Effects of follicle-stimulating hormone on energy balance and tissue metabolic health after loss of ovarian function.

Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E2 and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (P < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.NEW & NOTEWORTHY We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.

High-fat/high-sucrose diet worsens metabolic outcomes and widespread hypersensitivity following early-life stress exposure in female mice.

Exposure to stress early in life has been associated with adult-onset comorbidities such as chronic pain, metabolic dysregulation, obesity, and inactivity. We have established an early-life stress model using neonatal maternal separation (NMS) in mice, which displays evidence of increased body weight and adiposity, widespread mechanical allodynia, and hypothalamic-pituitary-adrenal axis dysregulation in male mice. Early-life stress and consumption of a Western-style diet contribute to the development of obesity; however, relatively few preclinical studies have been performed in female rodents, which are known to be protected against diet-induced obesity and metabolic dysfunction. In this study, we gave naïve and NMS female mice access to a high-fat/high-sucrose (HFS) diet beginning at 4 wk of age. Robust increases in body weight and fat were observed in HFS-fed NMS mice during the first 10 wk on the diet, driven partly by increased food intake. Female NMS mice on an HFS diet showed widespread mechanical hypersensitivity compared with either naïve mice on an HFS diet or NMS mice on a control diet. HFS diet-fed NMS mice also had impaired glucose tolerance and fasting hyperinsulinemia. Strikingly, female NMS mice on an HFS diet showed evidence of hepatic steatosis with increased triglyceride levels and altered glucocorticoid receptor levels and phosphorylation state. They also exhibited increased energy expenditure as observed via indirect calorimetry and expression of proinflammatory markers in perigonadal adipose. Altogether, our data suggest that early-life stress exposure increased the susceptibility of female mice to develop diet-induced metabolic dysfunction and pain-like behaviors.

Compensatory eating behaviors in male and female rats in response to exercise training.

Exercise is often used as a strategy for weight loss maintenance. In preclinical models, we have shown that exercise may be beneficial because it counters the biological drive to regain weight. However, our studies have demonstrated sex differences in the response to exercise in this context. In the present study, we sought to better understand why females and males exhibit different compensatory food eating behaviors in response to regular exercise. Using a forced treadmill exercise paradigm, we measured weight gain, energy expenditure, food intake in real time, and the anorectic effects of leptin. The 4-wk exercise training resulted in reduced weight gain in males and sustained weight gain in females. In male rats, exercise decreased intake, whereas it increased food intake in females. Our results suggest that the anorectic effects of leptin were not responsible for these sex differences in appetite in response to exercise. If these results translate to the human condition, they may reveal important information for the use and application of regular exercise programs.

Compensation for cold-induced thermogenesis during weight loss maintenance and regain.

Prevalence of obesity is exacerbated by low rates of successful long-term weight loss maintenance (WLM). In part, relapse from WLM to obesity is due to a reduction in energy expenditure (EE) that persists throughout WLM and relapse. Thus, interventions that increase EE might facilitate WLM. In obese mice that were calorically restricted to reduce body weight by ~20%, we manipulated EE throughout WLM and early relapse using intermittent cold exposure (ICE; 4°C, 90 min/day, 5 days/wk, within the last 3 h of the light cycle). EE, energy intake, and spontaneous physical activity were measured during the obese, WLM, and relapse phases. During WLM and relapse, the ICE group expended more energy during the light cycle because of cold exposure but expended less energy in the dark cycle, which led to no overall difference in total daily EE. The compensation in EE appeared to be mediated by activity, whereby the ICE group was more active during the light cycle because of cold exposure but less active during the dark cycle, which led to no overall effect on total daily activity during WLM and relapse. In brown adipose tissue of relapsing mice, the ICE group had greater mRNA expression of Dio2 and protein expression of UCP1 but lower mRNA expression of Prdm16. In summary, these findings indicate that despite robust increases in EE during cold exposures, ICE is unable to alter total daily EE during WLM or early relapse, likely due to compensatory behaviors in activity.

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner.

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced.

Yoga resilience training to prevent the development of posttraumatic stress disorder in active-duty first responders: A cluster randomized controlled trial.

OBJECTIVE: Evidence on effective prevention of posttraumatic stress disorder (PTSD) is sparse, particularly among first responders. This study evaluated the effectiveness of a Tactical Mind-Body Resilience Training program on PTSD symptoms in first responders. METHOD: Active-duty first responders (n = 80; Mage = 41.8 years, 82.5% men) were randomized to the intervention group or the waitlist control condition. PTSD symptoms as measured by the PTSD-8 were the primary outcome assessed at postintervention and at 3-month follow-up. Secondary outcomes were cognitive and emotional coping strategies, resilience, somatic symptoms, work performance, and sickness absence. RESULTS: At postintervention, the intervention group had significantly reduced PTSD symptoms compared to the control group (d = -0.26, difference = -2.52, 95% confidence interval [CI] [-4.93, -0.11], p = .040); however, this difference was attenuated at 3-month follow-up (d = -0.07, difference = -1.41, 95% CI [-3.83, 1.01], p = .248). The intervention group had significant improvements in cognitive reappraisal and resilience at postintervention compared to the control group, which were sustained at 3 months. The remaining secondary outcomes had statistically nonsignificant improvements. CONCLUSIONS: This workplace-delivered intervention shows potential in preventing the development of PTSD in first responders. Further research is needed on maintaining long-term benefits of this training. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Exposure to early-life stress impairs weight-loss maintenance success in mice.

OBJECTIVE: The impact of early-life stress on weight-loss maintenance is unknown. METHODS: Mice underwent neonatal maternal separation (NMS) from 0 to 3 weeks and were weaned onto a high-fat sucrose diet (HFSD) from 3 to 20 weeks. Calorie-restricted weight loss on a low-fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half of the mice received running wheels, and the other half remained sedentary. Mice were then fed ad libitum on an HFSD or LFSD for 10 weeks and were allowed to regain body weight. RESULTS: NMS mice had greater weight regain, total body weight, and adiposity compared with naïve mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naïve mice. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naïve females were more susceptible to HFSD-induced weight regain. Exercise was beneficial in the first week of regain in male mice, but, long-term, only those on the LFSD benefited from exercise. As expected, HFSD led to greater weight regain than LFSD. CONCLUSIONS: Early-life stress increases weight regain in mice.

Web-Based Mind-Body Tactical Resilience Training Program for First Responders: Pre-Post Study Assessing Feasibility, Acceptability, and Usability.

BACKGROUND: First responders report elevated rates of mental disorders, including posttraumatic stress disorder (PTSD), yet many are reluctant to seek care. Preventative resilience training programs attempt to proactively address this issue, and there is evidence showing promise for programs targeting cognitive processes. However, these programs rarely address the physical health conditions associated with PTSD. There is emerging evidence of mind-body exercise training improving PTSD symptoms as well as its associated physical health symptoms. However, the feasibility and acceptability of delivering a web-based mind-body resilience training among first responders are not yet known. OBJECTIVE: This study aimed to evaluate the feasibility, usability, and acceptability of a web-based mind-body tactical resilience training program designed for first responders. In addition, we explored the preliminary effectiveness of the training program on mental health outcomes, adaptive cognitive strategies, and work productivity. METHODS: A total of 42 first responders based in the United States enrolled in the web-based training program. Participants were administered web-based surveys before enrolling in the 6-week web-based program and at the end of the program. The primary outcomes of feasibility were measured using the number of training hours, program adherence rates, and self-reported data on frequency of practice. Acceptability and usability were measured using self-reported data. Secondary outcomes were symptoms of PTSD, psychological distress, emotion regulation, stress mindset, psychological preparedness, and work performance. RESULTS: Overall, the training program was feasible based on the median number of training hours spent on the web-based program (7.57 hours out of an expected total of 6 to 9 hours), and 55% (23/42) of the enrolled participants completed more than half of the program. Although acceptability, usability, and frequency of practice were rated as high, this was based on only 29% (12/42) of the respondents who provided follow-up data. Secondary outcomes showed a significant improvement in the adaptive cognitive strategy of the stress mindset, with a mean difference of -5.42 (SD 4.81; 95% CI -8.475 to -2.358; t11=-3.898; P=.002). All other secondary outcomes were not significant. However, the secondary outcomes were exploratory only, and this study was neither designed nor powered to adequately assess efficacy. CONCLUSIONS: These findings suggest that a mind-body tactical resilience training program delivered in a web-based format is feasible and acceptable among first responders; however, further refinements may be required to improve adherence rates. Further research using a larger, more rigorous trial design is warranted to examine the effectiveness of this type of training as a possible prevention or treatment strategy for this population.

Exposure to early life stress impairs weight loss maintenance success in mice.

Early life stress increases obesity risk, but its impact on weight loss maintenance is unknown. Mice underwent neonatal maternal separation (NMS) from 0-3 weeks and were weaned onto high fat sucrose diet (HFSD) from 3-20 weeks. Calorie-restricted weight loss on a low fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half the mice received running wheels (EX) the other half remained sedentary (SED). Mice were then fed ad libitum on HFSD or LFSD for 10 weeks and allowed to regain body weight. NMS mice had greater weight regain, total body weight and adiposity compared to naïve mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naïve mice, but total energy expenditure was not affected by NMS. Female mice were more susceptible to NMS-induced effects, including increases in adiposity. NMS and naïve females were more susceptible to HFSD-induce weight regain. Exercise was beneficial in the first week of regain in male mice, but long-term only those on LFSD benefited from EX. As expected, HFSD led to greater weight regain than LFSD.

Incorporating Yoga into a Pediatric Weight Management Program: A Pilot Study.

Purpose: To assess the feasibility and acceptability of yoga incorporated into a pediatric weight management program (promoting health in teens; PHIT Yoga) to racially diverse caregivers and youth and to compare this program with a cohort that received a program that did not include yoga (PHIT Kids). Methods: Thirty children with obesity were enrolled in a 12-week pediatric weight management intervention (PHIT Kids, n = 17; PHIT Yoga, n = 13). Weight, BMI z-score (BMIz), BMI percent of the 95th percentile, and health habits assessment were obtained from both cohorts pre- and post intervention. Acceptability was assessed in the yoga cohort. Results: Fifty-four percent of children in the PHIT Yoga cohort and 65% of children in the PHIT Kids cohort attended ≥75% of the intervention sessions. Survey results support that the PHIT Yoga was acceptable to both caregivers and children. Improvements in BMIz were observed in 50% of children in each cohort and both groups improved on five of seven health habits; cohorts overlapped on three habits (breakfast, screen time, and sugar-sweetened drinks). Conclusion: Findings support that yoga classes added to a pediatric weight management program are feasible and acceptable in racially diverse children with severe obesity and their caregivers.

Sex differences in the effect of diet, obesity, and exercise on bone quality and fracture toughness.

Bone fragility and obesity are both diseases that are multifactorial in etiology and pathology. The contributing role of high fat diet (HFD) versus energy overconsumption on bone health is controversial. Exercise is often prescribed for improving bone health, but it is unclear whether HFD or overconsumption influences skeletal adaptations to exercise. Female and male Wistar rats were fed HFD or low fat diet (LFD) for 10 weeks, starting at 8 weeks of age. Within HFD, rats were labeled Obesity-Resistant (OR) or Obesity-Prone (OP) based on weight and fat gain. Within each diet and phenotype group, rats were randomized to treadmill exercise or sedentary control (SED) for the final 4 weeks. Femurs were assessed for fracture toughness. Cortical lamellar and nonlamellar bone microscale material behavior and chemistry were assessed using nanoindentation and Raman spectroscopy. Female bones had higher fracture toughness and mineral: matrix ratio than male bones. Diet and energy overconsumption affected bone characteristics in a sex-dependent manner, where the divergence between OP and OR in response to HFD occurred more rapidly in males. Diet composition, in general, had a stronger effect on bone quality than overconsumption. HFD dramatically decreased bone size and lamellar mineral:matrix compared to LFD. Effects of short-term exercise training on microscale tissue properties were generally more robust with LFD. Exercise enhanced the contrast between lamellar and nonlamellar bone for nanoindentation modulus but decreased this contrast for plastic work. Our data demonstrate the complexities in the relationship between diet and obesity and highlight the importance of addressing both aspects when characterizing bone quality and fracture resistance.

An Omega-3-rich Anti-inflammatory Diet Improved Widespread Allodynia and Worsened Metabolic Outcomes in Adult Mice Exposed to Neonatal Maternal Separation.

Inflammation plays a key role in the progression and maintenance of chronic pain, which impacts the lives of millions of Americans. Despite growing evidence that chronic pain can be improved by treating underlying inflammation, successful treatments are lacking and pharmaceutical interventions are limited due to drug side effects. Here we are testing whether a 'healthy human' diet (HHD), with or without anti-inflammatory components (HHAID), improves pain-like behaviors in a preclinical model of chronic widespread hypersensitivity induced by neonatal maternal separation (NMS). The HHD and HHAID are isocaloric and macronutrient-matched, have a low glycemic index, and fat content (35 kcal%) that is high in omega-3 fatty acids, while only the HHAID includes a combination of key anti-inflammatory compounds, at clinically relevant doses. Mice on these diets were compared to mice on a control diet with a macronutrient composition commonly used in rodents (20% protein, 70% carbohydrate, 10% fat). Our results demonstrate a benefit of the HHAID on pain-like behaviors in both male and female mice, despite increased caloric intake, adiposity, and weight gain. In female mice, HHAID specifically increased measures of metabolic syndrome and inflammation compared to the HHD and control diet groups. Male mice were susceptible to worsening metabolic measures on both the HHAID and HHD. This work highlights important sexual dimorphic outcomes related to early life stress exposure and dietary interventions, as well as a potential disconnect between improvements in pain-like behaviors and metabolic measures.

Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure.

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.

Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice.

Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

Impact of Exercise and Activity on Weight Regain and Musculoskeletal Health Post-Ovariectomy.

The purpose of this study was to determine whether obesity and/or exercise training alters weight regain and musculoskeletal health after ovariectomy (OVX). Female rats were fed high-fat diet (HFD) to reveal obesity-prone (OP) and obesity-resistant (OR) phenotypes. The OP and OR exercising (EX) and sedentary (SED) rats were calorically restricted to lose 15% of body weight using medium-fat diet. Rats were then maintained in energy balance for 8 wk before OVX. After OVX and a brief calorically limited phase, rats were allowed to eat ad libitum until body weight plateaued. Starting at weight loss, EX ran 1 h·d, 6 d·wk, 15 m·min. Energy intake, spontaneous physical activity (SPA), and total energy expenditure were evaluated at the end of weight maintenance pre-OVX, and at three time points post-OVX: before weight regain, during early regain, and after regain. Data are presented as mean ± SE. Exercise attenuated weight regain after OVX in OP only (OP-EX, 123 ± 10 g; OP-SED, 165 ± 12 g; OR-EX, 121 ± 6 g; OR-SED, 116 ± 6 g), which was primarily an attenuation of fat gain. The early post-OVX increase in energy intake explained much of the weight regain, and was similar across groups. Exercising improved bone strength, as did maintaining SPA. Group differences in muscle mitochondrial respiration were not significant. The large decrease in SPA due to OVX was persistent, but early weight regain was dependent on decreased SPA. In conclusion, leanness and exercise do not necessarily protect from OVX-induced weight gain. Exercise prevented weight gain in obese rats, but loss of SPA was the greatest contributor to post-OVX weight gain. Thus, understanding the mechanisms resulting in reduction in SPA after ovarian hormone loss is critical in the prevention of menopause-associated metabolic dysfunction.

Attenuating the Biologic Drive for Weight Regain Following Weight Loss: Must What Goes Down Always Go Back Up?

Metabolic adaptations occur with weight loss that result in increased hunger with discordant simultaneous reductions in energy requirements-producing the so-called energy gap in which more energy is desired than is required. The increased hunger is associated with elevation of the orexigenic hormone ghrelin and decrements in anorexigenic hormones. The lower total daily energy expenditure with diet-induced weight loss results from (1) a disproportionately greater decrease in circulating leptin and resting metabolic rate (RMR) than would be predicted based on the decline in body mass, (2) decreased thermic effect of food (TEF), and (3) increased energy efficiency at work intensities characteristic of activities of daily living. These metabolic adaptations can readily promote weight regain. While more experimental research is needed to identify effective strategies to narrow the energy gap and attenuate weight regain, some factors contributing to long-term weight loss maintenance have been identified. Less hunger and greater satiation have been associated with higher intakes of protein and dietary fiber, and lower glycemic load diets. High levels of physical activity are characteristic of most successful weight maintainers. A high energy flux state characterized by high daily energy expenditure and matching energy intake may attenuate the declines in RMR and TEF, and may also result in more accurate regulation of energy intake to match daily energy expenditure.

Prior weight loss exacerbates the biological drive to gain weight after the loss of ovarian function.

Both the history of obesity and weight loss may change how menopause affects metabolic health. The purpose was to determine whether obesity and/or weight loss status alters energy balance (EB) and subsequent weight gain after the loss of ovarian function. Female lean and obese Wistar rats were randomized to 15% weight loss (WL) or ad libitum fed controls (CON). After the weight loss period, WL rats were kept in EB at the reduced weight for 8 weeks prior to ovariectomy (OVX). After OVX, all rats were allowed to eat ad libitum until weight plateaued. Energy intake (EI), spontaneous physical activity, and total energy expenditure (TEE) were measured with indirect calorimetry before OVX, immediately after OVX, and after weight plateau. Changes in energy intake (EI), TEE, and weight gain immediately after OVX were similar between lean and obese rats. However, obese rats gained more total weight and fat mass than lean rats over the full regain period. Post-OVX, EI increased more (P ≤ 0.03) in WL rats (58.9 ± 3.5 kcal/d) than CON rats (8.5 ± 5.2 kcal/d), and EI partially normalized (change from preOVX: 20.5 ± 4.2 vs. 1.5 ± 4.9 kcal/day) by the end of the study. As a result, WL rats gained weight (week 1:44 ± 20 vs. 7 ± 25 g) more rapidly (mean = 44 ± 20 vs. 7 ± 25 g/week; P < 0.001) than CON Prior obesity did not affect changes in EB or weight regain following OVX, whereas a history of weight loss prior to OVX augmented disruptions in EB after OVX, resulting in more rapid weight regain.

The Androgen Receptor Supports Tumor Progression After the Loss of Ovarian Function in a Preclinical Model of Obesity and Breast Cancer.

The androgen receptor (AR) has context-dependent roles in breast cancer growth and progression. Overall, high tumor AR levels predict a favorable patient outcome, but several studies have established a tumor promotional role for AR, particularly in supporting the growth of estrogen receptor positive (ER-positive) breast cancers after endocrine therapy. Our previous studies have demonstrated that obesity promotes mammary tumor progression after ovariectomy (OVX) in a rat model of postmenopausal breast cancer. Here, we investigated a potential role for AR in obesity-associated post-OVX mammary tumor progression following ovarian estrogen loss. In this model, we found that obese but not lean rats had nuclear localized AR in tumors that progressed 3 weeks after OVX, compared to those that regressed. AR nuclear localization is consistent with activation of AR-dependent transcription. Longer-term studies (8 weeks post-OVX) showed that AR nuclear localization and expression were maintained in tumors that had progressed, but AR expression was nearly lost in tumors that were regressing. The anti-androgen enzalutamide effectively blocked tumor progression in obese rats by promoting tumor necrosis and also prevented the formation of new tumors after OVX. Neither circulating nor mammary adipose tissue levels of the AR ligand testosterone were elevated in obese compared to lean rats; however, IL-6, which we previously reported to be higher in plasma from obese versus lean rats, sensitized breast cancer cells to low levels of testosterone. Our study demonstrates that, in the context of obesity, AR plays a role in driving ER-positive mammary tumor progression in an environment of low estrogen availability, and that circulating factors unique to the obese host, including IL-6, may influence how cancer cells respond to steroid hormones.

Increasing energy flux to decrease the biological drive toward weight regain after weight loss - A proof-of-concept pilot study.

OBJECTIVE: Weight loss induces compensatory biological adjustments that increase hunger and decrease resting metabolic rate (RMR), which increase propensity for weight regain. In non-obese adults high levels of physical activity coupled with high energy intake (high energy flux) are associated with higher RMR and reduced hunger. We tested the possibility that a high flux state attenuates the increase in hunger and the decrease in RMR characteristic of diet-induced weight loss. METHODS: Six obese adults [age (mean ± SE) = 42 ± 12 y; body mass index (BMI) = 35.7 ± 3.7 kg/m2] underwent measures of RMR, the thermic effect of a meal (TEM), and fasting and postprandial measures of hunger and fullness as well as plasma glucose and insulin. Following weight loss, subjects completed two 5-day conditions of energy balance in random order-Low Flux (LF): sedentary with energy intake (EI) = RMR (kcal/d) × 1.35; and High Flux (HF): net exercise energy cost of ∼500 kcal/d and EI = RMR (kcal/d) × 1.7. RMR was measured daily for each flux condition. The morning following each of the respective experimentally controlled HF and LF conditions (flux day 5), they underwent the same pre-weight loss tests and also reported their perceptions of hunger and fullness during the previous four days of HF and LF, respectively. RESULTS: Average daily RMR was higher during HF (1926 ± 138 kcal/day) compared to LF (1847 ± 126 kcal/day; P < 0.05). Perceived hunger at the end of day was lower (p < 0.03) and fullness throughout the day was higher (p < 0.02) in HF compared to LF conditions. On day 5 of each flux condition, the thermic effect of a meal and circulating glucose and insulin after the meal did not differ between HF and LF. CONCLUSION: Following weight loss, compared to a sedentary LF state of energy balance, a short-term HF energy balance state is associated with higher RMR, lower perceived hunger, and greater perceived fullness, all of which could help attenuate the biologic drive to regain weight. Given the pilot nature of this study and the relatively short period of time spent in the high and low flux states, future research is needed to address this research question in a larger sample over a longer time period.