P. Schrauwen

Cold-Activated Brown Adipose Tissue in Healthy Men

BACKGROUNDnStudies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism.nnnMETHODSnWe studied 24 healthy men--10 who were lean (body-mass index [BMI] [the weight in kilograms divided by the square of the height in meters], < 25) and 14 who were overweight or obese (BMI, > or = 25)--under thermoneutral conditions (22 degrees C) and during mild cold exposure (16 degrees C). Putative brown-adipose-tissue activity was determined with the use of integrated (18)F-fluorodeoxyglucose positron-emission tomography and computed tomography. Body composition and energy expenditure were measured with the use of dual-energy x-ray absorptiometry and indirect calorimetry.nnnRESULTSnBrown-adipose-tissue activity was observed in 23 of the 24 subjects (96%) during cold exposure but not under thermoneutral conditions. The activity was significantly lower in the overweight or obese subjects than in the lean subjects (P=0.007). BMI and percentage of body fat both had significant negative correlations with brown adipose tissue, whereas resting metabolic rate had a significant positive correlation.nnnCONCLUSIONSnThe percentage of young men with brown adipose tissue is high, but its activity is reduced in men who are overweight or obese. Brown adipose tissue may be metabolically important in men, and the fact that it is reduced yet present in most overweight or obese subjects may make it a target for the treatment of obesity.

Implications of nonshivering thermogenesis for energy balance regulation in humans.

The incidence of the metabolic syndrome has reached epidemic levels in the Western world. With respect to the energy balance, most attention has been given to reducing energy (food) intake. Increasing energy expenditure is an important alternative strategy. Facultative thermogenesis, which is the increase in energy expenditure in response to cold or diet, may be an effective way to affect the energy balance. The recent identification of functional brown adipose tissue (BAT) in adult humans promoted a renewed interest in nonshivering thermogenesis (NST). The purpose of this review is to highlight the recent insight in NST, general aspects of its regulation, the major tissues involved, and its metabolic consequences. Sustainable NST in adult humans amounts to 15% of the average daily energy expenditure. Calculations based on the limited available literature show that BAT thermogenesis can amount to 5% of the basal metabolic rate. It is likely that at least a substantial part of NST can be attributed to BAT, but it is possible that other tissues contribute to NST. Several studies on mitochondrial uncoupling indicate that skeletal muscle is another potential contributor to facultative thermogenesis in humans. The general and synergistic role of the sympathetic nervous system and the thyroid axis in relation to NST is discussed. Finally, perspectives on BAT and skeletal muscle NST are given.

Increase in Brown Adipose Tissue Activity after Weight Loss in Morbidly Obese Subjects

CONTEXTnStimulation of thermogenesis in brown adipose tissue (BAT) is a potential target to treat obesity. We earlier demonstrated that BAT activity is relatively low in obese subjects. It is unknown whether BAT can be recruited in adult humans.nnnOBJECTIVEnTo study the dynamics of BAT, we observed BAT activity in morbidly obese subjects before and after weight loss induced by bariatric surgery.nnnDESIGNnThis was an observational prospective cohort study.nnnSETTINGnThe study was conducted at a referral center.nnnPATIENTSnTen morbidly obese subjects eligible for laparoscopic adjustable gastric banding surgery were studied before and 1 yr after bariatric surgery.nnnMAIN OUTCOME MEASUREnThe main outcome measure was BAT activity, as determined after acute cold stimulation using (18)F-fluorodeoxyglucose positron emission tomography and computed tomography.nnnRESULTSnBefore surgery, only two of 10 subjects showed active BAT. One year after surgery, the number of subjects with active BAT was increased to five. After weight loss, BAT-positive subjects had significantly higher nonshivering thermogenesis compared with BAT-negative subjects (P < 0.05).nnnCONCLUSIONSnThe results show that in humans BAT can be recruited in the regions in which it was also reported in lean subjects before. These results for the first time show recruitment of BAT in humans and may open the door for BAT-targeted treatments of obesity.

Energy metabolism in humans at a lowered ambient temperature

Objective: Assessment of the effect of a lowered ambient temperature, ie 16°C (61°F), compared to 22°C (72°F), on energy intake (EI), energy expenditure (EE) and respiratory quotient (RQ) in men.Design: Randomized within-subject design in which subjects stayed in a respiration chamber three times for 60u2005h each, once at 22°C, and twice at 16°C, wearing standardized clothing, executing a standardized daily activities protocol, and were fed in energy balance (EBI): no significant difference between EE and EI over 24u2005h). During the last 24u2005h at 22°C, and once during the last 24u2005h at 16°C, they were fed ad libitum.Subjects: Nine dietary unrestrained male subjects (ages 24±5u2005y, body mass index (BMI) 22.7±2.1u2005kg/m2, body weight 76.2±9.4u2005kg, height 1.83±0.06u2005m, 18±5% body fat).Results: At 16°C (EB), EE (total 24u2005h EE) was increased to 12.9±2.0u2005MJ/day as compared to 12.2±2.2u2005MJ/day at 22°C (P<0.01). The increase was due to increases in sleeping metabolic rate (SMR; the lowest EE during three consecutive hours with hardly any movements as indicated by radar): 7.6±0.7 vs 7.2±0.7u2005MJ/day (P<0.05) and diet-induced thermogenesis (DIT; EE-SMR, when activity induced energy expenditure as indicated by radar=0): 1.7±0.4 vs 1.0±0.4u2005MJ/day (P<0.01). Physical activity level (PAL; EE/SMR) was 1.63–1.68. At 16°C compared to at 22°C, rectal, proximal and distal skin temperatures had decreased (P<0.01). RQ was not different between the two ambient temperature situations. During ad libitum feeding, subjects overate by 32±12% (at 22°C) and by 34±14% (at 16°C). Under these circumstances, the decrease of rectal temperature at 16°C was attenuated, and inversely related to percentage overeating (r 2=0.7; P<0.01).Conclusion: We conclude that at 16°C, compared to 22°C, energy metabolism was increased, due to increases in SMR and DIT. Overeating under ad libitum circumstances at 16°C attenuated the decrease in rectal core body temperature.

Imaging cold-activated brown adipose tissue using dynamic T2*-weighted magnetic resonance imaging and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography.

ObjectivesThe objective of this study was to explore the use of magnetic resonance imaging (MRI) to identify and quantify active brown adipose tissue (BAT) in adult humans. 2-Deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography was used as a reference method to identify active BAT depots and to guide the MRI data analysis. Materials and MethodsThe ethics committee of the institute approved the protocol, and all participants provided written informed consent before participation. Both PET combined with computed tomography and MRI of BAT were performed in 11 healthy volunteers. Brown adipose tissue was activated by cooling the participants using a dedicated water-perfused suit. For the MRI examination of BAT, water-fat imaging and dynamic T2* imaging were performed at an effective temporal resolution of 2 minutes per volume. Water-fat images were derived from a multiecho MRI sequence using the Dixon technique. Results2-Deoxy-2-[18F]fluoro-D-glucose–PET identified active BAT in 8 of the 11 participants. Water-fat MRI showed that BAT depots had a fat fraction of 65.2% (7.0%) compared with 81.5% (5.4%) for the subcutaneous white adipose tissue (paired difference of 16.3% [4.9%]; P < 0.05). Dynamic T2* imaging during cold stimulation revealed signal fluctuations that were sensitive to BAT activation. The presence of these components correlated with BAT activation quantified from FDG-PET (r = 0.63; P < 0.05). ConclusionsAlthough FDG-PET has superior contrast for identifying active BAT, the MRI temporal resolution provides insight in activation dynamics. In addition, the flexibility of MRI allows for simultaneous mapping of tissue fat content and functional responses. The results indicate that MRI is a promising addition to PET for the identification of BAT and its activity responses to stimulation. An MRI-based methodology to quantify BAT activity is a highly desirable step in addressing the role of BAT in obesity disorders.

Skeletal muscle mitochondrial uncoupling, adaptive thermogenesis and energy expenditure

Purpose of reviewThe prevalence of obesity is still increasing, despite obesity treatment strategies that aim at reducing energy intake. In addition to this, exercise programmes designed to increase energy expenditure have only a low efficiency and have generated mixed results. Therefore, strategies based on increasing energy expenditure via nonexercise means are currently under investigation. One novel strategy is the modulation of adaptive thermogenesis. Recent findingsAmong others, adaptive thermogenesis can be modulated by changing dietary composition, treatment with hormone mimetics as well as by cold exposure. In humans, a large part of the adaptive thermogenic response is, in addition to a putative role of brown adipose tissue, determined by the skeletal muscle mass via the process of mitochondrial uncoupling. Here, we describe the molecular processes involved in mitochondrial uncoupling, state-of-the-art techniques to measure mitochondrial uncoupling in vitro and in vivo, as well as the current strategies to mitochondrial uncoupling. SummaryData generated in rodents and humans implicate that increasing adaptive thermogenesis by increasing skeletal muscle mitochondrial uncoupling indeed elevates total energy expenditure and thus may provide a promising target for the treatment of obesity.

Energy balance in a respiration chamber: individual adjustment of energy intake to energy expenditure.

OBJECTIVES: In studies on substrate utilization, a state of energy balance is often required. Energy requirements are based on measured or calculated sleeping metabolic rate (SMR) or basal metabolic rate (BMR). A study was performed to compare this protocol with adjustment of energy intake (EI) to 24u2005h energy expenditure (24u2005hu2005EE). DESIGN: In part one, eight subjects spent one night and the subsequent three days in a respiration chamber. On day 1 EI was set at 1.5*SMR. On day 2 and 3 EI was set at 24u2005hu2005EE of day 1. In part two of the study, an activity protocol was provided while staying in the chamber. 12 subjects spent one night and the subsequent two days in the respiration chamber. On day 1 EI was set at 1.55*SMR and on day 2 EI was set at 24u2005hu2005EE of day 1. MEASUREMENTS: Sleeping metabolic rate, diet induced thermogenesis, physical activity index and 24u2005h expenditure were measured using a respiration chamber. SUBJECTS: Eight healthy normal-weight females (age: 22±3, BMI: 20.9±1.8) in part one and twelve healthy normal-weight males and females (age: 26±2, BMI: 21.4±0.5) in part two of the study. RESULTS: Physical activity index (PAI=24u2005hu2005EE/SMR) on day 1 (part 1) was 1.55±0.04, close to the predicted value of 1.5, but between-subject variation was large (range: 1.39–1.68). Absolute deviation from energy balance reduced significantly from 1.35±0.30u2005MJ/d on day 1 to 0.51±0.21 and 0.31±0.10u2005MJ/d on day 2 and 3 respectively (P<0.05). The latter can be considered as near to energy balance. With the activity protocol (part 2) absolute deviation from energy balance reduced significantly from 0.93±0.20u2005MJ/d on day 1 to 0.27±0.11u2005MJ/d on day 2 (P<0.05). CONCLUSION: A three day stay in the chamber allows adjustment of energy intake to energy expenditure, in this way achieving a state close to energy balance. When prescribing an activity protocol the same results can be obtained within two days.