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Competing Interests: Competing interests statement:The authors declare no competing interest.

Conventionally, women are perceived to feel colder than men, but controlled comparisons are sparse. We measured the response of healthy, lean, young women and men to a range of ambient temperatures typical of the daily environment (17 to 31 °C). The Scholander model of thermoregulation defines the lower critical temperature as threshold of the thermoneutral zone, below which additional heat production is required to defend core body temperature. This parameter can be used to characterize the thermoregulatory phenotypes of endotherms on a spectrum from "arctic" to "tropical." We found that women had a cooler lower critical temperature (mean ± SD: 21.9 ± 1.3 °C vs. 22.9 ± 1.2 °C, P = 0.047), resembling an "arctic" shift compared to men. The more arctic profile of women was predominantly driven by higher insulation associated with more body fat compared to men, countering the lower basal metabolic rate associated with their smaller body size, which typically favors a "tropical" shift. We did not detect sex-based differences in secondary measures of thermoregulation including brown adipose tissue glucose uptake, muscle electrical activity, skin temperatures, cold-induced thermogenesis, or self-reported thermal comfort. In conclusion, the principal contributors to individual differences in human thermoregulation are physical attributes, including body size and composition, which may be partly mediated by sex., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D., Methods: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before and after 12 weeks. Stable isotope tracers were used to measure gluconeogenesis [2H2O] and glucose production [6,6-2H2]glucose after an overnight fast and during a continuous meal. β-cell function (sigma) and whole-body insulin sensitivity (mSI) were assessed during a frequently sampled 2-hour oral glucose tolerance test., Results: At baseline, gluconeogenesis, glucose production, and fasting and 2-hour glucose were comparable in both groups, though Met + Lira had higher hemoglobin A1C. Met + Lira had a greater decrease from baseline in fasting glucose (-2.0 ± 1.3 vs -0.6 ± 0.9 mmol/L, P = .008) and a greater increase in sigma (0.72 ± 0.68 vs -0.05 ± 0.71, P = .03). The change in fractional gluconeogenesis was similar between groups (Met + Lira: -0.36 ± 9.4 vs Met: 0.04 ± 12.3%, P = .9), and there were no changes in prandial gluconeogenesis or mSI. Increased glucose clearance in both groups was related to sigma (r = 0.63, P = .003) but not gluconeogenesis or mSI., Conclusion: Among Y-T2D, metformin with or without liraglutide improved glycemia but did not suppress high rates of gluconeogenesis. Novel therapies that will enhance β-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed., (Published by Oxford University Press on behalf of the Endocrine Society 2023.)

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Accelerometers are used to objectively measure physical behaviors in free-living environments, typically for seven consecutive days or more. We examined whether participants experience "wear fatigue," a decline in wear time day over day, during typical assessment period acquired in a nationally representative sample of 6- to 80-yr-olds in the United States., Methods: Participants were instructed to wear an ActiGraph GT3X+ on their nondominant wrist continuously for seven consecutive days. Participants with seven complete days of recorded data, regardless of wear status, were included in the analyses ( N = 13,649). Wear was scored with the sleep, wake, and nonwear algorithm., Results: Participants averaged 1248 ± 3.6 min·d -1 (mean ± SE) of wear over the assessment, but wear time linearly decreased from day 1 (1295 ± 3.2 min) to day 7 (1170 ± 5.3 min), resulting in a wear fatigue of -18.1 ± 0.7 min·d -1 ( β ± SE). Wear fatigue did not differ by sex but varied by age-group-highest in adolescents (-26.8 ± 2.4 min·d -1 ) and lowest in older adults (-9.3 ± 0.9 min·d -1 ). Wear was lower in evening (1800-2359 h) and early morning (0000-0559 h) compared with the middle of the day and on weekend days compared with weekdays. We verified similar wear fatigue (-23.5 ± 0.7 min·d -1 ) in a separate sample ( N = 14,631) with hip-worn devices and different wear scoring. Applying minimum wear criteria of ≥10 h·d -1 for ≥4 d reduced wear fatigue to -5.3 and -18.7 min·d -1 for the wrist and hip, respectively., Conclusions: Patterns of wear suggest noncompliance may disproportionately affect estimates of sleep and sedentary behavior, particularly for adolescents. Further study is needed to determine the effect of wear fatigue on longer assessments., (Copyright © 2023 by the American College of Sports Medicine.)

Background: Metabolic disease risk in youth is influenced by sedentary behaviors. Acute in-lab studies show that, during a single day, interrupting a sedentary period with short bouts of physical activity improves glucometabolic outcomes., Objective: To determine if acutely improved glucose metabolism persists after multi-day interruptions of sitting with walking brief bouts. We hypothesized that children who underwent interrupting sitting on multiple days would demonstrate lower insulin area under the curve during an oral glucose tolerance test compared to uninterrupted sitting., Methods: Healthy, normoglycemic children (N = 109) ages 7-11 years were randomized to one of two conditions: Control (3 h of daily Uninterrupted Sitting) or Interrupted Sitting (3-min of moderate-intensity walking every 30 min for 3 h daily); with dietary intake controlled through provision of foodstuffs for the entire experiment. Participants attended six consecutive daily visits at a research ambulatory unit. The primary outcome was insulin area under the curve during the oral glucose tolerance test on day 6 during interrupted or uninterrupted sitting; secondary outcomes included glucose and c-peptide area under the curve, energy intake at a buffet meal on day 6, and free-living activity., Results: Among 93 children (42 uninterrupted sitting, 51 interrupted sitting), daily interrupted sitting resulted in 21% lower insulin (β = 0.102 CI:0.032-0.172, p = 0.005) and a 10% lower C-peptide (β = 0.043, CI:0.001-0.084, p = 0.045) area under the curve. Matsuda and Glucose Effectiveness Indices were also improved (p's < 0.05). There were no group differences in energy intake or expenditure., Conclusions: Sustained behavioral change by interrupting sedentary behaviors is a promising intervention strategy for improving metabolic risk in children., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Background & Aims: Hepatic energy metabolism is a dynamic process modulated by multiple stimuli. In nonalcoholic fatty liver disease (NAFLD), human studies typically focus on the static fasting state. We hypothesized that unique postprandial alterations in hepatic lipid metabolism are present in NAFLD., Methods: In a prospective clinical study, 37 patients with NAFLD and 10 healthy control subjects ingested a standardized liquid meal with pre- and postprandial blood sampling. Postprandial plasma lipid kinetics were characterized at the molecular lipid species level by untargeted lipidomics, cluster analysis, and lipid particle isolation, then confirmed in a mouse model., Results: There was a specific increase of multiple plasma diacylglycerol (DAG) species at 4 hours postprandially in patients with NAFLD but not in controls. This was replicated in a nonalcoholic steatohepatitis mouse model, where postprandial DAGs increased in plasma and concomitantly decreased in the liver. The increase in plasma DAGs appears early in the disease course, is dissociated from NAFLD severity and obesity, and correlates with postprandial insulin levels. Immunocapture isolation of very low density lipoprotein in human samples and stable isotope tracer studies in mice revealed that elevated postprandial plasma DAGs reflect hepatic secretion of endogenous, rather than meal-derived lipids., Conclusions: We identified a selective insulin-related increase in hepatic secretion of endogenously derived DAGs after a mixed meal as a unique feature of NAFLD. DAGs are known to be lipotoxic and associated with atherosclerosis. Although it is still unknown whether the increased exposure to hepatic DAGs contributes to extrahepatic manifestations and cardiovascular risk in NAFLD, our study highlights the importance of extending NAFLD research beyond the fasting state., (Published by Elsevier Inc.)

Sleep has been shown to affect cognitive function in laboratory studies; however, its association to the academic performance of adolescents has largely been demonstrated using self-reported measures. Studies with objective measures of both sleep and academic performance are limited. The aim of the present study was to determine whether the free-living sleep quantity, quality, and timing of 15-year-old adolescents measured with wrist actiography are associated with their scores on national standardised examinations as an objective measure of academic achievement. We measured sleep with wrist actiography for 1 week in 253 (150 girls) Icelandic adolescents with a mean (SD) age of 15.9 (0.3) years. Multiple linear regression was used to assess associations between sleep parameters and combined standardised examination scores in mathematics, English, and Icelandic obtained from the Icelandic Directorate of Education. We found that students went to bed at 00:49 hours (± 51.8 min) and slept for a mean (SD) of 6.6 (0.7) hr/night, with a median (interquartile range) night-to-night variation in sleep duration of 1.2 (0.7) hr and an efficiency of 88.1 (5.3)%. Combined analyses adjusted for sex, demonstrated that both bedtime and night-to-night variability in total sleep time were negatively associated with the average score across all topics. Sex-specific associations did not indicate clear differences between boys and girls. These findings suggest that, in addition to appropriate sleep duration, public health guidance should also highlight the importance of early and consistent sleep schedules to academic achievement for both boys and girls., (© 2021 European Sleep Research Society.)

Studies of adolescent body image and screen use are mostly limited to girls, and longitudinal data are scarce. We examined cross-sectional and longitudinal associations between these variables in mid-adolescent boys and girls. Data was collected when participants were at age 15 and 17, by questionnaire and objective measurements ( n = 152 had complete data). Sex-specific linear regression was used to explore cross-sectional and longitudinal associations of self-reported screen use (total use, and time spent in gaming, TV/DVD/internet-based watching and internet use for communication) and body image, adjusting for vigorous physical activity, symptoms of depression, and body composition. Screen time was negatively associated with body image at both time points, although more strongly at age 15, and for girls only. Gaming and TV/DVD/internet watching was more strongly associated with body image than internet use for communication. Girls with above median screen time at both ages had 14% lower body image score at age 17 than girls with below median screen time at both time points. Our results suggest that screen use is likely to play a role in the development of body dissatisfaction among adolescent females. Limiting screen time may, therefore, help to mitigate body dissatisfaction in adolescent girls.

An appealing strategy for treatment of metabolic disease in humans is activation of brown adipose tissue (BAT), a thermogenic organ best visualized through 18 F-FDG PET/CT. BAT has been activated to varying degrees by mild cold exposure. However, this approach can cause undesirable stress, and there remains no consensus protocol. Here, we describe standardized methods for both acute and chronic activation of BAT using the orally administered β3-adrenergic receptor (AR) agonist, mirabegron. Acute pharmacological stimulation has enabled quantification of whole-body BAT volume and metabolic activity using PET/CT imaging, and chronic stimulation increases these properties of BAT over time., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Gluconeogenesis (GNG), the formation of glucose from noncarbohydrate precursors, requires adenosine triphosphate (ATP). Previous studies have estimated the energetic cost of GNG in humans based on theoretical calculations of rates of GNG, moles of oxygen consumption by GNG, and average oxygen consumption. Few human studies have measured the energy expenditure (EE) due to GNG. We estimated EE attributable to GNG in patients with three insulin resistance conditions and high GNG rates (insulin receptor pathogenic variants, lipodystrophy, and type 2 diabetes) and obesity without diabetes. Fractional GNG was measured by incorporation of deuterium from body water into newly formed glucose, endogenous glucose production (EGP) as glucose appearance following administration of [6,6- 2 H 2 ]glucose, and total GNG as fractional GNG × EGP. EE was measured by indirect calorimetry and compared with predicted EE from the Mifflin St. Jeor equation. EE attributable to GNG was estimated using linear regression after accounting for age and fat-free mass (FFM). EE in patients with insulin resistance was significantly higher than predicted by the Mifflin St. Jeor equation. GNG correlated with resting EE (REE). EE attributable to GNG in patients with insulin resistance was almost one-third of REE, substantially higher than theorized in healthy subjects. Our findings demonstrate that GNG is a significant contributor to EE in insulin-resistant states. Prediction equations may underestimate caloric needs in patients with insulin resistance. Therefore, targeting caloric needs to account for higher EE due to increased GNG should be considered in energy balance studies in patients with insulin resistance. NEW & NOTEWORTHY Gluconeogenesis is an energy-requiring process that is upregulated in diabetes, contributing to hyperglycemia. Previous studies have estimated that gluconeogenesis accounts for less than 10% of resting energy expenditure. This study estimates the energy expenditure attributable to gluconeogenesis in uncommon and severe forms of insulin resistance and common, milder forms of insulin resistance. In these populations, gluconeogenesis accounts for almost one-third of resting energy expenditure, substantially higher than previously theorized in the literature.

Context: Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency decreases energy expenditure (EE), which is corrected following leptin replacement. In humans, data are mixed regarding leptin-mediated effects on EE., Objective: To determine the effects of metreleptin on EE in patients with lipodystrophy., Design, Setting, and Patients: Nonrandomized crossover study of 25 patients with lipodystrophy (National Institutes of Health, 2013-2018)., Intervention: The initiation cohort consisted of 17 patients without prior exposure to metreleptin, studied before and after 14 days of metreleptin. The withdrawal cohort consisted of 8 previously metreleptin-treated patients, studied before and after 14 days of metreleptin withdrawal., Main Outcomes: 24-h total energy expenditure (TEE), resting energy expenditure (REE), autonomic nervous system activity [heart rate variability (HrV)], plasma-free triiodothyronine (T3), free thyroxine (T4), epinephrine, norepinephrine, and dopamine., Results: In the initiation cohort, TEE and REE decreased by 5.0% (121 ± 152 kcal/day; P = 0.006) and 5.9% (120 ± 175 kcal/day; P = 0.02). Free T3 increased by 19.4% (40 ± 49 pg/dL; P = 0.01). No changes in catecholamines or HrV were observed. In the withdrawal cohort, free T3 decreased by 8.0% (P = 0.04), free T4 decreased by 11.9% (P = 0.002), and norepinephrine decreased by 34.2% (P = 0.03), but no changes in EE, epinephrine, dopamine, or HrV were observed., Conclusions: Metreleptin initiation decreased EE in patients with lipodystrophy, but no changes were observed after metreleptin withdrawal. Thyroid hormone was higher on metreleptin in both initiation and withdrawal cohorts. Decreased EE after metreleptin in lipodystrophy may result from reductions in energy-requiring metabolic processes that counteract increases in EE via adipose tissue-specific neuroendocrine and adrenergic signaling., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Objectives: Sleep duration and physical activity decline with age during adolescence. Earlier school schedules may contribute to these declines. The aim of this longitudinal study was to track changes in sleep and activity of Icelandic youth from primary to secondary school and compare students who enrolled in secondary schools with traditional and college-style schedules., Methods: We measured free-living sleep and activity with wrist actigraphy and body composition by dual-energy x-ray absorptiometry in 145 students at age 15 and age 17, when 58% attended schools with college-style scheduling. Differences from 15 to 17 and between students of different school structures were assessed with mixed-effect models., Results: Actigraphs were worn for 7.1 ± 0.4 nights at 15 and 6.9 ± 0.4 nights at 17. Overall, sleep duration decreased from 6.6 ± 0.7 h/night to 6.2 ± 0.7 h/night from age 15 to 17 (P < .001). Students with traditional schedules reduced school-night sleep duration 26 min/night at follow-up (P< .001), while sleep duration did not change for college-style students. All students went to bed later on school nights at follow-up, but only college-style students rose later. Sleep efficiency and awakenings did not differ by schedule-type. Neither sex changed body fat percentage, but average school-day activity decreased by 19% (P< .001) on follow-up and did not differ by schedule-type., Conclusions: Over the 2-year period, adolescents decreased weekly sleep duration and activity, but only those continuing traditional schedules reduced school-night sleep. This suggests greater individual control of school schedule may preserve sleep duration in this age group, which may be beneficial during the transition into adulthood., (Published by Elsevier Inc.)

In laboratory studies, imposed sleep restriction consistently reduces cognitive performance. However, the association between objectively measured, free-living sleep and cognitive function has not been studied in older adolescents. To address this gap, we measured one week of sleep with a wrist-worn GT3X+ actigraph in 160 adolescents (96 girls, 17.7 ± 0.3 years) followed by assessment of working memory with an n-back task and visual attention with a Posner cue-target task. Over the week, participants spent 7.1 ± 0.8 h/night in bed and slept 6.2 ± 0.8 h/night with 88.5 ± 4.8% efficiency and considerable intra-participant night-to-night variation, with a standard deviation in sleep duration of 1.2 ± 0.7 h. Sleep measures the night before cognitive testing were similar to weekly averages. Time in bed the night before cognitive testing was negatively associated with response times during the most challenging memory task (3-back; p = 0.005). However, sleep measures the night before did not correlate with performance on the attention task and weekly sleep parameters were not associated with either cognitive task. Our data suggests shorter acute free-living sleep may negatively impact difficult memory tasks, however the relationship between free-living sleep and cognitive task performance in healthy adolescents is less clear than that of laboratory findings, perhaps due to high night-to-night sleep variation.

Objectives: Emerging evidence suggests that inconsistent sleep may affect physical and psychological health. Thus, it is important to identify modifiable determinants of sleep variability. Screen time and physical activity are both thought to affect sleep, but studies of their relationship to sleep variability using objective measures are lacking. We examined cross-sectional associations between these variables in mid-teen adolescents using objectively measured sleep and activity., Methods: Wrist-worn accelerometers were used to measure one week of sleep and activity in 315 tenth grade students (mean age 15.8y) from six Reykjavík compulsory schools. Participants reported their daily hours of screen time. Regression analysis was used to explore associations of screen time and physical activity with variability in duration, quality, and timing of sleep, adjusting for DXA-measured body fat percentage, parental education, and physical activity or screen time., Results: Screen time, especially game playing, was associated with variability in duration, timing, and quality of sleep, most strongly with variation in bedtime. Physical activity was inversely associated with variability in duration, timing, and quality of sleep, most strongly with variation in the number of awakenings. Boys had less stable sleep patterns and higher screen time than girls, and sex-specific associations of screen time with sleep variability parameters were significant for boys only., Conclusions: Less screen time and more physical activity were independently associated with less sleep variability among mid-teen adolescents. Our results indicate that encouraging youngsters toward an active lifestyle with limited screen use may be important to achieve more consistent sleep., (Copyright © 2020 National Sleep Foundation. All rights reserved.)

Background: Sleep and physical activity are modifiable behaviors that play an important role in preventing overweight, obesity, and metabolic health problems. Studies of the association between concurrent objective measures of sleep, physical activity, and metabolic risk factors among adolescents are limited., Objective: The aim of the study was to examine the association between metabolic risk factors and objectively measured school day physical activity and sleep duration, quality, onset, and variability in adolescents., Materials and Methods: We measured one school week of free-living sleep and physical activity with wrist actigraphy in 252 adolescents (146 girls), aged 15.8±0.3 years. Metabolic risk factors included body mass index, waist circumference, total body and trunk fat percentage, resting blood pressure, and fasting glucose and insulin levels. Multiple linear regression adjusted for sex, parental education, and day length was used to assess associations between metabolic risk factors and sleep and activity parameters., Results: On average, participants went to bed at 00:22±0.88 hours and slept 6.2±0.7 hours/night, with 0.83±0.36 hours of awakenings/night. However, night-to-night variability in sleep duration was considerable (mean ± interquartile range) 0.75±0.55 hours) and bedtime (0.64±0.53 hours) respectively. Neither average sleep duration nor mean bedtime was associated with any metabolic risk factors. However, greater night-to-night variability in sleep duration and bedtime was associated with higher total body and trunk fat percentage, and less physical activity was associated with higher trunk fat percentage and insulin levels., Conclusion: Greater nightly variation in sleep duration and in bedtime and less physical activity were associated with a less favorable metabolic profile in adolescents. These findings support the idea that, along with an adequate amount of physical activity, a regular sleep schedule is important for the metabolic health of adolescents., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Sedentary time relates to higher anxiety and more negative affect in children. This study assessed whether interrupting sitting over 3 hours is sufficient to influence state anxiety, positive affect, or negative affect, and tested weight status as a moderator., Methods: Analyses were the second (preplanned) purpose of a larger study. Children (N = 61; age: mean [SD] = 9.5 [1.3]; 43% healthy weight) completed 2 experimental conditions: continuous sitting for 3 hours and sitting for 3 hours interrupted with walking for 3 minutes in every 30 minutes. State anxiety, positive affect, and negative affect were reported at pretest and posttest. Multilevel models for repeated measures assessed whether experimental condition predicted posttest scores., Results: Experimental condition was unrelated to posttest state anxiety or positive affect. Weight status moderated how experimental condition influenced posttest negative affect (P = .003). Negative affect was lower in the children of healthy weight after interrupted sitting (vs continuous sitting; β = -0.8; 95% confidence interval, -1.5 to 0.0, P = .05), but it was higher in the children with overweight/obesity after interrupted sitting (vs continuous sitting; β = 0.6; 95% confidence interval, 0.0 to 1.2, P = .06)., Conclusions: Interrupting sitting acutely reduced negative affect in children of healthy weight, but not in children with overweight. Further research is needed to better understand the potential emotional benefits of sitting interruptions in youth.

BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

Context: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume., Objective: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation., Design: Single-arm, open-label study of liothyronine., Setting: National Institutes of Health., Participants: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation., Intervention: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4)., Outcomes: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c., Results: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism., Conclusion: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897., (Published by Oxford University Press on behalf of the Endocrine Society 2019.)

The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.

Objective: This study aimed to quantify and compare the amount, activity, and anatomical distribution of cold-activated brown adipose tissue (BAT) in healthy, young, lean women and men., Methods: BAT volume and 18 F-fluorodeoxyglucose uptake were measured by positron emission tomography and computerized tomography in 12 women and 12 men (BMI 18.5-25 kg/m 2 , aged 18-35 years) after 5 hours of exposure to their coldest temperature before overt shivering., Results: Women had a lower detectable BAT volume than men (P = 0.03), but there was no difference after normalizing to body size. The mean BAT glucose uptake and relative distribution of BAT did not differ by sex. 18 F-fluorodeoxyglucose uptake consistent with BAT was observed in superficial dorsocervical adipose tissue of 6 of 12 women but only 1 of 12 men (P = 0.02). This potential BAT depot would pose fewer biopsy risks than other depots., Conclusions: Despite differences in adiposity and total BAT volume, we found that healthy, lean, young women and men do not differ in the relative amount, glucose uptake, and distribution of BAT. Dorsocervical 18 F-fluorodeoxyglucose uptake was more prevalent in women and may be a remnant of interscapular BAT seen in human newborns. Future studies are needed to discern how BAT contributes to whole-body thermal physiology and body weight regulation in women and men., (© 2020 The Obesity Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Introduction: Sleep is often quantified using self-report or actigraphy. Self-report is practical and less technically challenging, but prone to bias. We sought to determine whether these methods have comparable sensitivity to measure longitudinal changes in adolescent bedtimes., Methods: We measured one week of free-living sleep with wrist actigraphy and usual bedtime on school nights and non-school nights with self-report questionnaire in 144 students at 15 y and 17 y., Results: Self-reported and actigraphy-measured bedtimes were correlated with one another at 15 y and 17 y ( p < .001), but reported bedtime was consistently earlier (>30 minutes, p < .001) and with wide inter-method confidence intervals (> ±106 minutes). Mean inter-method discrepancy did not differ on school nights at 15 y and 17 y but was greater at 17 y on non-school nights ( p = .002). Inter-method discrepancy at 15 y was not correlated to that at 17 y. Mean change in self-reported school night bedtime from 15 y to 17 y did not differ from that by actigraphy, but self-reported bedtime changed less on non-school nights ( p = .002). Two-year changes in self-reported bedtime did not correlate with changes measured by actigraphy., Conclusions: Although methods were correlated, consistently earlier self-reported bedtime suggests report-bias. More varied non-school night bedtimes challenge the accuracy of self-report and actigraphy, reducing sensitivity to change. On school nights, the methods did not differ in group-level sensitivity to changes in bedtime. However, lack of correlation between bedtime changes by each method suggests sensitivity to individual-level change was different. Methodological differences in sensitivity to individual- and group-level change should be considered in longitudinal studies of adolescent sleep patterns.

Objective: Cold exposure increases energy expenditure (EE) and could have a role in combating obesity. To understand this potential, we determined the capacity for cold-induced thermogenesis (CIT), the EE increase above the basal metabolic rate at the individualized coldest tolerable temperature before overt shivering., Design: During a 13-day inpatient protocol, we quantitated the EE of 12 lean men and 9 men with obesity at various randomly ordered ambient temperatures in a room calorimeter. Subjects underwent brown fat imaging after exposure to their coldest tolerable temperature., Results: CIT capacity was 300 ± 218 kcal/d (mean ± SD) or 17 ± 11% in lean men and 125 ± 146 kcal/d or 6 ± 7% in men with obesity (P = 0.01). The temperature below which EE increased, lower critical temperature (Tlc), was warmer in lean men than men with obesity (22.9 ± 1.2 vs 21.1 ± 1.7°C, P = 0.03), but both had similar skin temperature (Tskin) changes and coldest tolerable temperatures. Whereas lean subjects had higher brown fat activity, skeletal muscle activity increased synchronously with CIT beginning at the Tlc in both groups, indicating that muscle is recruited for CIT in parallel with brown fat, not sequentially after nonshivering thermogenesis is maximal., Conclusions: Despite greater insulation from fat, men with obesity had a narrower range of tolerable cool temperatures available for increasing EE and less capacity for CIT than lean men, likely as a result of greater basal heat production and similar perception to Tskin cooling. Further study of the reduced CIT capacity in men with obesity may inform treatment opportunities for obesity., (This article is a U.S. Government work-for-hire and is therefore in the public domain in the U.S.)

Dynamic sitting, such as fidgeting and desk work, might be associated with health, but remains difficult to identify out of accelerometry data. We examined, in a laboratory study, whether dynamic sitting can be identified out of triaxial activity counts. Among 18 participants (56% men, 27.3 ± 6.5 years), up to 236 counts per minute were recorded in the anteroposterior and mediolateral axes during dynamic sitting using a hip-worn accelerometer. Subsequently, we examined in 621 participants (38% men, 80.0 ± 4.7 years) from the AGES-Reykjavik Study whether dynamic sitting was associated with cardio-metabolic health. Compared to participants who recorded the fewest dynamic sitting minutes (Q 1 ), those with more dynamic sitting minutes had a lower BMI (Q 2  = -1.39 (95%CI = -2.33;-0.46); Q 3  = -1.87 (-2.82;-0.92); Q 4  = -3.38 (-4.32;-2.45)), a smaller waist circumference (Q 2  = -2.95 (-5.44;-0.46); Q 3  = -3.47 (-6.01;-0.93); Q 4  = -8.21 (-10.72;-5.71)), and a lower odds for the metabolic syndrome (Q 2  = 0.74 [0.45;1.20] Q 3  = 0.58 [0.36;0.95]; Q 4  = 0.36 [0.22;0.59]). Our findings suggest that dynamic sitting might be identified using accelerometry and that this behaviour was associated with health. This might be important given the large amounts of time people spend sitting. Future studies with a focus on validation, causation and physiological pathways are needed to further examine the possible relevance of dynamic sitting.

Poor physical fitness contributes to the early progression of cardiometabolic disease, yet the physiological and psychological factors underpinning poor fitness in at-risk adolescents are not well understood. In this study, we sought to determine the relationship of physical fitness with two developmental phenomena of adolescence, insulin resistance and depression/anxiety symptoms among at-risk youth. We conducted secondary data analyses of 241 overweight or obese adolescents (12-17 years), drawn from two study cohorts. Insulin sensitivity index was derived from oral glucose tolerance tests. Adolescents self-reported depressive symptoms and anxiety symptoms on validated surveys. A walk/run test was administered to determine perceived exertion and physical fitness (distance traveled). Insulin sensitivity was positively associated with walk/run distance ( b =0.16, P< 0.01), even after accounting for all covariates. Anxiety symptoms were inversely related to perceived exertion ( b =-0.11, P< 0.05), adjusting for covariates. These findings suggest that insulin resistance and anxiety symptoms are associated with different dimensions of physical fitness in overweight or obese adolescents and could both potentially contribute to declining fitness and worsening metabolic outcomes in at-risk youth.

Background: Self-reported short sleep duration is associated with greater risk for metabolic syndrome (MetS), obesity, and higher energy intake (EI). However, studies of these associations in children using objective methods are sparse., Objectives: The study aims to determine the associations for sleep patterns with MetS indices, body composition, and EI using objective measures in children., Methods: Free-living sleep and physical activity were measured in 125 children (aged 8-17 years, BMI z = 0.57 ± 1.0, 55% female) using wrist-worn actigraphs for 14 nights. Blood pressure, fasting blood levels of lipids, insulin, glucose, waist circumference, and body composition (dual-energy X-ray absorptiometry [DXA]) were obtained during outpatient visits. EI was assessed during an ad libitum buffet meal., Results: Later weekday and weekend bedtimes were associated with higher systolic blood pressure (Ps < 0.05). Sleep duration and bedtime were not significantly associated with other components of MetS, body composition, or EI. Short sleepers (duration less than 7 hours) consumed a greater percentage of carbohydrates than those with adequate (greater than or equal to 7 hours) sleep (P < 0.05)., Conclusion: Indicators of sleep duration were variably associated with children's eating patterns and risk for chronic disease. Prospective data are needed to determine whether these indicators of sleep quality represent unique or shared risk factors for poor health outcomes., (© 2019 World Obesity Federation.)

The diagnosis of neuropathic postural tachycardia syndrome (POTS) requires research techniques not available clinically. We hypothesized that these patients will have impaired vagal and sympathetic cardiovascular control that can be characterized with clinical autonomic tests. We included 12 POTS patients with possible neuropathic subtype because of normal plasma norepinephrine and no increase in upright blood pressure. We compared them to 10 healthy subjects. We assessed hemodynamics, heart rate and blood pressure variability, baroreflex sensitivity, raw and integrated muscle sympathetic nerve activity, and blood volume. To understand the vagal/sympathetic control, we dissected the phase 2 of Valsalva maneuver (VM) into early (VM2e) and late (VM2l). POTS' upright heart rate increased 43±3 bpm. Patients had normal plasma volume but reduced red blood cell volume (1.29 L versus predicted normal values 1.58 L; P=0.02). Vagal indices of heart rate variability, HF RRI (430±130 versus 1680±900; P=0.04), PNN50, and root mean squared of successive differences were lower in POTS. Patients showed a decrease in vagal baroreflex sensitivity (VM2e; P=0.04). In POTS, integrated muscle sympathetic nerve activity was lower at rest (12±1.5 versus 20±2 burst/min; P=0.004) and raw muscle sympathetic nerve activity spike analysis showed blunted responses during VM2e, despite a greater drop in systolic blood pressure (34±5 in POTS and 14±6 mm Hg in controls; P=0.01). This cohort of POTS patients enriched for possible neuropathic subtype had lower resting muscle sympathetic nerve activity, impaired vagal cardiac control, and exaggerated drop in blood pressure in response to VM and a delay in the sympathetic cardiovascular responsiveness during hypotensive challenge.

In endothermic animals, brown adipose tissue (BAT) is activated to produce heat for defending body temperature in response to cold. BAT's ability to expend energy has made it a potential target for novel therapies to ameliorate obesity and associated metabolic disorders in humans. Though this tissue has been well studied in small animals, BAT's thermogenic capacity in humans remains largely unknown due to the difficulties of measuring its volume, activity, and distribution. Identifying and quantifying active human BAT is commonly performed using 18 F-Fluorodeoxyglucose ( 18 F-FDG) positron emission tomography and computed tomography (PET/CT) scans following cold-exposure or pharmacological activation. Here we describe a detailed image-analysis approach to quantify total-body human BAT from 18 F-FDG PET/CT scans using an open-source software. We demonstrate the drawing of user-specified regions of interest to identify metabolically active adipose tissue while avoiding common non-BAT tissues, to measure BAT volume and activity, and to further characterize its anatomical distribution. Although this rigorous approach is time-consuming, we believe it will ultimately provide a foundation to develop future automated BAT quantification algorithms.

Objectives: Lipodystrophies are characterized by regional or generalized loss of adipose tissue and severe metabolic complications. The role of visceral adipose tissue (VAT) in the development of metabolic derangements in lipodystrophy is unknown. The study aim was to investigate VAT contribution to metabolic disease in lipodystrophy versus healthy controls., Methods: Analysis of correlations between VAT volume and biomarkers of metabolic disease in 93 patients and 93 age/sex-matched healthy controls., Results: Patients with generalized lipodystrophy ( n  = 43) had lower VAT compared with matched controls, while those with partial lipodystrophy ( n  = 50) had higher VAT versus controls. Both groups with lipodystrophy had lower leg fat mass versus controls ( p  < 0.05 for all; unpaired t -test). In both generalized and partial lipodystrophy, there was no correlation between VAT and glucose, triglycerides or high-density lipoprotein cholesterol ( p  > 0.05 for all; Spearman correlation). In controls matched to patients with generalized or partial lipodystrophy, VAT correlated with glucose ( R  = 0.42 and 0.36), triglycerides ( R  = 0.36 and 0.60) and high-density lipoprotein cholesterol ( R  = -0.34 and -0.64) ( p  < 0.05 for all; Spearman correlation)., Conclusions: In contrast to healthy controls, metabolic derangements in lipodystrophy did not correlate with VAT volume. These data suggest that, in lipodystrophy, impaired peripheral subcutaneous fat deposition may exert a larger effect than VAT accumulation on the development of metabolic complications. Interventions aimed at increasing functional subcutaneous adipose tissue may provide metabolic benefit., Competing Interests: The authors declared no conflict of interest.

Accurate estimation of energy expenditure (EE) from accelerometer outputs remains a challenge in older adults. The aim of this study was to validate different ActiGraph (AG) equations for predicting EE in older adults. Forty older adults (age = 77.4 ± 8.1 yrs) completed a set of household/gardening activities in their residence, while wearing an AG at the hip (GT3X+) and a portable calorimeter (MetaMax 3B - criterion). Predicted EEs from AG were calculated using five equations (Freedson, refined Crouter, Sasaki and Santos-Lozano (vertical-axis, vectormagnitude)). Accuracy of equations was assessed using root-mean-square error (RMSE) and mean bias. The Sasaki equation showed the lowest RMSE for all activities (0.47 METs) and across physical activity intensities (PAIs) (range 0.18-0.48 METs). The Freedson and Santos-Lozano equations tended to overestimate EE for sedentary activities (range: 0.48 to 0.97 METs), while EEs for moderate-to-vigorous activities (MVPA) were underestimated (range: -1.02 to -0.64 METs). The refined Crouter and Sasaki equations showed no systematic bias, but they respectively overestimated and underestimated EE across PAIs. In conclusion, none of the equations was completely accurate for predicting EE across the range of PAIs. However, the refined Crouter and Sasaki equations showed better overall accuracy and precision when compared with the other methods.

β3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human β3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the β3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [ 18 F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ⋅ mean standardized uptake value [SUV mean ] ⋅ g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human β3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective β3-AR agonists to treat obesity-related complications., (© 2018 by the American Diabetes Association.)

Objective: Sedentary children have greater risk of developing abnormalities in glucose homeostasis. We investigated whether interrupting sedentary behavior (sitting) with very short periods of walking would improve glucose metabolism without affecting dietary intake in children with overweight or obesity. We hypothesized that interrupting sitting with short bouts of moderate-intensity walking would decrease insulin area under the curve (AUC) during an oral glucose tolerance test (OGTT) compared with uninterrupted sitting., Research Design and Methods: Overweight/obese (BMI ≥85th percentile) children 7-11 years of age underwent two experimental conditions in random order: prolonged sitting (3 h of continuous sitting) and interrupted sitting (3 min of moderate-intensity walking at 80% of ventilatory threshold every 30 min for 3 h). Insulin, C-peptide, and glucose were measured every 30 min for 3 h during an OGTT. Each session was followed by a buffet meal. Primary outcomes were differences in OGTT hormones and substrates and in buffet meal intake by condition., Results: Among 35 children with complete data, mixed-model results identified lower insulin and C-peptide in the interrupted condition ( P = 0.007 and P = 0.029, respectively); the intervention reduced insulin AUC by 21% ( P < 0.001) and C-peptide AUC 18% ( P = 0.001) and improved estimated insulin sensitivity ( P = 0.013). Neither buffet total energy intake (1,262 ± 480 vs. 1,260 ± 475 kcal; P = 0.89) nor macronutrient composition of the meal ( P values >0.38) differed between conditions significantly., Conclusions: Interrupting sitting with brief moderate-intensity walking improved glucose metabolism without significantly increasing energy intake in children with overweight or obesity. Interrupting sedentary behavior may be a promising intervention strategy for reducing metabolic risk in such children., (© 2018 by the American Diabetes Association.)

Background: Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant., Methods: Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy., Results: With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover)., Conclusion: Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake., Trial Registration: ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK.

Objective: Few studies have explored the potential interrelated associations of screen time and physical activity with mental health in youth, particularly using objective methods. We examined cross-sectional associations of these variables among Icelandic adolescents, using objective and subjective measurements of physical activity., Methods: Data were collected in the spring of 2015 from 315 tenth grade students (mean age 15.8 years) in six elementary schools in metropolitan Reykjavík, Iceland. Participants reported, via questionnaire, on demographics, weekly frequency of vigorous physical activity, daily hours of screen time and mental health status (symptoms of depression, anxiety and somatic complaints, self-esteem and life satisfaction). Total physical activity was measured over one week with wrist-worn accelerometers. Body composition was determined by DXA-scanning. Poisson regression analysis was used to explore independent and interactive associations of screen time and physical activity with mental health variables, adjusting for gender, body fat percentage and maternal education., Results: Less screen time (below the group median of 5.3 h/day) and more frequent vigorous physical activity (≥4x/week) were each associated with reporting fewer symptoms of depression, anxiety, low self-esteem, and life dissatisfaction. No significant associations were observed between objectively measured physical activity and mental health outcomes. Interactive regression analysis showed that the group reporting both less screen time and more frequent vigorous physical activity had the lowest risk of reporting symptoms of depression, anxiety, low self-esteem, and life dissatisfaction., Conclusions: Reports of less screen time and more frequent vigorous physical activity were associated with lower risk of reporting mental health problems among Icelandic adolescents. Those who reported a combination of engaging in less screen time and more frequent vigorous physical activity had the lowest risk, suggesting a synergistic relationship between the two behaviors on mental health outcomes. Our results support guiding youth towards more active and less sedentary/screen-based lifestyle.

Introduction: Physical activity and sleep are major determinants of overall health. According to international recommendations, adolescents should engage in moderate to vigorous physical activity for at least 60 min each day and sleep eight to ten hours each night. The association between physical activity and sleep in adolescents is not well known. The aim of the study was to estimate a) the proportion of Icelandic adolescents that achieves recommended physical activity and sleep, b) if there is an association between physical activity and sleep patterns, and c) sex differences in physical activity and sleep., Material and Methods: A total of 411 adolescents from the 10th grade in six schools in Reykjavik were invited to participate in a cross-sectional study in the spring of 2015. Valid data was obtained from 106 boys and 160 girls. Objective and subjective measures of physical activity and sleep were made by wrist-worn accelerometers and a questionnaire., Results: Almost half of the participants fulfilled the physical activity recommendations according to the questionnaire. Although 51.1% reported usually getting enough sleep, only 22.9% achieved the recommended sleep length according to objective assessment. No associations were observed between sleep and subjective physical activity. Girls had higher accelerometer-measured physical activity than boys on non-school days (p<0.01), but weekly averages were not different between sexes. Girls and boys did not differ in subjective or objective measures of sleep., Conclusion: The behavior of Icelandic adolescents does not reflect recommended amount of sleep and physical activity. Only 22.9% obtained the recommended sleep length and just 11.3% fulfilled recommendations of both sleep and physical activity.

In Iceland, there is a large variation in daylight between summer and winter. The aim of the study was to identify how this large variation influences physical activity (PA) and sedentary behavior (SB). Free living PA was measured by a waist-worn accelerometer for one week during waking hours in 138 community-dwelling older adults (61.1% women, 80.3 ± 4.9 years) during summer and winter months. In general, SB occupied about 75% of the registered wear-time and was highly correlated with age (β = 0.36). Although the differences were small, more time was spent during the summer in all PA categories, except for the moderate-to-vigorous PA (MVPA), and SB was reduced. More lifestyle PA (LSPA) was accumulated in ≥5-min bouts during summer than winter, especially among highly active participants. This information could be important for policy makers and health professionals working with older adults. Accounting for seasonal difference is necessary in analyzing SB and PA data.

Human brown adipose tissue (BAT) can be activated to increase glucose uptake and energy expenditure, making it a potential target for treating obesity and metabolic disease. Data on the functional and anatomic characteristics of BAT are limited, however. In 20 healthy young men [12 lean, mean body mass index (BMI) 23.2 ± 1.9 kg/m 2 ; 8 obese, BMI 34.8 ± 3.3 kg/m 2 ] after 5 h of tolerable cold exposure, we measured BAT volume and activity by 18 F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT). Obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL) with a wide range (0.1-71%) in the ratio of activated BAT to inactive fat between individuals. Six anatomic regions had activated BAT-cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal-with 67 ± 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The amount and activity of BAT was significantly influenced by region of interest selection methods, PET threshold criteria, and PET resolutions. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated thermogenic potential., Competing Interests: The authors declare no conflict of interest.

Aims: The purpose of this study was to objectively measure, with wrist-worn actigraphy, free-living sleeping patterns in Icelandic adolescents, and to compare sleep duration, sleep quality and clock times between school days (SchD) and non-school days (NSchD) and the association between sleep and body mass index (BMI)., Methods: A cross-sectional study on 15.9-year-old (±0.3) adolescents from six schools in Reykjavík, Iceland, took place in the spring of 2015. Free-living sleep was measured on 301 subjects (122 boys and 179 girls) over seven days using wrist-worn actigraphy accelerometers. Total rest time (TRT), total sleep time (TST), sleep quality markers, and clock times for sleep were quantified and compared between SchD and NSchD and between the sexes, using paired and group t-tests as appropriate. Linear regression was used to assess the association between sleep parameters and BMI., Results: On SchD, TST was 6.2 ± 0.7 h, with sleep efficiency (SLE) of 87.9 ± 4.4% for the group. On NSchD, TST increased to 7.3 ± 1.1 h (p < 0.001), although SLE decreased to 87.4 ± 4.7% (p < 0.05). On SchD and NSchD, 67% and 93% had bed times after midnight, respectively, and on SchD 10.7% met sleep recommendations (8 h/night). There was no association between BMI and average sleep parameters., Conclusion: The majority of Icelandic adolescents did not get the recommended number of hours of sleep, especially on SchD. While TST increased on NSchD, many participants still did not achieve the recommendations. These findings provide information on the sleep patterns of adolescents and may serve as reference for development of policies and interventions to promote better sleep practices., (Copyright © 2017. Published by Elsevier B.V.)

A basic property of endothermic thermoregulation is the ability to generate heat by increasing metabolism in response to cold ambient temperatures to maintain a stable core body temperature. This process, known as cold-induced thermogenesis (CIT), has been measured in humans as early as 1780 by Antoine Lavoisier, but has found renewed interest because of the recent 'rediscovery' of thermogenic, cold-activated brown adipose tissue (BAT) in adult humans. In this review, we summarize some of the key findings of the work involving CIT over the past two centuries and highlight some of the seminal studies focused on this topic. There has been a substantial range of variability in the reported CIT in these studies, from 0 to 280% above basal metabolism. We identify and discuss several potential sources of this variability, including both methodological (measurement device, cold exposure temperature and duration) and biological (age and body composition of subject population) discrepancies. These factors should be considered when measuring CIT going forward to better assess whether BAT or other thermogenic organs are viable targets to combat chronic positive energy balance based on their relative capacities to elevate human metabolism.

Bombesin-like receptor 3 (BRS-3) is an orphan G protein-coupled receptor that regulates energy expenditure, food intake, and body weight. We examined the effects of BRS-3 deletion and activation on blood pressure and heart rate. In free-living, telemetered Brs3 null mice the resting heart rate was 10% lower than wild-type controls, while the resting mean arterial pressure was unchanged. During physical activity, the heart rate and blood pressure increased more in Brs3 null mice, reaching a similar heart rate and higher mean arterial pressure than control mice. When sympathetic input was blocked with propranolol, the heart rate of Brs3 null mice was unchanged, while the heart rate in control mice was reduced to the level of the null mice. The intrinsic heart rate, measured after both sympathetic and parasympathetic blockade, was similar in Brs3 null and control mice. Intravenous infusion of the BRS-3 agonist MK-5046 increased mean arterial pressure and heart rate in wild-type but not in Brs3 null mice, and this increase was blocked by pretreatment with clonidine, a sympatholytic, centrally acting α2-adrenergic agonist. In anesthetized mice, hypothalamic infusion of MK-5046 also increased both mean arterial pressure and heart rate. Taken together, these data demonstrate that BRS-3 contributes to resting cardiac sympathetic tone, but is not required for activity-induced increases in heart rate and blood pressure. The data suggest that BRS-3 activation increases heart rate and blood pressure via a central sympathetic mechanism.

Study Objectives: To identify cross-sectional and seasonal patterns of sleep and physical activity (PA) in community-dwelling, older Icelandic adults using accelerometers., Methods: A seven-day free-living protocol of 244 (110 female) adults aged 79.7 ± 4.9 years was conducted as part of a larger population-based longitudinal observational-cohort study in the greater Reykjavik area of Iceland. A subpopulation (n = 72) repeated the 7-day measurement during seasonal periods with greater (13.4 ± 1.4 h) and lesser (7.7 ± 1.8 h) daylight., Results: Cross-sectional analyses using multiple linear regression models revealed that day length was a significant independent predictor of sleep duration, mid-sleep, and rise time (all p < 0.05). However, the actual within-individual differences in sleep patterns of the repeaters were rather subtle between periods of longer and shorter day-lengths. Compared to women, men had a shorter sleep duration (462 ± 80 vs. 487 ± 68 minutes, p = 0.008), earlier rise time, and a greater number of awakenings per night (46.5 ± 18.3 vs. 40.2 ± 15.7, p = 0.007), but sleep efficiency and onset latency were similar between the two sexes. Daily PA was also similar between men and women and between periods of longer and shorter day-lengths. BMI, age, gender, and overall PA all contributed to the variations in sleep parameters using multiple regression analysis., Conclusions: The sleep and PA characteristics of this unique population revealed some gender differences, but there was limited variation in response to significant daylight changes which may be due to long-term adaptation., (© 2015 American Academy of Sleep Medicine.)

Many studies have examined the hypothesis that greater participation in physical activity (PA) is associated with less brain atrophy. Here we examine, in a sub-sample (n=352, mean age 79.1 years) of the Age, Gene/Environment Susceptibility-Reykjavik Study cohort, the association of the baseline and 5-year change in magnetic resonance imaging (MRI)-derived volumes of gray matter (GM) and white matter (WM) to active and sedentary behavior (SB) measured at the end of the 5-year period by a hip-worn accelerometer for seven consecutive days. More GM (β=0.11; p=0.044) and WM (β=0.11; p=0.030) at baseline was associated with more total physical activity (TPA). Also, when adjusting for baseline values, the 5-year change in GM (β=0.14; p=0.0037) and WM (β=0.11; p=0.030) was associated with TPA. The 5-year change in WM was associated with SB (β=-0.11; p=0.0007). These data suggest that objectively measured PA and SB late in life are associated with current and prior cross-sectional measures of brain atrophy, and that change over time is associated with PA and SB in expected directions., Competing Interests: statement The authors have no conflicts to disclose., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Context: Limited data suggest that interrupting sedentary behaviors with activity improves metabolic parameters in adults., Objective: We tested whether interrupting sitting with short, moderate-intensity walking bouts improved glucose tolerance in children., Design: Participants underwent two experimental conditions in random order on different days: continuous sitting for 3 hours or sitting interrupted by walking (3 min of moderate-intensity walking every 30 min). Insulin, C-peptide, glucose, and free fatty acids were measured every 30 minutes for 3 hours during an oral glucose tolerance test. Area under the curve (AUC) was calculated from hormone and substrate measurements. Children were given a buffet meal after each condition., Setting: The study was conducted at the National Institutes of Health Hatfield Clinical Research Center., Participants: Twenty-eight normal-weight 7-11 year olds participated., Main Outcomes: Patterns of substrate/hormone secretion and AUC, as well as energy intake, were examined by experimental condition., Results: Interrupting sitting resulted in a 32% lower insulin AUC (P < .001), 17% lower C-peptide AUC (P < .001), and 7% lower glucose AUC (P = .018) vs continuous sitting. Mixed model results indicated that insulin (P = .036) and free fatty acid concentrations (P = .009) were significantly lower in the interrupted vs the continuous sitting condition. Lunchtime buffet meal energy intake did not significantly differ between the conditions (975 ± 387 vs 963 ± 309 kcal; P = .85)., Conclusions: Interrupting sedentary time with brief moderate-intensity walking improved short-term metabolic function in non-overweight children without increasing subsequent energy intake. These findings suggest that interrupting sedentary behavior may be a promising prevention strategy for reducing cardiometabolic risk in children.

Background: Abdominal visceral fat, typically measured by computer tomography (CT) or magnetic resonance imaging (MRI), has been shown to correlate with cardiometabolic risks. The purpose of this study was to examine whether a newly developed and validated visceral fat measurement from dual-energy X-ray absorptiometry (DXA) provides added predictive value to the cross-sectional differences of cardiometabolic parameters beyond the traditional anthropometric and DXA adiposity parameters., Method: A heterogeneous cohort of 194 adults (81 males and 113 females) with a BMI of 19 to 54 kg/m(2) participated in this cross-sectional study. Body composition was measured with a DXA densitometer. Visceral fat was then computed with a proprietary algorithm. Insulin sensitivity index (SI, measured by intravenous glucose tolerance test), blood pressures, and lipid profiles, and peak oxygen uptake were also measured as cardiometabolic risk parameters., Results: DXA-estimated visceral fat mass was associated with HDL cholesterol (regression coefficient [β] = -5.15, P < .01, adjusted R(2) = .21), triglyceride (β = 26.01, P < .01, adjusted R(2) = .14), and peak oxygen uptake (β = -3.15, P < .01, adjusted R(2) = .57) after adjusting for age, gender, and ethnicity. A subanalysis stratifying gender-specific BMI tertiles showed visceral fat, together with ethnicity, was independently associated with SI in overweight men and moderately obese women (second tertile)., Conclusions: Without requiring additional CT or MRI-based measurements, visceral fat detected by DXA might offer certain advantages over the traditional DXA adiposity parameters as means of assessing cardiometabolic risks., (© 2015 Diabetes Technology Society.)

Purpose: This study compared sitting, standing, and stepping classifications from thigh-worn ActiGraph and activPAL monitors under laboratory and free-living conditions., Methods: Adults wore both monitors on the right thigh while performing activities (six sitting, two standing, nine stepping, and one cycling) and writing on a whiteboard with intermittent stepping under laboratory conditions (n = 21) and under free-living conditions for 3 d (n = 18). Percent time correctly classified was calculated under laboratory conditions. Between-monitor agreement and weighted κ were calculated under free-living conditions., Results: In the laboratory, both monitors correctly classified 100% of standing time and >95% of the time spent in four of six sitting postures. Both monitors demonstrated misclassification of laboratory stool sitting time (ActiGraph 14% vs. activPAL 95%). ActivPAL misclassified 14% of the time spent sitting with legs outstretched; ActiGraph was 100% accurate. Monitors were >95% accurate for stepping, although ActiGraph was less so for descending stairs (86%), ascending stairs (92%), and running at 2.91 m·s(-1) (93%). Monitors classified whiteboard writing differently (ActiGraph 83% standing/15% stepping vs. activPAL 98% standing/2% stepping). ActivPAL classified 93% of cycling time as stepping, whereas ActiGraph classified <1% of cycling time as stepping. During free-living wear, monitors had substantial agreement (86% observed; weighted κ = 0.77). Monitors classified similar amounts of time as sitting (ActiGraph 64% vs. activPAL 62%). There were differences in time recorded as standing (ActiGraph 21% vs. activPAL 27%) and stepping (ActiGraph 15% vs. activPAL 11%)., Conclusions: Differences in data processing algorithms may have resulted in the observed disagreement in posture and activity classification between thigh-worn ActiGraph and activPAL. Despite between-monitor agreement in classifying sitting time under free-living conditions, ActiGraph appears to be more sensitive to free-living upright walking motions than activPAL.

Context: Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date., Objective, Design, and Setting: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist RM-493 on resting energy expenditure (REE) in obese subjects in an inpatient setting., Study Participants and Methods: Twelve healthy adults (6 men and 6 women) with body mass index of 35.7 ± 2.9 kg/m(2) (mean ± SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, and 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter, and REE in the fasting state was defined as the mean of 2 30-minute resting periods., Results: RM-493 increased REE vs placebo by 6.4% (95% confidence interval, 0.68-13.02%), on average by 111 kcal/24 h (95% confidence interval, 15-207 kcal, P = .03). Total daily EE trended higher, whereas the thermic effect of a test meal and exercise EE did not differ significantly. The 23-hour nonexercise respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs 0.848 ± 0.022, P = .02). No adverse effect on heart rate or blood pressure was observed., Conclusions: Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.

In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism have not been investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance, and substrate metabolism in a prospective crossover study of 4-month duration, consisting of four consecutive blocks of 1-month overnight temperature acclimation (24 °C [month 1] → 19 °C [month 2] → 24 °C [month 3] → 27 °C [month 4]) of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (P < 0.05), respectively, independent of seasonal fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05), evident only after cold acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold-acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)