Brown Fat Activation Mediates Cold-Induced Thermogenesis in Adult Humans in Response to a Mild Decrease in Ambient Temperature

Abstract

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 Ϯ 5.9%, P Ͻ .001), indicating CIT response and mean BAT activity (10.5 Ϯ 11.1%, P Ͻ .001). Multiple regression analysis indicated that a difference in BAT activity (P Ͻ .001), age (P ϭ .01), and gender (P ϭ .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. J C E M O N L I N E B r i e f R e p o r t -E n d o c r i n e R e s e a r c h

Influence of environmental temperature on risk of gestational diabetes

“…Studies using positron emission tomography and involving small numbers of participants have shown the presence of stores of functional brown adipose tissue in humans that can be stimulated by even brief exposure to cold temperatures, with an exposure to cold as short as 2 hours augmenting insulin sensitivity. [6][7][8][9][10][11][12][13][14][15] In small trials involving humans, cold acclimatization over weeks or months was associated with an expansion of volume of brown adipose tissue and increases in both energy expenditure and insulin sensitivity. [16][17][18] Furthermore, there appears to be an inverse relation between activity of brown adipose tissue and both BMI and visceral adiposity.…”

“…However, such misclassification would have minimally affected our findings, given the low prevalence of diabetes in women of reproductive age and no indication for screening for gestational diabetes mellitus in women with pregestational diabetes. 22 Although cold exposure has been shown to have direct effects on brown adipose tissue and insulin sensitivity, [7][8][9][10][11][12][15][16][17][18] neither could be measured in our population. The relation between temperature and gestational diabetes mellitus persisted when comparing 2 consecutive pregnancies within the same woman, which suggests a lack of influence of unmeasured confounding.…”

“…[4][5][6] Based on findings from studies involving animals and humans, the effects of brown adipose tissue activation extend beyond thermogenesis, by influencing whole-body metabolism and possibly overall body weight. [7][8][9][10][11][12][13][14][15][16][17][18] Small intervention trials involving humans have suggested that even mild exposure to ambient cold -such as lowering a thermostat from 24°C to 19°C -can increase activity of brown adipose tissue by 30%-40%, resulting in substantial improvements in insulin sensitivity. [15][16][17][18] In theory, greater insulin sensitivity should improve glucose handling, but whole-population studies evaluating the potential for cold exposure to reduce glucose mishandling are lacking.…”

Human Brown Adipose Tissue: What We Have Learned So Far

“…Repeated intermittent exposure of healthy Japanese men without detectable BAT at baseline (mean BMI 22 kg/m 2 , n = 12) to mild cold (17°C for 2 h/day) during 6 weeks recruited and expanded BAT, and led to a decrease in body fat mass (52). In a similar experiment, the reduction of ambient temperature from 24°C to 19°C resulted in a mean cold-induced increase in energy expenditure of 5%, and of BAT activity of 10% in 24 healthy volunteers (101). These environmental strategies are backed by the seasonal variation of BAT prevalence and UCP1 expression in human adults, with the highest amounts seen during the cold season (2,53).…”

Role of histone deacetylase 9 in regulating adipogenic differentiation and high fat diet-induced metabolic disease

“…20 Indeed, pharmacological activation of b3 adrenergic receptors augments beige phenotypic changes of white adipose tissue. 21 These adipogenic precursor cells also undergo b-adrenergic receptor-independent activation of their beige adipogenic differentiation program, 22,23 pointing to involvement of potentially multiple mechanisms. Identification of HDAC9, a nutrient sensitive gene, as a critical regulator of the calorie burning beige adipogenic program provides molecular insight how dietary caloric intake regulates caloric consumption pathways.…”