism in the current study.
A recent study reported that, compared to control/sedentary obese OLETF rats, rats completing a 12-wk wheel run had significantly higher testosterone concentrations; no group difference was seen between control/sedentary rats and rats under food restriction to achieve weight loss similar to that achieved by exercising rats (13). These results support that aerobic exercise training has an independent effect on testosterone metabolism in mildly obese animals. Another animal study reported that, compared to sedentary rats, rats completing 12 wk of high-intensity/volume treadmill walking had lower testosterone concentrations; however, there were no group differences between the sedentary group and the low- or moderate-intensity group (7). Apparently, the dose of exercise plays an important role in determining testosterone responses. These findings are similar to those in human studies, indicating that there is an exercise volume threshold in altering testosterone concentrations in males (3). In the current study, our exercise protocol only altered testosterone concentrations in genetically, severely obese animals. Attenuation of hypogonadism in obesity is of importance for future research because it creates a model for future exercise studies on hypogonadism and metabolic syndrome in severe obesity.
Similarly, we studied the effects of chronic aerobic exercise on several pathways that may regulate testosterone concentrations in obesity. We did not see an exercise effect on circulating concentrations of insulin, leptin, or adiponectin, although there was a clear trend that exercise might reduce insulin concentrations. Because exercise reduced serum MCP-1 concentrations, we further studied if obesity and exercise also influence regional adipose tissue MCP-1 production. Similarly, exercise reduced epididymal adipose tissue MCP-1 release. These findings support previous studies, indicating that chronic aerobic exercise lowers white adipose tissue MCP-1 gene expression in obese rodents (34,35). It is interesting to note that the testosterone concentrations were only significantly related to MCP-1 released by intra-abdominal adipose tissue depot adjacent to sex organs and not subcutaneous adipose tissue. Our findings indicate that local adipose tissue inflammation might be an important factor in regulating obesity and in regulating the effects of exercise on testosterone metabolism in those male animals.
The findings that aerobic exercise training attenuated hypogonadism in obesity and that this effect may be related to regional adipose tissue inflammation are interesting. Previous studies indicate that LH-stimulated testosterone production was inhibited by secreted proinflammatory cytokines from macrophages (27). In addition, vitamin K, an anti-inflammatory vitamin, alleviates the reduction in testosterone production induced by lipopolysaccharide in rats (29). It is notable that we did not measure the direct influence of regional adipose tissue inflammation on testicular testosterone production. An in vitro study may be more appropriate to answer if there is such an effect and how an inflammatory factor results in low testosterone production. One of the limitations of the current study is that the sample size in each group was relatively small. With a bigger sample size, we would likely be able to detect a significant exercise effect on concentrations of several metabolic variables and hormones. In addition, it would be interesting to study if other types of exercise, such as resistance training, improved obesity-related hypogonadism in animals and humans.
In summary, aerobic exercise training attenuated hypogonadism in obese male rats but did not change testosterone concentrations in lean male rats. Circulating and testicular concentrations of testosterone were inversely related to intra-abdominal, but not subcutaneous, adipose tissue MCP-1 production, indicating that regional adipose tissue inflammation may be a factor that influences testosterone during obesity and exercise intervention. Further studies need to focus on the influences of different types of chronic exercise on hypogonadism and on the mechanism of local effects of inflammation on testosterone production in sex organs.
This study was supported by funds from the School of Public Health and Health Professions, State University of New York at Buffalo, and from the College of Nursing and Health Sciences, University of Massachusetts Boston.
The authors thank Drs. Gaspar Farkas, Atif Awad, Luc Gosselin, Robyn Hannigan, Kenneth Campbell, and Ling Shi for their technical support, and Milind Chaudhari, Jiwoon Ryu, Amanda Blair, Jacqueline Tricarico, Ricky Yu, Ross Carhart, Justin Lucia, and Bryanna Broadaway for their assistance on this project.
The authors declare no conflict of interest.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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