Physiology and relevance of human adaptive thermogenesis response

ArticleinTrends in Endocrinology and Metabolism 26(5) · April 2015with 47 Reads
Abstract
In homoeothermic organisms, the preservation of core temperature represents a primal function, and its costs in terms of energy expenditure can be considerable. In modern humans, the endogenous thermoregulation mechanisms have been replaced by clothing and environmental control, and the maintenance of thermoneutrality has been successfully achieved by manipulation of the micro- and macroenvironment. The rediscovery of the presence and activity of brown adipose tissue in adult humans has renewed the interest on adaptive thermogenesis (AT) as a means to facilitate weight loss and improve carbohydrate metabolism. The aim of this review is to describe the recent advancements in the study of this function, and to assess the potential and limitations of exploiting AT for environmental/behavioral, and pharmacological interventions. Copyright © 2015. Published by Elsevier Ltd.
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    Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.
  • Article
    To evaluate the efficacy and safety of the β3 -adrenoceptor agonist, mirabegron, in a Japanese population with overactive bladder (OAB). This randomized, double-blind, placebo-controlled Phase III study enrolled adult patients experiencing OAB symptoms for ≥24 weeks. Patients with ≥8 micturitions/24 h and ≥1 urgency episode/24 h or ≥1 urgency incontinence episode/24 h were randomized to once-daily placebo, mirabegron 50 mg, or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks. Primary endpoint was change from baseline to final assessment in mean number of micturitions/24 h. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality of life (QOL) domain scores on the King's Health Questionnaire (KHQ). Safety assessments included adverse events (AEs), post-void residual volume, laboratory parameters, vital signs, and 12-lead electrocardiogram (ECG). Registered at clinical trials.gov (NCT00966004). A total of 1139 patients were randomized to receive placebo (n = 381), mirabegron 50 mg (n = 380), or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar across groups. At final assessment, mirabegron showed significant improvements vs placebo in mean [SD] change from baseline in number of micturitions/24 h (-1.67 [2.212] vs -0.86 [2.354]; P < 0.001) and in the secondary endpoints: number of urgency episodes/24 h (-1.85 [2.555] vs -1.37 [3.191]; P = 0.025), incontinence episodes/24 h (-1.12 [1.475] vs -0.66 [1.861]; P = 0.003), urgency incontinence episodes/24 h (-1.01 [1.338] vs -0.60 [1.745]; P = 0.008), volume voided/micturition (24.300 [35.4767] mL vs 9.715 [29.0864] mL; P < 0.001). The incidence of AEs in the mirabegron group was similar to placebo; most AEs were mild and none were severe. Mirabegron 50 mg once-daily is an effective treatment for OAB symptoms, with a low occurrence of side effects, in a Japanese population.
  • Article
    Full-text available
    Context: Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence of its thermogenic potential and role in clearing circulating glucose and fatty acids under acute mild cold exposure. In contrast, early indications suggest that BAT metabolism is defective in obesity and type 2 diabetes, which may have important pathological and therapeutic implications. Although many mammalian models have demonstrated the phenotypic flexibility of this tissue through chronic cold exposure, little is known about the metabolic plasticity of BAT in humans. Objective: Our objective was to determine whether 4 weeks of daily cold exposure could increase both the volume of metabolically active BAT and its oxidative capacity. Design: Six nonacclimated men were exposed to 10°C for 2 hours daily for 4 weeks (5 d/wk), using a liquid-conditioned suit. Using electromyography combined with positron emission tomography with [(11)C]acetate and [(18)F]fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism, glucose uptake, and volume before and after 4 weeks of cold acclimation were examined under controlled acute cold-exposure conditions. Results: The 4-week acclimation protocol elicited a 45% increase in BAT volume of activity (from 66 ± 30 to 95 ± 28 mL, P < .05) and a 2.2-fold increase in cold-induced total BAT oxidative metabolism (from 0.725 ± 0.300 to 1.591 ± 0.326 mL·s(-1), P < .05). Shivering intensity was not significantly different before compared with after acclimation (2.1% ± 0.7% vs 2.0% ± 0.5% maximal voluntary contraction, respectively). Fractional glucose uptake in BAT increased after acclimation (from 0.035 ± 0.014 to 0.048 ± 0.012 min(-1)), and net glucose uptake also trended toward an increase (from 163 ± 60 to 209 ± 50 nmol·g(-1)·min(-1)). Conclusions: These findings demonstrate that daily cold exposure not only increases the volume of metabolically active BAT but also increases its oxidative capacity and thus its contribution to cold-induced thermogenesis.
  • Article
    Full-text available
    Previous studies have shown active brown adipose tissue is present in adults and may play important roles in regulating energy homeostasis. However, nearly every study was done with patients undergoing scanning for cancer surveillance whose metabolism and BAT activity may not reflect that seen in healthy individuals. The objective of this study was to investigate the prevalence and predictors of active BAT in Chinese adults, particularly in healthy individuals. In this study, a total of 31,088 consecutive subjects with age≥18 years old performed PET/CT scans in the site. We measured BAT activity via 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography in these subjects who underwent scanning for either routine medical check-up (MC) or cancer surveillance (CS) in Shanghai. Then we investigated the predictors of active BAT, particularly in healthy individuals. In both groups, the prevalence of BAT was higher in women than men. Using a multivariate logistic analysis, we found in the MC group, age, sex, BMI, and thyroid high glucose uptake were significant predictors of BAT activity. Similarly, in the CS group, age, sex, and BMI were significant predictors of BAT activity, but not thyroid high glucose uptake. In Chinese adults, BAT activity correlates inversely with BMI and thyroid high glucose uptake, which reinforces the central role of brown fat in adult metabolism and clues to a potential means for treating metabolic syndrome.
  • Article
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    The recent advancements in unraveling novel mechanisms that control the induction, (trans)differentiation, proliferation, and thermogenic activity and capacity of brown adipose tissue (BAT), together with the application of imaging techniques for human BAT visualization, have generated optimism that these advances will provide novel strategies for targeting BAT thermogenesis, leading to efficacious and safe obesity therapies. This paper first provides an overview of landmark events of the past few decades that have been driving the search for pharmaceutical and nutraceutical compounds that would increase BAT thermogenesis for obesity management. It then addresses issues about what could be expected from an ideal thermogenic antiobesity approach, in particular to what extent daily energy expenditure will need to increase in order to achieve long-term weight loss currently achievable only through bariatric surgery, and whether the human body will have enough thermogenic capacity to reach this target weight loss by future therapies focused on BAT.
  • Article
    Cold exposure activates brown adipose tissue (BAT), the major site of sympathetically activated nonshivering thermognenesis, via transient receptor potential (TRP) channels. Capsaicin and its nonpungent analogue (capsinoids) are agonists for a vanilloid subtype one of TRP, and have the potential to increase whole-body energy expenditure and reduce body fat. This article reviews the regulatory roles of BAT for energy expenditure and body fat in humans, particularly focusing on food ingredients activating the TRP-BAT axis. Acute cold exposure increased energy expenditure in humans with metabolically active BAT, but not those without it. Quite similar responses were found after a single oral ingestion of either capsinoids or an alcohol extract of Guinea pepper seeds, indicating that these food ingredients activate BAT and thereby increase energy expenditure. When individuals without active BAT were exposed to cold every day for 6 weeks, BAT was recruited in association with increased energy expenditure and decreased body fat. A 6-week daily ingestion of capsinoids mimicked the effects of repeated cold exposure. These findings indicate that human BAT can be reactivated/recruited, thereby increasing energy expenditure and decreasing body fat. Human BAT recruited by prolonged ingestion of a vanilloid subtype one of TRP agonists increases energy expenditure and decreases body fat. In addition to capsinoids, there are numerous food ingredients acting as TRP agonists, which are expected to activate BAT and so be useful for the prevention of obesity in daily life.
  • Article
    In terms of total number of publications, the laboratory mouse (Mus musculus) has emerged as the most popular test subject in biomedical research. Mice are used as models to study obesity, diabetes, CNS diseases and variety of other pathologies. Mice are classified as homeotherms and regulate their core temperature over a relatively wide range of ambient temperatures. However, researchers find that the thermoregulatory system of mice is easily affected by drugs, chemicals, and a variety of pathological conditions, effects that can be exacerbated by changes in ambient temperature. To this end, a thorough review of the thermal physiology of mice, including their sensitivity and regulatory limits to changes in ambient temperature is the primary focus of this review. Specifically, the zone of thermoneutrality for metabolic rate and how it corresponds to that for growth, reproduction, development, thermal comfort, and many other variables is covered. A key point of the review is to show that behavioral thermoregulation of mice is geared to minimize energy expenditure. Their zone of thermal comfort is essentially wedged between the thresholds to increase heat production and heat loss; however, this zone is above the recommended guidelines for animal vivariums. Future work is needed to better understand the behavioral and autonomic thermoregulatory responses of this most popular test species.
  • Article
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    In recent years, it has been shown that humans have active brown adipose tissue (BAT) depots, raising the question of whether activation and recruitment of BAT can be a target to counterbalance the current obesity pandemic. Here, we show that a 10-day cold acclimation protocol in humans increases BAT activity in parallel with an increase in nonshivering thermogenesis (NST). No sex differences in BAT presence and activity were found either before or after cold acclimation. Respiration measurements in permeabilized fibers and isolated mitochondria revealed no significant contribution of skeletal muscle mitochondrial uncoupling to the increased NST. Based on cell-specific markers and on uncoupling protein-1 (characteristic of both BAT and beige/brite cells), this study did not show "browning" of abdominal subcutaneous white adipose tissue upon cold acclimation. The observed physiological acclimation is in line with the subjective changes in temperature sensation; upon cold acclimation, the subjects judged the environment warmer, felt more comfortable in the cold, and reported less shivering. The combined results suggest that a variable indoor environment with frequent cold exposures might be an acceptable and economic manner to increase energy expenditure and may contribute to counteracting the current obesity epidemic.
  • Article
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    Brown adipose tissue (BAT) burns fat to produce heat when the body is exposed to cold and plays a role in energy metabolism. Using fluorodeoxyglucose-positron emission tomography and computed tomography, we previously reported that BAT decreases with age and thereby accelerates age-related accumulation of body fat in humans. Thus, the recruitment of BAT may be effective for body fat reduction. In this study, we examined the effects of repeated stimulation by cold and capsinoids (nonpungent capsaicin analogs) in healthy human subjects with low BAT activity. Acute cold exposure at 19°C for 2 hours increased energy expenditure (EE). Cold-induced increments of EE (CIT) strongly correlated with BAT activity independently of age and fat-free mass. Daily 2-hour cold exposure at 17°C for 6 weeks resulted in a parallel increase in BAT activity and CIT and a concomitant decrease in body fat mass. Changes in BAT activity and body fat mass were negatively correlated. Similarly, daily ingestion of capsinoids for 6 weeks increased CIT. These results demonstrate that human BAT can be recruited even in individuals with decreased BAT activity, thereby contributing to body fat reduction.
  • Article
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    Because visceral obesity predicts insulin resistance, we studied whether alterations in the gene encoding for the beta 3-adrenergic receptor in visceral fat are associated with insulin resistance. We studied the frequency of a cytosine-to-thymidine mutation that results in the replacement of tryptophan by arginine at position 64 (Trp64Arg) of the beta 3-adrenergic receptor by restriction-enzyme digestion with BstOl in 335 subjects from western Finland, 207 of whom were nondiabetic and 128 of whom had non-insulin-dependent diabetes mellitus (NIDDM). We also determined the frequency of the mutation in 156 subjects from southern Finland. Sensitivity to insulin was measured by the hyperinsulinemic-euglycemic clamp technique in 66 randomly selected nondiabetic subjects. In the subjects from western Finland, the frequency of the mutated allele was similar in the nondiabetic subjects and the subjects with NIDDM (12 vs. 11 percent). The mean age of the subjects at the onset of diabetes was lower among those with the mutation than those without it (56 vs. 61 years, P = 0.04). Among the nondiabetic subjects, those with the mutation had a higher ratio of waist to hip circumference (P = 0.02), a greater increase in the serum insulin response after the oral administration of glucose (P = 0.05), a higher diastolic blood pressure (82 vs. 78 mm Hg, P = 0.01), and a lower rate of glucose disposal during the clamp study (5.3 vs. 6.5 mg [29 vs. 36 mumol] per kilogram of body weight per minute; P = 0.04) than the subjects without the mutated allele. In an analysis of sibling pairs, the siblings with the mutation generally had higher waist:hip ratios (P = 0.05) and higher responses of blood glucose and serum insulin after the oral administration of glucose than their siblings without the mutation (P = 0.02 and P = 0.005, respectively). The Trp64Arg allele of the beta 3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM:
  • Article
    The beta 3-adrenergic receptor, located mainly in adipose tissue, is involved in the regulation of lipolysis and thermogenesis. The potential relevance of this receptor to obesity in humans led us to screen obese French patients for a recently identified mutation in the gene for the receptor. We used the polymerase chain reaction to amplify a region of the gene for the beta 3-adrenergic receptor encoding amino acid residues 27 to 110 in genomic DNA extracted from leukocytes from 185 patients with morbid obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], > 40) and 94 normal subjects. A mutation resulting in the replacement of tryptophan by arginine at position 64 (Trp64Arg) was detected by an analysis of restriction-fragment-length polymorphisms with the use of the endonuclease BstNl, which discriminates between the normal and mutant sequences. The frequency of the Trp64Arg allele was similar in the morbidly obese patients and the normal subjects (0.08 and 0.10, respectively). However, the patients with morbid obesity who were heterozygous for the Trp64Arg mutation had an increased capacity to gain weight; the mean weight in the 14 heterozygous patients was 140 kg, as compared with 126 kg in the 171 patients without the mutation (P = 0.03). There were no homozygotes in this sample. The cumulative 25-year change in weight (from the age of 20 years) was 67 kg in the Trp64Arg heterozygotes, as compared with 51 kg in those without the mutation. The maximal weight differential (the maximal lifetime weight minus the weight at 20 years of age) in the Trp64Arg heterozygotes was 74 kg, as compared with 59 kg in the patients without the mutation (P = 0.02). People with the Trp64Arg mutation of the gene for the beta 3-adrenergic receptor may have an increased capacity to gain weight.
  • Article
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    Classic brown fat and inducible beige fat both dissipate chemical energy in the form of heat through the actions of mitochondrial uncoupling protein 1. This nonshivering thermogenesis is crucial for mammals as a defense against cold and obesity/diabetes. Cold is known to act indirectly through the sympathetic nervous systems and β-adrenergic signaling, but here we report that cool temperature (27-33 °C) can directly activate a thermogenic gene program in adipocytes in a cell-autonomous manner. White and beige fat cells respond to cool temperatures, but classic brown fat cells do not. Importantly, this activation in isolated cells is independent of the canonical cAMP/Protein Kinase A/cAMP response element-binding protein pathway downstream of the β-adrenergic receptors. These findings provide an unusual insight into the role of adipose tissues in thermoregulation, as well as an alternative way to target nonshivering thermogenesis for treatment of obesity and metabolic diseases.
  • Article
    Full-text available
    Context: The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations of both BAT activity and energy expenditure (EE). Objective: The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT). Design: This study was a single-blind, randomized crossover intervention. Setting: The study was conducted at the National Institutes of Health Clinical Center. Study participants: Thirty-one healthy volunteers participated in the study. Interventions: The intervention included mild cold exposure. Main outcomes: CIT and BAT activation were the main outcomes in this study. Methods: Overnight EE measurement by whole-room indirect calorimeter at 24 °C or 19 °C was followed by 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures. Results: Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24 °C, exposure at 19 °C resulted in increased EE (5.3 ± 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 ± 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT. Conclusions: A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment.
  • Article
    Objective: To assess the efficacy and tolerability of mirabegron 25 mg and 50 mg once-daily vs placebo in patients with overactive bladder (OAB). Materials and methods: Patients ≥18 years with OAB symptoms were recruited to a 2-week, single-blind, placebo run-in. Those with ≥8 micturitions per 24 hours and ≥3 urgency episodes were randomized 1:1:1 to once-daily mirabegron 25 mg or 50 mg, or placebo for 12 weeks. Primary endpoints were changes to final visit in mean number of incontinence episodes and micturitions per 24 hours. Key secondary endpoints were changes to final visit in mean volume voided or micturition, change to week 4 in mean number of incontinence episodes and micturitions per 24 hours, changes to final visit in mean level of urgency, number of urgency incontinence episodes, and urgency (grade 3 or 4) episodes per 24 hours. Patient-reported outcomes were assessed using the OAB-questionnaire, Patient Perception of Bladder Condition, and Treatment-Satisfaction-Visual Analog Scale. Results: Both mirabegron groups demonstrated statistically significant improvements in coprimary endpoints vs placebo. Mirabegron 50 mg demonstrated significantly greater improvements vs placebo in the following: change to final visit in mean volume voided per micturition and change to week 4 in mean number of incontinence episodes per 24 hours. Statistically significant improvements vs placebo were demonstrated by mirabegron 50 mg in all patient-reported outcome scales with no increase in the incidence of treatment-emergent adverse events vs placebo. Conclusion: Mirabegron 25 mg and 50 mg were associated with significant improvements in efficacy measures of incontinence episodes and micturition frequency. Mirabegron was well tolerated vs placebo.
  • Article
    Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of β3-adrenergic receptor (AR) agonists stimulates rodent BAT, but this activity has never been demonstrated in humans. Here we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a β3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via (18)F-fluorodeoxyglucose ((18)F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 ± 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a β3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease. Copyright © 2015 Elsevier Inc. All rights reserved.
  • Article
    It has been shown in rodents and newborn babies that brown adipose tissue (BAT) plays an important role in the generation of heat for maintenance of core body temperature. BAT is responsible for the process of adaptive thermogenesis, which involves heat generation in response to a drop in the environment's temperature or to high energy intake from diet. In rodents, the process of BAT thermogenesis is controlled by activation of the β3-adrenergic receptor (β3-AR), which has a protective effect against obesity development. In the past, it was generally thought that, in humans, BAT dissipated after childhood and adopted an insignificant role in human physiology. However, over the past few years it has been discovered that adult humans still possess fully functional BAT. Through imaging with F-FDG PET-CT scans, it has been determined that not only does human BAT exist, but it is still responsive to stimuli, such as a drop in the environment's temperature. Although some evidence exists for β3-AR control of BAT thermogenesis in humans, this fact remains unclear due to a lack of highly selective β3-AR agonists and antagonists which have an effect on the human body. With further investigation on thermogenesis receptor control and BAT metabolism's effect on whole body energy expenditure, BAT may serve as a potential target for the treatment and prevention of obesity and other metabolic conditions in humans.
  • Article
    Full-text available
    The (18)F-fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), is enhanced by cold stimulus and modulated by other factors that still have to be disentangled. We investigated the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in a population of adults living in the temperate climatic zone of the Rome area. We retrospectively analyzed 6454 patients who underwent (18)F-FDG positron emission tomography/computed tomography (PET/CT) examinations. We found (18)F-FDG BAT in 217 of the 6454 patients (3.36%). Some of them underwent more than one scan and the positive scans were 278 among 8004 (3.47%). The prevalence of patients with at least one positive scan was lower in men (1.77%; 56 of 3161) compared with women (4.88%; 161 of 3293). The BAT positive patients were most frequently younger, thinner and with lower plasma glucose levels compared with BAT negative patients. The amount of BAT in the defined region of interest, the activity of BAT and the number of positive sites of active BAT were similar in both sexes. The prevalence of patients with (18)F-FDG positive PET/CT was highest in December-February, lower in March-May and September-November, and lowest in June-August and was positively correlated with night length and negatively correlated with ambient temperature. Changes in day length and variations of temperature, associated with the prevalence of positive BAT patients. Among the patients who had multiple scans, outdoor temperature was significantly lower and day length was shorter on the occasion when BAT was detected. This study identifies day length, outdoor temperature, age, sex, BMI, and plasma glucose levels as major determinants of the prevalence, mass, and activity of (18)F-FDG-detected BAT.
  • Article
    In rodents, brown adipose tissue (BAT) is a metabolic organ that produces heat in response to cold and dietary intake through mitochondrial uncoupling. For long time, BAT was considered to be solely important in small mammals and infants, however recent studies have shown that BAT is also functional in adult humans. Interestingly, the presence and/or functionality of this thermogenic tissue is diminished in obese people, suggesting a link between human BAT and body weight regulation. In the last years, evidence has also emerged for the existence of adipocytes that may have an intermediate thermogenic phenotype between white and brown adipocytes, so called brite or beige adipocytes. Together, these findings have resulted in a renewed interested in (human) brown adipose tissue and pathways to increase the activity and recruitment of these thermogenic cells. Stimulating BAT hypertrophy and hyperplasia in humans could be a potential strategy to target obesity. Here we will review suggested pathways leading to BAT activation in humans, and discuss novel putative BAT activators in rodents into human perspective.
  • Article
    Full-text available
    The imbalance between energy intake and expenditure is the underlying cause of the current obesity and diabetes pandemics. Central to these pathologies is the fat depot: white adipose tissue (WAT) stores excess calories, and brown adipose tissue (BAT) consumes fuel for thermogenesis using tissue-specific uncoupling protein 1 (UCP1). BAT was once thought to have a functional role in rodents and human infants only, but it has been recently shown that in response to mild cold exposure, adult human BAT consumes more glucose per gram than any other tissue. In addition to this nonshivering thermogenesis, human BAT may also combat weight gain by becoming more active in the setting of increased whole-body energy intake. This phenomenon of BAT-mediated diet-induced thermogenesis has been observed in rodents and suggests that activation of human BAT could be used as a safe treatment for obesity and metabolic dysregulation. In this study, we isolated anatomically defined neck fat from adult human volunteers and compared its gene expression, differentiation capacity and basal oxygen consumption to different mouse adipose depots. Although the properties of human neck fat vary substantially between individuals, some human samples share many similarities with classical, also called constitutive, rodent BAT.
  • Article
    Objective: Inactive brown adipose tissue (BAT) may predispose to weight gain. This study was designed to measure metabolism in the BAT of obese humans, and to compare it to that in lean subjects. The impact of weight loss on BAT and the association of detectable BAT with various metabolic characteristics were also assessed. Design and methods: Using positron emission tomography (PET), cold- and insulin-stimulated glucose uptake and blood flow in the BAT of obese and lean humans were quantified. Further, cold-induced glucose uptake was measured in obese subjects before and after a 5-month conventional weight loss. Results: Mean responses in BAT glucose uptake rate to both cold and insulin stimulation were twice as large in lean as in obese subjects. Blood flow in BAT was also lower in obese subjects under cold conditions. The increase in cold-induced BAT glucose uptake rate after weight loss was not statistically significant. Subjects with cold-activated detectable BAT were leaner and had higher whole-body insulin sensitivity than BAT-negative subjects, irrespective of age and gender. Conclusions: The effects of cold and insulin on BAT activity are severely blunted in obesity, and the presence of detectable BAT may contribute to a metabolically healthy status.
  • Article
    Full-text available
    The measurement of energy expenditure (EE) is recommended as an important component of comprehensive clinical nutrition assessments in patients with altered metabolic states, who failed to respond to nutrition support and with critical illness that require individualized nutrition support. There is evidence that EE is variable in patients with metabolic diseases, such as chronic renal disease, cirrhosis, HIV, cancer cachexia, cystic fibrosis and patients under intensive care. By using appropriate techniques and interpretations of basal or resting EE, clinicians can facilitate the adequate nutrition support with minimum negative impacts from under- or overfeeding in these patients. This review is based on our current understanding of the different components of EE and the techniques to measure them, and to re-examine advances and challenges to determine energy needs in clinical populations with more focuses on the obese, pediatric and elderly patients. In addition, technological advances have expanded the choices of market-available equipments for assessing EE, which also bring specific challenges and rewards in selecting the right equipment with specific performance criteria. Lastly, analytical considerations of interpreting the results of EE in the context of changing body composition are presented and discussed.European Journal of Clinical Nutrition advance online publication, 27 February 2013; doi:10.1038/ejcn.2013.38.
  • Article
    Full-text available
    Background: Brown adipose tissue (BAT) was considered essentially nonexistent in adults until recent evidence obtained using 18-fluorodeoxyglucose (18-FDG) positron emission tomography/computed tomography. It seems to play a role in whole body metabolism, but it has not been evaluated in underweight conditions, such as in young females with constitutional leanness (CL) or anorexia nervosa (AN). Subjects and methods: Thirty-eight subjects were evaluated from October 2011 to March 2012 : 7 CL (21.7 ± 3.6 y, body mass index [BMI] 16.2 ± 1.0 kg/m(2)), 7 AN (23.4 ± 4.5 y, BMI 15.5 ± 0.8), 3 of the 7 AN after stable refeeding (R-AN, 21.3 ± 1.5 y, BMI 18.8 ± 1.1), and 24 normal weight (NW) women (25.6 ± 3.9 y, BMI 22.2 ± 1.5). Fasting resting metabolic rate and respiratory quotient were measured by indirect calorimetry, body composition by bioimpedentiometry (only in CL, AN, and refed AN), and BAT activity by 18-FDG positron emission tomography/computed tomography scan, all in standardized conditions. Results: All CL (100%), none of the AN and refed AN (0%), and 3 of the 24 NW (12%) subjects showed FDG uptake. Average FDG maximum standardized uptake value was 11.4 + 6.7 g/mL in CL and 5.5 ± 1.2 g/mL (min 3.7, max 8.3) in the 3 NW subjects. In CL, the maximum standardized uptake value was directly correlated to resting metabolic rate, corrected for fat-free mass, and inversely correlated with respiratory quotient. Conclusion: BAT activity has been shown in CL in resting thermoneutral conditions and may exert a role against adipose tissue deposition.
  • Article
    Unlabelled: Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake. Methods: Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5°C [60°F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of (18)F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical-supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE. Results: The mass of activated BAT was 59.1 ± 17.5 g (range, 32-85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 ± 5.5 y) and 2.2 ± 3.6 g (range, 0-9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 ± 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 ± 3.9 vs. 2.1 ± 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 ± 4.1 vs. 5.9 ± 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 ± 3.4 vs. 5.7 ± 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 ± 1.9 vs. 3.9 ± 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 ± 0.17 in high-BAT group vs. 0.47 ± 0.18 in low-BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 ± 0.53 to 1.42 ± 0.68 mL/100 g/min (P = 0.04) in the high-BAT group and were significantly higher than those determined in the low-BAT group (0.40 ± 0.28 vs. 0.51 ± 0.23, P = 0.67). The increase in DEE associated with BAT oxidative metabolism was highly variable in the high-BAT group, with an average of 3.2 ± 2.4 kcal/d (range, 1.9-4.6 kcal/d) at rest, and increased to 6.3 ± 3.5 kcal/d (range, 4.0-9.9 kcal/d) during exposure to mild cold. Although BAT accounted for only a small fraction of the cold-induced increase in DEE, such increases were not observed in subjects lacking BAT. Conclusion: Mild cold-induced thermogenesis in BAT accounts for 15-25 kcal/d in subjects with relatively large BAT depots. Thus, although the presence of active BAT is correlated with cold-induced energy expenditure, direct measurement of MRO2 indicates that BAT is a minor source of thermogenesis in humans.
  • Article
    Brown adipose tissue (BAT) is responsible for cold- and diet-induced thermogenesis, and thereby contributes to the control of whole-body energy expenditure (EE) and body fat content. BAT activity can be assessed by fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) in human subjects. Grains of paradise (GP, Aframomum melegueta), a species of the ginger family, contain pungent, aromatic ketones such as 6-paradol, 6-gingerol and 6-shogaol. An alcohol extract of GP seeds and 6-paradol are known to activate BAT thermogenesis in small rodents. The present study aimed to examine the effects of the GP extract on whole-body EE and to analyse its relation to BAT activity in men. A total of nineteen healthy male volunteers aged 20-32 years underwent FDG-PET after 2 h of exposure to cold at 19°C with light clothing. A total of twelve subjects showed marked FDG uptake into the adipose tissue of the supraclavicular and paraspinal regions (BAT positive). The remaining seven showed no detectable uptake (BAT negative). Within 4 weeks after the FDG-PET examination, whole-body EE was measured at 27°C before and after oral ingestion of GP extract (40 mg) in a single-blind, randomised, placebo-controlled, crossover design. The resting EE of the BAT-positive group did not differ from that of the BAT-negative group. After GP extract ingestion, the EE of the BAT-positive group increased within 2 h to a significantly greater (P< 0·01) level than that of the BAT-negative group. Placebo ingestion produced no significant change in EE. These results suggest that oral ingestion of GP extract increases whole-body EE through the activation of BAT in human subjects.
  • Article
    Background: The uptake of F-FDG in brown adipose tissue (BAT) may have important implications in understanding the pathophysiology of BAT and obesity. Because of the thermal implications of BAT uptake of F-FDG, this study aimed to contribute to existing knowledge by assessing patients scanned in a subtropical environment with particular reference to ethnicity. Patients and methods: A retrospective study was carried out to determine the prevalence and pattern of BAT uptake in patients undergoing F-FDG PET-CT imaging in a PET facility located in a subtropical climatic zone. Standardized uptake values were obtained for regions of BAT uptake of F-FDG, and the distribution pattern was assessed according to anatomical region, sex, age, BMI and ethnicity. Results: Following a reveiw of a total of 386 scans, 38 patients showed BAT uptake of F-FDG (9.85%), with the mass and activity of BAT being greater in women than in men (11.95 and 6.88%, respectively). BAT uptake of F-FDG in the neck/supraclavicular, axillary and mediastinal regions was greater in adults whose BMI was less than 18 kg/m. However, perirenal BAT activity was shown to be greater in obese individuals. The frequency of BAT uptake of F-FDG was 55% in winter as against 45% during summer (P<0.012). There was no statistical difference in BAT uptake between black and white patients. Conclusion: This study shows the pattern and prevalence of BAT in patients in a subtropical environment. Although the average seasonal temperatures are higher in a subtropical climate, a seasonal variation in BAT expression was observed, although there were no differences with respect to patient ethnicity.
  • Article
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    Context: Cold exposure stimulates fibroblast growth factor 21 (FGF21) secretion in animals, enhancing the cold-induced thermogenesis (CIT) response through browning of white adipose tissue. In humans, the effects of cold exposure on circulating FGF21 levels are unknown. Objective: Our objective was to evaluate the effects of mild cold exposure on circulating FGF21 and its relationship with CIT and lipolysis in humans. Design and setting: We conducted a randomized, single-blind, crossover intervention study at the National Institutes of Health Clinical Center. Participants: Participants were healthy adults. Intervention: Subjects were exposed to a 12-h exposure to 24 or 19 C in a whole-room indirect calorimeter. Outcome measures: Energy expenditure, plasma FGF 21, nonesterified fatty acid, and adipose tissue microdialysis glycerol concentrations were evaluated. Results: At 24 C, plasma FGF21 exhibited a diurnal rhythm, peaking at 0800 h [110 (59-178) pg/ml], and progressively dropped to a nadir at 1700 h [41 (21-71) pg/ml, P < 0.0001] before rising at 1900 h [60 (11-81) pg/ml, P < 0.0001]. Exposure at 19 C lessened the diurnal reduction of FGF21 observed at 24 C from 0800-1700 h and augmented overall FGF21 levels by 37 ± 45% (P = 0.01). The change in area under the curve plasma FGF21 between 19 and 24 C correlated positively with the change in area under the curve adipose microdialysate glycerol (R(2) = 0.35, P = 0.04) but not with nonesterified fatty acid. Cold-induced increase in FGF21 predicted greater rise in energy expenditure during cold exposure (β = 0.66, P = 0.027), independent of age, gender, fat mass, and lean mass. Conclusions: Mild cold exposure increased circulating FGF21 levels, predicting greater lipolysis and CIT. A small reduction in environmental temperature is sufficient to modulate FGF21 diurnal rhythm in humans, which may mediate cold-induced metabolic changes similar to those in animals.
  • Article
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    Aims/hypothesis: Brown adipose tissue (BAT) activation increases energy consumption and may help in the treatment of obesity. Cold exposure is the main physiological stimulus for BAT thermogenesis and the sympathetic nervous system, which innervates BAT, is essential in this process. However, cold-induced BAT activation is impaired in obese humans. To explore the therapeutic potential of BAT, it is essential to determine whether pharmacological agents can activate BAT. Methods: We aimed to determine whether BAT can be activated in lean and obese humans after acute administration of an orally bioavailable sympathomimetic. In a randomised, double-blinded, crossover trial, we administered 2.5 mg/kg of oral ephedrine to nine lean (BMI 22 ± 1 kg/m²) and nine obese (BMI 36 ± 1 kg/m²) young men. On a separate day, a placebo was administered to the same participants. BAT activity was assessed by measuring glucose uptake with [¹⁸F]fluorodeoxyglucose and positron emission tomography-computed tomography imaging. Results: BAT activity was increased by ephedrine compared with placebo in the lean, but unchanged in the obese, participants. The change in BAT activity after ephedrine compared with placebo was negatively correlated with various indices of body fatness. Conclusions/interpretation: BAT can be activated via acute, oral administration of the sympathomimetic ephedrine in lean, but not in obese humans.
  • Article
    The role of brown adipose tissue (BAT) in adult metabolism is poorly understood. This study aimed to examine the differential effects of an overnight fast and the postprandial state on BAT activity. We included 10 healthy, lean male volunteers. BAT uptake of glucose was visualized using (18)F-FDG PET/CT during mild cold exposure. Each subject underwent PET/CT twice. The first scan was obtained after an overnight fast; the second after a standardized meal. (18)F-FDG uptake in BAT was observed in 6 of 10 volunteers. These subjects were found to have a higher maximal standardized uptake value when fasting (median, 13.1 g/mL; range, 6.1-27.6 g/mL) than when in the postprandial state (median, 6.8 g/mL; range, 2.1-13.4 g/mL) (P = 0.03). Cold-stimulated (18)F-FDG uptake by BAT in humans is more pronounced during fasting. The lower maximal standardized uptake value in the postprandial state may be explained by increased insulin-stimulated glucose uptake in muscle.
  • Article
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    When mice were living in groups they developed less brown adipose tissue (BAT) during cold adaptation as compared with single mice. This effect of social aggregation was more pronounced in genetically hairless mice than in furred mice. In both races of mice the most significant difference in BAT growth was found between single mice and pairs of mice, indicating that the formation of pairs causes the relatively most effective improvement of thermal balance.
  • Article
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    Purpose: The object of this study was to evaluate the prevalence and characteristics of brown adipose tissue (BAT) in Korean subjects using (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET). Methods: Six thousand and five consecutive (18)F-FDG PET/CT scans of 5,115 patients (3,007 females and 2,108 males, mean age 53.5 years) were retrospectively reviewed. We characterized the nature of BAT, such as its location, and we assessed the influence of sex, age, body mass index (BMI), and temperature on BAT. Results: The prevalence of BAT in Koreans in a single (18)F-FDG PET/CT scan in average conditions was 1.07%. The BAT detection rate was higher in females than males (1.32% vs 0.73%), and also with younger age (7.94% vs 0.73%), lower BMI (BMI with BAT, 21.1 vs BMI without BAT, 23.15) and cold outdoor temperature (1.65% vs 0.49%). The most frequent location of BAT was the supraclavicular area (left, 0.91%; right, 0.88%) and ventral neck area (left, 0.62%; right, 0.63%). Conclusions: The characteristics of BAT in Koreans are not different from those described for Caucasians. However, the low prevalence of BAT in our study might be related to some scan condition like ambient temperature, but further study is needed.
  • Article
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    As potential activators of brown adipose tissue (BAT), mild cold exposure and sympathomimetic drugs have been considered as treatments for obesity and diabetes, but whether they activate the same pathways is unknown. In 10 healthy human volunteers, we found that the sympathomimetic ephedrine raised blood pressure, heart rate, and energy expenditure, and increased multiple circulating metabolites, including glucose, insulin, and thyroid hormones. Cold exposure also increased blood pressure and energy expenditure, but decreased heart rate and had little effect on metabolites. Importantly, cold increased BAT activity as measured by (18)F-fluorodeoxyglucose PET-CT in every volunteer, whereas ephedrine failed to stimulate BAT. Thus, at doses leading to broad activation of the sympathetic nervous system, ephedrine does not stimulate BAT in humans. In contrast, mild cold exposure stimulates BAT energy expenditure with fewer other systemic effects, suggesting that cold activates specific sympathetic pathways. Agents that mimic cold activation of BAT could provide a promising approach to treating obesity while minimizing systemic effects.
  • Article
    To assess the prevalence of brown fat in patients with cancer, compare demographic characteristics of those with and those without brown fat, and correlate these characteristics with the mean and maximum standardized uptake values of brown fat. This case-control study was institutional review board approved and HIPAA compliant. Informed consent was waived. Reports of 12 195 consecutive positron emission tomography/computed tomography examinations performed in 6867 patients between January 2004 and November 2008 were reviewed for documented fluorodeoxyglucose (FDG) uptake in brown fat (n = 298). Control patients (n = 298) without brown fat were chosen and matched for age, sex, and month and year of examination. Age, sex, weight, body mass index, ethnicity, and examination stage (initial vs restaging) were compared between groups. Paired Student t test, χ(2) test, Pearson correlation coefficient, and analysis of variance were used for statistical analysis. Uptake of FDG in brown fat was demonstrated in 298 of 6867 (4.33%) patients. Prevalence of brown fat was significantly higher in female (5.9% [211 of 3587]) than in male patients (2.65% [87 of 3280]; P < .001). Those with brown fat had significantly lower body weight (147.5 lb ± 3.8 vs 168.61 lb ± 5.0; P < .001) and body mass index (24.3 ± 0.54 vs 27.6 ± 0.77; P < .001) than control patients. There was no significant difference in the prevalence of brown fat among ethnic groups. The maximum standardized uptake value of brown fat had a significant inverse correlation with age (r = -0.3, P < .001). Patients with brown fat were more likely to be female and thinner than those without brown fat. Younger patients were more likely to have higher maximum standardized uptake values of brown fat.
  • Article
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    Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.
  • Article
    1.1. Infrared scans were taken of 29 mammal species ranging from 20 g white-footed mouse to 4000 kg African elephant and percent of surface area available for heat exchange determined.2.2. An index of vasomotion (VMI) which reflects the animal's dependency upon and ability to control surface temperature was created by combining metabolic output, thermal limits, and effective surface area (ESA).3.3. VMI scales positively with body weight by the equation VMI = 0.27717 + 0.27929 log(wt) suggesting the ability to control surface temperature becomes increasingly more important as surface area to volume ratio decreases.4.4. A value for functional conductance was calculated using part of the same VMI equation. Values ranged from 1.453 to 6.15 W/m2/C with no apparent correlation to weight.5.5. Functional conductance considers only those surfaces which are available for regulation of heat exchange and is essentially the same for all animals studied, indicating heat is conducted from bare skin at the same rate in all animals.6.6. It is the ability to change the ESA which causes the VMI to scale by weight.
  • Article
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    Capsinoids-nonpungent capsaicin analogs-are known to activate brown adipose tissue (BAT) thermogenesis and whole-body energy expenditure (EE) in small rodents. BAT activity can be assessed by [¹⁸F]fluorodeoxyglucose-positron emission tomography (FDG-PET) in humans. The aims of the current study were to examine the acute effects of capsinoid ingestion on EE and to analyze its relation to BAT activity in humans. Eighteen healthy men aged 20-32 y underwent FDG-PET after 2 h of cold exposure (19°C) while wearing light clothing. Whole-body EE and skin temperature, after oral ingestion of capsinoids (9 mg), were measured for 2 h under warm conditions (27°C) in a single-blind, randomized, placebo-controlled, crossover design. When exposed to cold, 10 subjects showed marked FDG uptake into adipose tissue of the supraclavicular and paraspinal regions (BAT-positive group), whereas the remaining 8 subjects (BAT-negative group) showed no detectable uptake. Under warm conditions (27°C), the mean (±SEM) resting EE was 6114 ± 226 kJ/d in the BAT-positive group and 6307 ± 156 kJ/d in the BAT-negative group (NS). EE increased by 15.2 ± 2.6 kJ/h in 1 h in the BAT-positive group and by 1.7 ± 3.8 kJ/h in the BAT-negative group after oral ingestion of capsinoids (P < 0.01). Placebo ingestion produced no significant change in either group. Neither capsinoids nor placebo changed the skin temperature in various regions, including regions close to BAT deposits. Capsinoid ingestion increases EE through the activation of BAT in humans. This trial was registered at http://www.umin.ac.jp/ctr/ as UMIN 000006073.
  • Article
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    Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of brown adipose tissue (BAT). Whether BAT contributes to cold-induced non-shivering thermogenesis has however not been proven in adult humans. Using PET with 11C-acetate, 18FDG and 18F-fluoro-thiaheptadecanoic acid (18FTHA, a fatty acid tracer), BAT oxidative metabolism, glucose and nonesterified fatty acid (NEFA) turnover were quantified in six healthy men under controlled cold exposure condition designed to minimize shivering. Upon cold exposure, we showed significant NEFA uptake in addition to glucose uptake. We demonstrated significant cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This was associated with a 1.8-fold increase in total energy expenditure. We found a significant inverse relationship between BAT volume of activity and shivering and significant increase in BAT radio-density, indicating reduced BAT triglyceride content. The present study demonstrates that BAT represents a non-shivering thermogenesis effector in humans.
  • Article
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    Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue (BAT). Here we report that despite a normal plasma 3,5,3'-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2(-/-)) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss. This occurs despite normal basal mitochondrial uncoupling protein 1 (UCP1) concentration. In Dio2(-/-) brown adipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced increases in lipolysis, UCP1 mRNA, and O(2) consumption are all reduced due to impaired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies suggest that UCP1 is primarily dependent on thyroid hormone receptor beta (TR beta) while the normal sympathetic response of brown adipocytes requires TR alpha. Intracellularly generated T3 may be required to saturate the TR alpha, which has an approximately fourfold lower T3-binding affinity than does TR beta. Thus, D2 is an essential component in the thyroid-sympathetic synergism required for thermal homeostasis in small mammals.