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.

Validation of the doubly labeled water method using off-axis integrated cavity output spectroscopy and isotope ratio mass spectrometry.

When the doubly labeled water (DLW) method is used to measure total daily energy expenditure (TDEE), isotope measurements are typically performed using isotope ratio mass spectrometry (IRMS). New technologies, such as off-axis integrated cavity output spectroscopy (OA-ICOS) provide comparable isotopic measurements of standard waters and human urine samples, but the accuracy of carbon dioxide production (V̇co2) determined with OA-ICOS has not been demonstrated. We compared simultaneous measurement V̇co2 obtained using whole-room indirect calorimetry (IC) with DLW-based measurements from IRMS and OA-ICOS. Seventeen subjects (10 female; 22 to 63 yr) were studied for 7 consecutive days in the IC. Subjects consumed a dose of 0.25 g H218O (98% APE) and 0.14 g 2H2O (99.8% APE) per kilogram of total body water, and urine samples were obtained on days 1 and 8 to measure average daily V̇co2 using OA-ICOS and IRMS. V̇co2 was calculated using both the plateau and intercept methods. There were no differences in V̇co2 measured by OA-ICOS or IRMS compared with IC when the plateau method was used. When the intercept method was used, V̇co2 using OA-ICOS did not differ from IC, but V̇co2 measured using IRMS was significantly lower than IC. Accuracy (~1-5%), precision (~8%), intraclass correlation coefficients ( R = 0.87-90), and root mean squared error (30-40 liters/day) of V̇co2 measured by OA-ICOS and IRMS were similar. Both OA-ICOS and IRMS produced measurements of V̇co2 with comparable accuracy and precision compared with IC.

The Case for the Patient-Centric Development of Novel Digital Sleep Assessment Tools in Major Depressive Disorder.

Background: Depression imposes a major burden on public health as the leading cause of disability worldwide. Sleep disturbance is a core symptom of depression that affects the vast majority of patients. Nonetheless, it is frequently not resolved by depression treatment and may even be worsened through some pharmaceutical interventions. Disturbed sleep negatively impact patients' quality of life, and persistent sleep disturbance increases the risk of recurrence, relapse, and even suicide. However, the development of novel treatments that might improve sleep problems is hindered by the lack of reliable low-burden objective measures that can adequately assess disturbed sleep in this population. Summary: Developing improved digital measurement tools that are fit for use in clinical trials for major depressive disorder could promote the inclusion of sleep as a focus for treatment, clinical drug development, and research. This perspective piece explores the path toward the development of novel digital measures, reviews the existing evidence on the meaningfulness of sleep in depression, and summarizes existing methods of sleep assessments, including the use of digital health technologies. Key Messages: Our objective was to make a clear call to action and path forward for the qualification of new digital outcome measures which would enable assessment of sleep disturbance as an aspect of health that truly matters to patients, promoting sleep as an important outcome for clinical development, and ultimately ensure that disturbed sleep will not remain the forgotten symptom of depression.

Maximizing precision and accuracy of the doubly labeled water method via optimal sampling protocol, calculation choices, and incorporation of 17O measurements.

BACKGROUND/OBJECTIVES: The doubly labeled water (DLW) method is the gold standard methodology for determination of free-living, total daily energy expenditure (TEE). However, there is no single accepted approach for either the sampling protocols (daily vs. two-point, in which samples are collected after dosing and at the end of the measurement period) or the calculations used in the determination of the rate of carbon dioxide production (rCO2) and TEE. Moreover, fluctuations in natural background abundances introduce error in the calculation of rCO2 and TEE. The advent of new technologies makes feasible the possibility of including additional isotope measures (17O) to account for background variation, which may improve accuracy. SUBJECTS/METHODS: Sixteen subjects were studied for 7 consecutive days in a whole-room indirect calorimeter (IC) with concurrent measurement of TEE by DLW. Daily urine samples were obtained and isotope ratios were determined using off-axis integrated cavity output spectroscopy (OA-ICOS). RESULTS: We determined the best combination of approaches for estimating dilution spaces and elimination rates and calculated average daily volume of carbon dioxide production (VCO2) using six different published equations. Using this best combination, multi-point fitting of isotope elimination rates using the daily urine samples substantially improved the average precision (4.5% vs. 6.0%) and accuracy (-0.5% vs. -3.0%) compared with the two-point method. This improvement may partly reflect the less variable day-to-day chamber measurements of energy expenditure. Utilizing 17O measurements to correct for errors due to background isotope fluctuations provided additional but minor improvements in precision (4.2% vs. 4.5%) and accuracy (0.2% vs. 0.5%). CONCLUSIONS: This work shows that optimizing sampling and calculation protocols can improve the accuracy and precision of DLW measurements.

Automatic Recognition of Activities of Daily Living Utilizing Insole-Based and Wrist-Worn Wearable Sensors.

Automatic recognition of activities of daily living (ADL) is an important component in understanding of energy balance, quality of life, and other areas of health and well-being. In our previous work, we had proposed an insole-based activity monitor-SmartStep, designed to be socially acceptable and comfortable. The goals of the current study were: first, validation of SmartStep in recognition of a broad set of ADL; second, comparison of the SmartStep to a wrist sensor and testing these in combination; third, evaluation of SmartStep's accuracy in measuring wear noncompliance and a novel activity class (driving); fourth, performing the validation in free living against a well-studied criterion measure (ActivPAL, PAL Technologies); and fifth, quantitative evaluation of the perceived comfort of SmartStep. The activity classification models were developed from a laboratory study consisting of 13 different activities under controlled conditions. Leave-one-out cross validation showed 89% accuracy for the combined SmartStep and wrist sensor, 81% for the SmartStep alone, and 69% for the wrist sensor alone. When household activities were grouped together as one class, SmartStep performed equally well compared to the combination of SmartStep and wrist-worn sensor (90% versus 94%), whereas the accuracy of the wrist sensor increased marginally (73% from 69%). SmartStep achieved 92% accuracy in recognition of nonwear and 82% in recognition of driving. Participants then were studied for a day under free-living conditions. The overall agreement with ActivPAL was 82.5% (compared to 97% for the laboratory study). The SmartStep scored the best on the perceived comfort reported at the end of the study. These results suggest that insole-based activity sensors may present a compelling alternative or companion to commonly used wrist devices.

Time since menopause and skeletal muscle estrogen receptors, PGC-1α, and AMPK.

OBJECTIVE: Short-term administration of estradiol (E2) improves insulin-stimulated glucose disposal rate in early postmenopausal (EPM) women compared with a reduction in late postmenopausal (LPM) women. The underlying mechanisms by which E2 action on glucose disposal rate reversed from beneficial early to harmful late in menopause is unknown, but might include adverse changes in estrogen receptors (ERs) or other biomarkers of cellular energy metabolism with age or duration of estrogen deficiency. METHODS: We retrospectively analyzed skeletal muscle samples from 27 postmenopausal women who were 6 years or less past menopause (EPM; n = 13) or at least 10 years past menopause (LPM; n = 14). Fasted skeletal muscle (vastus lateralis) samples were collected after 1 week administration of transdermal E2 or placebo, in random cross-over design. RESULTS: Compared with EPM, LPM had reduced skeletal muscle ERα and ERß nuclear protein. Short-term E2 treatment did not change nuclear ERα or ERß, but decreased cytosolic ERα, so the proportion of ERα in the nucleus compared with the cytosol tended to increase. There was a group-by-treatment interaction (P < 0.05) for nuclear proliferator-activated receptor γ co-activator 1-α and phosphorylated adenosine monophosphate-activated protein kinase, such that E2 increased these proteins in EPM, but decreased these proteins in LPM. CONCLUSIONS: These preliminary studies of skeletal muscle from early and late postmenopausal women treated with E2 suggest there may be declines in skeletal muscle ER and changes in the E2-mediated regulation of cellular energy homeostasis with increasing time since menopause.

Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor α and ß in postmenopausal women.

We recently demonstrated that short-term estradiol (E2) treatment improved insulin-mediated suppression of lipolysis in postmenopausal women, but to a greater extent in those who were late compared to early postmenopausal. In this follow-up study we tested whether subcutaneous adipose tissue (SAT) expression of estrogen receptors (ER) α and ß differs between early and late postmenopausal women. We further tested whether the balance of ERα to ERß in SAT determined the effect of E2 on SAT insulin sensitivity. The present study included 35 women who were ≤6 years past menopause (EPM; n = 16) or ≥10 years past menopause (LPM; n = 19). Fasted SAT samples were taken following 1-week transdermal E2 treatment or placebo (PL) in a random cross-over design. Samples were analyzed for nuclear/cytosolic protein content and mRNA expression using Western blot and qPCR, respectively. While ESR1 increased slightly (~1.4-fold) following E2 treatment in both groups, ERα and ERß protein expression did not differ between groups at baseline or in response to E2. However, the balance of ERα/ERß protein in the SAT nuclear fraction increased 10% in EPM compared to a 25% decrease in LPM women (group x treatment interaction, p<0.05). A greater proportion of ERα/ERß protein in the nuclear fraction of SAT at baseline (placebo day) was associated with greater reduction in SAT insulin resistance (i.e., better suppression of lipolysis, EC50) in response to E2 (r = -0.431, p<0.05). In conclusion, there do not appear to be differences in the proportion of adipose tissue ERα/ERß protein in late, compared to early, postmenopausal women. However, the balance of ERα/ERß may be important for E2-mediated improvement in adipose tissue insulin sensitivity. TRIAL REGISTRATION: Clinical Trials#: NCT01605071.

Estimating energy expenditure using heat flux measured at a single body site.

INTRODUCTION: The Personal Calorie Monitor (PCM) is a portable direct calorimeter that estimates energy expenditure (EE) from measured heat flux (i.e., the sum of conductive, convective, radiative, and evaporative heat). PURPOSE: The primary aim of this study was to compare EE estimated from measures of heat flux with those measured using indirect calorimetry in a thermoneutral environment (26°C). A secondary aim was to determine whether exposure to ambient temperature below thermoneutral condition (19°C) influences the accuracy of the PCM. METHODS: Thirty-four adults (mean ± SD: age, 28 ± 5 yr; body mass index, 22.9 ± 2.6 kg · m(-2)) were studied for 5 h in a whole-room indirect calorimeter (IC) in thermoneutral and cool conditions. Participants wore the PCM on their upper arm and completed two 20-min treadmill walking bouts (0% grade, 3 mph). The remaining time was spent sedentary (e.g., watching television, using a computer). RESULTS: In thermoneutral conditions, EE values (mean (95% confidence interval)) measured by IC and PCM were 560.0 (526.5-593.5) and 623.3 (535.5-711.1) kcal, respectively. In cool conditions, EE values measured by IC and PCM were 572.5 (540.9-604.0) and 745.5 (668.1-822.8) kcal, respectively. Under thermoneutral conditions, mean PCM minute-by-minute EE tracked closely with IC, resulting in a small nonsignificant bias (63 kcal (-5.8 to 132.4)). During cool conditions, mean PCM minute-by-minute EE did not track IC, resulting in a large bias (173.0 kcal (93.9-252.1)) (P <; 0.001). CONCLUSIONS: This study demonstrated the validity of using measured heat flux to estimate EE. However, accuracy may be impaired in cool conditions possibly because of excess heat loss from the exposed limbs.

Total daily energy expenditure is increased following a single bout of sprint interval training.

REGULAR ENDURANCE EXERCISE IS AN EFFECTIVE STRATEGY FOR HEALTHY WEIGHT MAINTENANCE, MEDIATED VIA INCREASED TOTAL DAILY ENERGY EXPENDITURE (TDEE), AND POSSIBLY AN INCREASE IN RESTING METABOLIC RATE (RMR: the single largest component of TDEE). Sprint interval training (SIT) is a low-volume alternative to endurance exercise; however, the utility of SIT for healthy weight maintenance is less clear. In this regard, it is feasible that SIT may evoke a thermogenic response above and beyond the estimates required for prevention of weight gain (i.e., >200-600 kJ). The purpose of these studies was to investigate the hypotheses that a single bout of SIT would increase RMR and/or TDEE. Study 1: RMR (ventilated hood) was determined on four separate occasions in 15 healthy men. Measurements were performed over two pairs of consecutive mornings; each pair was separated by 7 days. Immediately following either the first or third RMR measurement (randomly assigned) subjects completed a single bout of SIT (cycle ergometer exercise). RMR was unaffected by a single bout of SIT (7195 ± 285 kJ/day vs. 7147 ± 222, 7149 ± 246 and 6987 ± 245 kJ/day (mean ± SE); P = 0.12). Study 2: TDEE (whole-room calorimeter) was measured in 12 healthy men, on two consecutive days, one of which began with a single bout of SIT (random order). Sprint exercise increased TDEE in every research participant (9169 ± 243 vs. 10,111 ± 260 kJ/day; P < 0.0001); the magnitude of increase was 946 ± 62 kJ/day (∼10%). These data provide support for SIT as a strategy for increasing TDEE, and may have implications for healthy body weight maintenance.

My baby, my move: examination of perceived barriers and motivating factors related to antenatal physical activity.

INTRODUCTION: Based on a socioecological model, the present study examined multilevel barriers and facilitators related to physical activity engagement during pregnancy in women of low socioeconomic status. METHODS: Individual and paired interviews were conducted with 25 pregnant women (aged 18-46 years, 17-40 weeks' gestation) to ask about motivational factors and to compare differences in activity level and parity. Atlas/Ti software was used to code verbatim interview transcripts by organizing codes into categories that reflect symbolic domains of meaning, relational patterns, and overarching themes. RESULTS: Perceived barriers and motivating factors differed between exercisers and nonexercisers at intrapersonal, interpersonal, and environmental levels. DISCUSSION: Future interventions should take into account key motivating multilevel factors and barriers to tailor more meaningful advice for pregnant women.