The thermoneutral zone in women takes an "arctic" shift compared to men.

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.

Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

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.

Glycemia and Gluconeogenesis With Metformin and Liraglutide: A Randomized Trial in Youth-onset Type 2 Diabetes.

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 ß-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. ß-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 ß-cell function and target the elevated rates of gluconeogenesis in Y-T2D are needed.

Does Wrist-Worn Accelerometer Wear Compliance Wane over a Free-Living Assessment Period? An NHANES Analysis.

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 ( ß ± 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.

Effects of interrupting daily sedentary behavior on children's glucose metabolism: A 6-day randomized controlled trial.

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 (ß = 0.102 CI:0.032-0.172, p = 0.005) and a 10% lower C-peptide (ß = 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.

Postprandial Plasma Lipidomics Reveal Specific Alteration of Hepatic-derived Diacylglycerols in Nonalcoholic Fatty Liver Disease.

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.

Activating Human Adipose Tissue with the ß3-Adrenergic Agonist Mirabegron.

An appealing strategy for treatment of metabolic disease in humans is activation of brown adipose tissue (BAT), a thermogenic organ best visualized through 18F-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 ß3-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.

Screen Time and Body Image in Icelandic Adolescents: Sex-Specific Cross-Sectional and Longitudinal Associations.

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.

Sleep timing and consistency are associated with the standardised test performance of Icelandic adolescents.

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.

Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance.

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 [6,6-2H2]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.

Leptin Decreases Energy Expenditure Despite Increased Thyroid Hormone in Patients With Lipodystrophy.

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 ±â€…152 kcal/day; P = 0.006) and 5.9% (120 ±â€…175 kcal/day; P = 0.02). Free T3 increased by 19.4% (40 ±â€…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.

Association between free-living sleep and memory and attention in healthy adolescents.

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.

Changes in sleep and activity from age 15 to 17 in students with traditional and college-style school schedules.

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.

Less physical activity and more varied and disrupted sleep is associated with a less favorable metabolic profile in adolescents.

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.

Less screen time and more physical activity is associated with more stable sleep patterns among Icelandic adolescents.

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.

The Effects of Interrupting Sitting Time on Affect and State Anxiety in Children of Healthy Weight and Overweight: A Randomized Crossover Trial.

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; ß = -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; ß = 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.

Sexual Dimorphisms in Adult Human Brown Adipose Tissue.

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/m2 , 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.

Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity.

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 ß-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.

Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.

BACKGROUNDMirabegron is a ß3-adrenergic receptor (ß3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that ß3-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 ß3-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).

Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations.

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.