Brown adipose tissue metabolism in women is dependent on ovarian status.

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

Comparison of postoperative mobilization measurements by activPAL versus Johns Hopkins Highest Level of Mobility scale after major abdominal surgery.

BACKGROUND: The Johns Hopkins Highest Level of Mobility scale is a validated tool for assessing patient mobility in the hospital. It has excellent inter-rater and test-retest reliabilities, but it is unknown how accurately Johns Hopkins Highest Level of Mobility documentation reflects the patients' mobility performance in the immediate postoperative period compared to objective measures such as accelerometers. METHODS: In this single-center observational study, consented adults undergoing open abdominal surgery wore a research-grade accelerometer, activPAL, starting immediately postoperatively until hospital discharge or up to 7 days. We collected the Johns Hopkins Highest Level of Mobility scores documented by hospital staff via retrospective chart review and evaluated their accuracy in describing the type, frequency, and volume of postoperative out-of-bed mobilization using the activPAL as the criterion. RESULTS: We analyzed data from 56 participants. The activPAL showed that participants spent 97.7% of their time lying in bed or sitting in a chair. Meanwhile, the Johns Hopkins Highest Level of Mobility documentation of preambulatory activities (scores 1-5) was rare. The activPAL detected 4 times more out-of-bed mobilization than routine Johns Hopkins Highest Level of Mobility documentation. Whereas the frequency of activPAL-measured out-of-bed mobilization increased steadily to a median of 9 sessions by postoperative day 6, the number of Johns Hopkins Highest Level of Mobility documentation remained around twice daily. ActivPAL measurements demonstrated that Johns Hopkins Highest Level of Mobility documentation of ambulatory sessions (scores 6-8) was accurate. CONCLUSIONS: We found that routine Johns Hopkins Highest Level of Mobility documentation did not accurately detect preambulatory activities or the overall frequency of out-of-bed mobility sessions, poorly reflecting the highly sedentary behaviors of the acute postoperative inpatients and highlighting the need to improve clinical documentation or use alternative methods to track postoperative mobilization.

Accelerometer-Measured Inpatient Physical Activity and Associated Outcomes After Major Abdominal Surgery: Systematic Review.

BACKGROUND: It remains unclear how inpatient physical activity after major abdominal surgery affects outcomes. Accelerometer research may provide further evidence for postoperative mobilization. OBJECTIVE: We aimed to summarize the current literature evaluating the impact of accelerometer-measured postoperative physical activity on outcomes after major abdominal surgery. METHODS: We searched PubMed and Google Scholar in October 2021 to conduct a systematic review. Studies were included if they used accelerometers to measure inpatient physical behaviors immediately after major abdominal surgery, defined as any nonobstetric procedures performed under general anesthesia requiring hospital admission. Studies were eligible only if they evaluated the effects of physical activity on postoperative outcomes such as postoperative complications, return of gastrointestinal function, hospital length of stay, discharge destination, and readmissions. We excluded studies involving participants aged <18 years. Risk of bias was assessed using the risk-of-bias assessment tool for nonrandomized studies (RoBANS) for observational studies and the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) for randomized controlled trials (RCTs). Findings were summarized by qualitative synthesis. RESULTS: We identified 15 studies. Risk of bias was high in 14 (93%) of the 15 studies. Most of the studies (11/15, 73%) had sample sizes of <100. Of the 15 studies, 13 (87%) included the general surgery population, 1 (7%) was a study of patients who had undergone gynecologic surgery, and 1 (7%) included a mixed (abdominal, thoracic, gynecologic, and orthopedic) surgical population. Of the 15 studies, 12 (80%) used consumer-grade accelerometers to measure physical behaviors. Step count was the most commonly reported physical activity outcome (12/15, 80%). In the observational studies (9/15, 60%), increased physical activity during the immediate postoperative period was associated with earlier return of gastrointestinal function, fewer surgical and pulmonary complications, shorter hospital length of stay, and fewer readmissions. In the RCTs (6/15, 40%), only 1 (17%) of the 6 studies demonstrated improved outcomes (shorter time to flatus and hospital length of stay) when a mobility-enhancing intervention was compared with usual care. Notably, mobility-enhancing interventions used in 4 (67%) of the 6 RCTs did not result in increased postoperative physical activity. CONCLUSIONS: Although observational studies show strong associations between postoperative physical activity and outcomes after major abdominal surgery, RCTs have not proved the benefit of mobility-enhancing interventions compared with usual care. The overall risk of bias was high, and we could not synthesize specific recommendations for postoperative mobilization. Future research would benefit from improving study design, increasing methodologic rigor, and measuring physical behaviors beyond step counts to understand the impact of postoperative mobilization on outcomes after major abdominal surgery.

The effects of resistance exercise on appetite sensations, appetite related hormones and energy intake in hormone receptor-positive breast cancer survivors.

Appetite is a determinant of dietary intake and is impacted by sex hormones, exercise, and body composition among individuals without chronic conditions. Whether appetite is altered by exercise in the context of estrogen suppression and cancer survivorship is unknown. This randomized cross-over study compared appetite and ad libitum energy intake (EI) after acute resistance exercise (REx) versus sedentary (SED) conditions and in relation to body composition and resting metabolic rate (RMR) in breast cancer survivors (BCS). Physically inactive premenopausal females with previous stage I-III estrogen receptor-positive breast cancer completed a single bout of REx or SED 35 minutes after a standardized breakfast meal. Appetite visual analog scales and hormones (total ghrelin and peptide-YY [PYY]) were measured before and 30, 90, 120, 150, and 180 minutes post-meal and expressed as area under the curve (AUC). Participants were offered a buffet-type meal 180 minutes after breakfast to assess ad libitum EI. Body composition (dual X-ray absorptiometry) and RMR (indirect calorimetry) were measured during a separate visit. Sixteen BCS were included (age: 46 ± 2 y, BMI: 24.9 ± 1.0 kg/m2). There were no differences in appetite ratings or EI between conditions. There were no differences in appetite hormone AUC, but REx resulted in lower ghrelin 120 (-85 ± 39 pg/mL, p = 0.031) and 180 (-114 ± 43 pg/mL, p = 0.018) minutes post-breakfast and higher PYY 90 (21 ± 10 pg/mL, p = 0.028) and 120 (14 ± 7 pg/mL, p = 0.041) minutes post-breakfast. Fat-free mass and RMR negatively correlated with hunger and prospective food consumption AUC after SED, but not REx. In sum, a single REx bout temporarily reduces orexigenic and increases anorexic appetite hormones, but not acute subjective appetite sensations or EI.

Proteomics, dietary intake, and changes in cardiometabolic health within a behavioral weight-loss intervention: A pilot study.

OBJECTIVE: Identifying associations among circulating proteins, dietary intakes, and clinically relevant indicators of cardiometabolic health during weight loss may elucidate biologically relevant pathways affected by diet, allowing for an incorporation of precision nutrition approaches when designing future interventions. This study hypothesized that plasma proteins would be associated with diet and cardiometabolic health indicators within a behavioral weight-loss intervention. METHODS: This secondary data analysis included participants (n = 20, mean [SD], age: 40.1 [9.5] years, BMI: 34.2 [4.0] kg/m2 ) who completed a 1-year behavioral weight-loss intervention. Cardiovascular disease-related plasma proteins, diet, and cardiometabolic health indicators were evaluated at baseline and 3 months. Associations were determined via linear regression and integrated networks created using Visualization Of LineAr Regression Elements (VOLARE). RESULTS: A total of 16 plasma proteins were associated with ≥1 diet or health indicator at baseline (p < 0.001); changes in 42 proteins were associated with changes in diet or health indicators from baseline to 3 months (p < 0.005). Baseline tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) was associated with intakes of dark green vegetables (r = -0.712), and fatty acid-binding protein 4 (FABP4) was associated with intakes of unsweetened coffee (r = -0.689). Changes in refined-grain intakes were associated with changes in scavenger receptor cysteine-rich type 1 protein M130 (CD163; r = 0.725), interleukin-1 receptor type 1 (IL1R-T1; r = 0.624), insulin (r = 0.656), and triglycerides (r = 0.648). CONCLUSIONS: Circulating cardiovascular disease-related proteins were associated with diet and cardiometabolic health indicators prior to and in response to weight loss.

Effect of sleep on weight loss and adherence to diet and physical activity recommendations during an 18-month behavioral weight loss intervention.

BACKGROUND/OBJECTIVES: To examine the association between indices of sleep quantity and quality with dietary adherence, physical activity adherence, and weight loss during a behavioral weight loss intervention. METHODS: Adults (n = 156) with overweight and obesity (40 ± 9 years, 84% female, BMI: 34.4 ± 4.2 kg/m2) participated in an 18-month behavioral weight loss intervention which prescribed a reduced calorie diet (1200-1800 kcal/d) and increased physical activity (300 min/wk). Body weight, indices of sleep (SenseWear armband; SWA), energy intake (EI, 3-day food records), and moderate-to-vigorous physical activity (SWA) were measured at baseline, 6, 12, and 18 months. Linear mixed effects models examined the association between sleep and weight change over time. Additional models were adjusted for covariates including age, BMI, sex, race, ethnicity, study completion, randomization, EI, and physical activity. Secondary analyses examined the association between sleep and adherence to diet and physical activity recommendations. RESULTS: Mean weight loss was 7.7 ± 5.4, 8.4 ± 7.9, and 7.1 ± 9.0 kg at 6, 12, and 18 months, respectively. Lower sleep efficiency, higher wake after sleep onset (WASO), more awakenings, and higher sleep onset latency (SOL) were significantly associated with attenuated weight loss (p < 0.05). Lower sleep efficiency, more awakenings, and higher SOL remained significantly associated with blunted weight loss after adjustment for covariates (p < 0.05). Later waketime, longer time in bed, longer sleep duration, higher WASO, more awakenings, and higher SOL were associated with lower odds of achieving ≥300 min/wk of moderate-to-vigorous physical activity, adjusted for covariates (FDR p < 0.05). CONCLUSIONS: Future studies should evaluate whether incorporating strategies to improve sleep health within a behavioral weight loss intervention leads to improved adherence to diet and physical activity recommendations and enhanced weight loss. CLINICAL TRIALS IDENTIFIER: NCT01985568.

Dietary Intake and Energy Expenditure in Breast Cancer Survivors: A Review.

Many breast cancer survivors (BCS) gain fat mass and lose fat-free mass during treatment (chemotherapy, radiation, surgery) and estrogen suppression therapy, which increases the risk of developing comorbidities. Whether these body composition alterations are a result of changes in dietary intake, energy expenditure, or both is unclear. Thus, we reviewed studies that have measured components of energy balance in BCS who have completed treatment. Longitudinal studies suggest that BCS reduce self-reported energy intake and increase fruit and vegetable consumption. Although some evidence suggests that resting metabolic rate is higher in BCS than in age-matched controls, no study has measured total daily energy expenditure (TDEE) in this population. Whether physical activity levels are altered in BCS is unclear, but evidence suggests that light-intensity physical activity is lower in BCS compared to age-matched controls. We also discuss the mechanisms through which estrogen suppression may impact energy balance and develop a theoretical framework of dietary intake and TDEE interactions in BCS. Preclinical and human experimental studies indicate that estrogen suppression likely elicits increased energy intake and decreased TDEE, although this has not been systematically investigated in BCS specifically. Estrogen suppression may modulate energy balance via alterations in appetite, fat-free mass, resting metabolic rate, and physical activity. There are several potential areas for future mechanistic energetic research in BCS (e.g., characterizing predictors of intervention response, appetite, dynamic changes in energy balance, and differences in cancer sub-types) that would ultimately support the development of more targeted and personalized behavioral interventions.

Higher amounts of sedentary time are associated with short sleep duration and poor sleep quality in postmenopausal women.

STUDY OBJECTIVES: To evaluate the associations between sedentary time, total (total-PA), light (light-PA), moderate (MOD-PA), and vigorous (VIG-PA) physical activity with indices of sleep in postmenopausal women. METHODS: Baseline self-reported data from the Women's Health Initiative Observational Study (n = 75 074) were used in this cross-sectional analysis. Total-PA, light-PA, MOD-PA, and VIG-PA were categorized by metabolic equivalents of the activity (MET-hour [hr]/week [wk]) and were estimated using validated questionnaires. Sedentary time was categorized by hr/day and was estimated via questionnaire. Logistic regression was used to examine the associations between these variables and short sleep (≤6 hr/night), long sleep (≥10 hr/night), poor sleep quality, and insomnia symptoms after adjustment for age, race, socioeconomic status, body mass index, health status, depressive symptoms, smoking status, alcohol use, hormone therapy, and comorbidities. RESULTS: Higher sedentary time (>11 hr/day) was associated with higher odds of short sleep (odds ratio [OR] = 1.80, 95% confidence interval [CI]: 1.72-1.88), poor sleep quality (OR = 1.85, 95% CI: 1.74-1.97), and insomnia symptoms (OR = 1.56, 95% CI: 1.49-1.64). Light-PA (>0 MET-hr/wk) was associated with lower odds of short sleep (OR = 0.96, 95% CI: 0.92-1.00), and higher amounts of total-PA (OR = 0.90, 95% CI: 0.84-0.97), light-PA (OR = 0.94, 95% CI: 0.89-1.00), and MOD-PA (OR = 0.91, 95% CI: 0.86-0.97) were associated with lower odds of poor sleep quality. CONCLUSIONS: Our findings suggest that higher levels of light and moderate intensity physical activity are associated with better sleep quality, whereas higher amounts of sedentary time are associated with short sleep and lower quality sleep. Future studies should investigate the directionality of these associations and potential causal pathways.

Dermal Calcium Loss Is Not the Primary Determinant of Parathyroid Hormone Secretion during Exercise.

INTRODUCTION: Exercise can cause a decrease in serum ionized calcium (iCa) concentration, which stimulates parathyroid hormone (PTH) secretion and activates bone resorption. We postulated that dermal Ca loss during cycling exercise is the major determinant of the serum iCa, PTH, and bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) responses. METHODS: To investigate this, women (n = 13) and men (n = 12) age 18 to 45 yr performed the same exercise bout under cool (18°C) and warm (26°C) conditions. Exercise was 60 min of cycling at ~75% of peak aerobic power. Sweat samples were obtained during exercise using a skin patch method, and blood samples were obtained before and during exercise and during 60 min of recovery. RESULTS: Sweat volume and estimated sweat Ca loss were 50% higher for the warm condition than the cool condition. Despite this, there were no differences between thermal conditions in the changes (mean, 95% confidence interval [95% CI]) in iCa (cool, -0.07 mg·dL; 95% CI, -0.16 to 0.03); warm, -0.07 mg·dL; 95% CI, -0.20 to 0.05), PTH (cool, 34.4 pg·mL; 95% CI, 23.6-45.2; warm: 35.8 pg·mL; 95% CI, 22.4-49.1), or CTX (cool, 0.11 ng·mL; 95% CI, 0.08-0.13; warm, 0.15 ng·mL; 95% CI, 0.11-0.18). Adjusting for exercise-related shifts in plasma volume revealed a marked decline in vascular iCa content in the first 15 min of exercise (cool, -0.85 mg·dL; 95% CI, -1.01 to -0.68; warm, -0.85 mg·dL; 95% CI, -1.05 to -0.66), before substantial sweat Ca loss had occurred. CONCLUSIONS: This indicates that dermal Ca loss was not the primary trigger for the increases in PTH and CTX during exercise. Further research is necessary to understand the causes and consequences of the disruption in Ca homeostasis during exercise and specifically the extravascular shift in iCa.

Modulation of Energy Expenditure by Estrogens and Exercise in Women.

Reducing estrogen in women results in decreases in energy expenditure, but the mechanism(s) remain largely unknown. We postulate that the loss of estrogens in women is associated with increased accumulation of bone marrow-derived adipocytes in white adipose tissue, decreased activity of brown adipose tissue, and reduced levels of physical activity. Regular exercise may counteract the effects of estrogen deficiency.

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome.

Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake-sleep/food intake-fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation.

Influence of Estradiol Status on Physical Activity in Premenopausal Women.

PURPOSE: This study aimed to determine the effects of 5 months of ovarian hormone suppression in premenopausal women on objectively measured physical activity (PA). METHODS: Participants (age, 35 ± 8 yr; body mass index, 27 ± 6 kg·m) received monthly intramuscular injections of gonadotropin-releasing hormone agonist (GnRHAG) therapy, which suppresses pituitary gonadotropins and results in suppression of ovarian sex hormones. Women were randomized to receive concurrent transdermal E2 (GnRHAG + E2; n = 30) or placebo (GnRHAG + PL, n = 31). PA was assessed for 1 wk before and during each month of the 5-month intervention using a hip-worn accelerometer (Actical, Mini Mitter Co., Inc., Bend, OR). Estimates of time spent in sedentary, light, and moderate-to-vigorous PA (MVPA) were derived using a previously published equation. Subsets of participants in each group were also randomized to a supervised progressive resistance exercise training program. RESULTS: Total MVPA tended toward being higher (P = 0.08) in the GnRHAG + E2 group at month 4. There were no significant effects of intervention or time in sedentary or light PA. In the subset of women who did not participate in structured exercise training for which Actical data were obtained (n = 16 in each group), total MVPA was higher at month 4 (P = 0.01). CONCLUSIONS: PA levels seem to be maintained at a higher level in women undergoing pharmacological suppression of ovarian function with E2 add-back when compared with women treated with placebo. These data provide proof-of-concept data that E2 contributes to the regulation of PA in humans. However, given the exploratory nature of this study, future confirmatory investigations will be necessary.

Regulation of energy expenditure by estradiol in premenopausal women.

Suppressing sex hormones in women for 1 wk reduces resting energy expenditure (REE). The effects of more chronic suppression on REE and other components of total energy expenditure (TEE), and whether the reduction in REE is specifically due to loss of estradiol (E2), are not known. We compared the effects of 5 mo of sex hormone suppression (gonadotropin releasing hormone agonist therapy, GnRHAG) with placebo (PL) or E2 add-back therapy on REE and the components of TEE. Premenopausal women received GnRHAG (leuprolide acetate 3.75 mg/mo) and were randomized to receive transdermal therapy that was either E2 (0.075 mg/d; n = 24; means ± SD, aged = 37 ± 8 yr, BMI = 27.3 ± 6.2 kg/m(2)) or placebo (n = 21; aged = 34 ± 9 yr, BMI = 26.8 ± 6.2 kg/m(2)). REE was measured by using a metabolic cart, and TEE, sleep EE (SEE), exercise EE (ExEE, 2 × 30 min bench stepping), non-Ex EE (NExEE), and the thermic effect of feeding (TEF) were measured by using whole room indirect calorimetry. REE decreased in GnRHAG+PL [mean (95% CI), -54 (-98, -15) kcal/d], but not GnRHAG+E2 [+6 (-33, +45) kcal/d] (difference in between-group changes, P < 0.05). TEE decreased in GnRHAG+PL [-128 (-214, -41) kcal/d] and GnRHAG+E2 [-96 (-159, -32) kcal/d], with no significant difference in between-group changes (P = 0.55). SEE decreased similarly in both GnRHAG+PL [-0.07 (-0.12, -0.03) kcal/min] and GnRHAG+E2 [-0.07 (-0.12, -0.02) kcal/min]. ExEE decreased in GnRHAG+PL [-0.46 (-0.79, -0.13) kcal/min], but not GnRHAG+E2 [-0.30 (-0.65, +0.06) kcal/min]. There were no changes in TEF or NExEE in either group. In summary, chronic pharmacologic suppression of sex hormones reduced REE and this was prevented by E2 therapy.

Physical activity after total knee arthroplasty: A critical review.

Total knee arthroplasty (TKA) is the most commonly performed elective surgery in the United States. TKA typically improves functional performance and reduces pain associated with knee osteoarthritis. Little is known about the influence of TKA on overall physical activity levels. Physical activity, defined as "any bodily movement produced by skeletal muscles that results in energy expenditure", confers many health benefits but typically decreases with endstage osteoarthritis. The purpose of this review is to describe the potential benefits (metabolic, functional, and orthopedic) of physical activity to patients undergoing TKA, present results from recent studies aimed to determine the effect of TKA on physical activity, and discuss potential sources of variability and conflicting results for physical activity outcomes. Several studies utilizing self-reported outcomes indicate that patients perceive themselves to be more physically active after TKA than they were before surgery. Accelerometry-based outcomes indicate that physical activity for patients after TKA remains at or below pre-surgical levels. Several different factors likely contributed to these variable results, including the use of different instruments, duration of follow-up, and characteristics of the subjects studied. Comparison to norms, however, suggests that daily physical activity for patients following TKA may fall short of healthy age-matched controls. We propose that further study of the relationship between TKA and physical activity needs to be performed using accelerometry-based outcome measures at multiple post-surgical time points.

Body composition and bone mineral density after ovarian hormone suppression with or without estradiol treatment.

OBJECTIVE: Suppression of ovarian hormones in premenopausal women on gonadotropin-releasing hormone agonist (GnRH(AG)) therapy can cause fat mass (FM) gain and fat-free mass (FFM) loss. Whether this is specifically caused by a decline in serum estradiol (E2) is unknown. This study aims to evaluate the effects of GnRH(AG) with placebo (PL) or E2 add-back therapy on FM, FFM, and bone mineral density (BMD). Our exploratory aim was to evaluate the effects of resistance exercise training on body composition during the drug intervention. METHODS: Seventy healthy premenopausal women underwent 5 months of GnRH(AG) therapy and were randomized to receive transdermal E2 (GnRH(AG) + E2, n = 35) or PL (GnRH(AG) + PL, n = 35) add-back therapy. As part of our exploratory aim to evaluate whether exercise can minimize the effects of hormone suppression, some women within each drug arm were randomized to undergo a resistance exercise program (GnRH(AG) + E2 + Ex, n = 12; GnRH(AG) + PL + Ex, n = 12). RESULTS: The groups did not differ in mean (SD) age (36 [8] and 35 [9] y) or mean (SD) body mass index (both 28 [6] kg/m). FFM declined in response to GnRH(AG) + PL (mean, -0.6 kg; 95% CI, -1.0 to -0.3) but not in response to GnRH(AG) + E2 (mean, 0.3 kg; 95% CI, -0.2 to 0.8) or GnRH(AG) + PL + Ex (mean, 0.1 kg; 95% CI, -0.6 to 0.7). Although FM did not change in either group, visceral fat area increased in response to GnRH(AG) + PL but not in response to GnRH(AG) + E2. GnRH(AG) + PL induced a decrease in BMD at the lumbar spine and proximal femur that was prevented by E2. Preliminary data suggest that exercise may have favorable effects on FM, FFM, and hip BMD. CONCLUSIONS: Suppression of ovarian E2 results in loss of bone and FFM and expansion of abdominal adipose depots. Failure of hormone suppression to increase total FM conflicts with previous studies of the effects of GnRH(AG). Further research is necessary to understand the role of estrogen in energy balance regulation and fat distribution.

Increasing dietary fat elicits similar changes in fat oxidation and markers of muscle oxidative capacity in lean and obese humans.

In lean humans, increasing dietary fat intake causes an increase in whole-body fat oxidation and changes in genes that regulate fat oxidation in skeletal muscle, but whether this occurs in obese humans is not known. We compared changes in whole-body fat oxidation and markers of muscle oxidative capacity differ in lean (LN) and obese (OB) adults exposed to a 2-day high-fat (HF) diet. Ten LN (BMI = 22.5±2.5 kg/m², age = 30±8 yrs) and nine OB (BMI = 35.9±4.93 kg/m², 38±5 yrs, Mean±SD) were studied in a room calorimeter for 24hr while consuming isocaloric low-fat (LF, 20% of energy) and HF (50% of energy) diets. A muscle biopsy was obtained the next morning following an overnight fast. 24h respiratory quotient (RQ) did not significantly differ between groups (LN: 0.91±0.01; OB: 0.92±0.01) during LF, and similarly decreased during HF in LN (0.86±0.01) and OB (0.85±0.01). The expression of pyruvate dehydrogenase kinase 4 (PDK4) and the fatty acid transporter CD36 increased in both LN and OB during HF. No other changes in mRNA or protein were observed. However, in both LN and OB, the amounts of acetylated peroxisome proliferator-activated receptor γ coactivator-1-α (PGC1-α) significantly decreased and phosphorylated 5-AMP-activated protein kinase (AMPK) significantly increased. In response to an isoenergetic increase in dietary fat, whole-body fat oxidation similarly increases in LN and OB, in association with a shift towards oxidative metabolism in skeletal muscle, suggesting that the ability to adapt to an acute increase in dietary fat is not impaired in obesity.