Cold exposure may be a potential therapy for diabetes by increasing brown adipose tissue (BAT) mass and activity. Here we report that 10 d of cold acclimation (14-15 °C) increased peripheral insulin sensitivity by ∼43% in eight type 2 diabetes subjects. Basal skeletal muscle GLUT4 translocation markedly increased, without effects on insulin signaling or AMP-activated protein kinase (AMPK) activation and only a minor increase in BAT glucose uptake.

Recruitment of brown adipose tissue (BAT) has emerged as a potential tool to combat obesity and associated metabolic complications. Short-term cold acclimation has been shown not only to enhance the presence and activity of BAT in lean humans but also to improve the metabolic profile of skeletal muscle to benefit glucose uptake in patients with type 2 diabetes. Here we examined whether short-term cold acclimation also induced such adaptations in 10 metabolically healthy obese male subjects. A 10-day cold acclimation period resulted in increased cold-induced glucose uptake in BAT, as assessed by [18F]fluorodeoxyglucose positron emission tomography/computed tomography. BAT activity was negatively related to age, with a similar trend for body fat percentage. In addition, cold-induced glucose uptake in BAT was positively related to glucose uptake in visceral white adipose tissue, although glucose uptake in visceral and subcutaneous white adipose tissue depots was unchanged upon cold acclimation. Cold-induced skeletal muscle glucose uptake tended to increase upon cold acclimation, which was paralleled by increased basal GLUT4 localization in the sarcolemma, as assessed through muscle biopsies. Proximal skin temperature was increased and subjective responses to cold were slightly improved at the end of the acclimation period. These metabolic adaptations to prolonged exposure to mild cold may lead to improved glucose metabolism or prevent the development of obesity-associated insulin resistance and hyperglycemia.

Brown adipose tissue (BAT) dissipates energy and its activity correlates with leanness in human adults. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography coupled with computer tomography (PET/CT) is still the standard for measuring BAT activity, but exposes subjects to ionizing radiation. To study BAT function in large human cohorts, novel diagnostic tools are needed. Here we show that brown adipocytes release exosomes and that BAT activation increases exosome release. Profiling miRNAs in exosomes released from brown adipocytes, and in exosomes isolated from mouse serum, we show that levels of miRNAs change after BAT activation in vitro and in vivo. One of these exosomal miRNAs, miR-92a, is also present in human serum exosomes. Importantly, serum concentrations of exosomal miR-92a inversely correlate with human BAT activity measured by 18F-FDG PET/CT in two unique and independent cohorts comprising 41 healthy individuals. Thus, exosomal miR-92a represents a potential serum biomarker for BAT activity in mice and humans.

The obesity pandemic has spurred a need for novel therapies to prevent and treat metabolic complications. The recent rediscovery of brown adipose tissue (BAT) in humans made this tissue a possible therapeutic target, due to its potentially substantial contributions to energy homeostasis. Fibroblast growth factor 21 (FGF21) has been identified as a facilitator of cold-induced thermogenesis in humans. Furthermore, pre-clinical studies revealed that FGF21 administration leads to improvement in the metabolic consequences of obesity, such as dyslipidemia and type 2 diabetes. Here we studied plasma FGF21 levels in two cohorts of human subjects, in whom BAT activity was determined using an individualized cooling protocol by [18F]FDG-PET/CT scan. Importantly, we found that circulating FGF21 levels correlated with BAT activity during acute cold exposure in male subjects. In addition, FGF21 levels were related to the change in core temperature upon acute cold exposure, indicating a role for FGF21 in maintaining normothermia, possibly via activation of BAT. Furthermore, cold acclimation increased BAT activity in parallel with increased FGF21 levels. In conclusion, our results demonstrate that FGF21 levels in humans are related to BAT activity, suggesting that FGF21 may represent a novel mechanism via which BAT activity in humans may be enhanced.

The ‘gold standard’ for measuring brown adipose tissue (BAT) in humans is [18F]FDG-PET/CT-imaging. With this technique subjects are exposed to ionizing radiation and are therefore limited in the number of scans that can be performed. We investigated the relation between supraclavicular skin temperatures and BAT activity values using a strictly temperature-controlled air-cooling protocol. Data of 36 male subjects was analyzed. BAT activity was evaluated by [18F]FDG-PET/CT-imaging and skin temperature was measured by means of wireless temperature sensors. Supraclavicular skin temperature dropped less compared to skin temperatures at other sites (all P values <0.01). A significant positive correlation was found between the change in supraclavicular skin temperature with BAT activity (R2 0.23), and the change in supraclavicular skin temperature and non-shivering thermogenesis (R2 0.18, both P values <0.01). The correlations indicate that supraclavicular skin temperature (changes) can potentially be used as a qualitative measure of BAT activity and BAT thermogenesis.