Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans

Mark J.W. Hanssen; Anouk A.J.J. van der Lans; Boudewijn Brans; Joris Hoeks; Kelly M.C. Jardon; Gert Schaart; Felix M. Mottaghy; Patrick Schrauwen; Wouter D. van Marken Lichtenbelt

Disclosures

Diabetes. 2016;65(5):1179-1189. 

In This Article

Abstract and Introduction

Abstract

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.

Introduction

Because of the ever-growing prevalence of global obesity, there is an ongoing search for effective strategies to enhance energy expenditure (EE) and subsequently counteract obesity and its negative metabolic consequences. Adaptive thermogenesis—that is, an increased capacity for heat production upon prolonged exposure to cold[1]—has gained considerable renewed interest in this context, especially because of the recent appreciation of considerable amounts of metabolically active brown adipose tissue (BAT) in adult humans.[2–4] BAT is highly specialized to convert energy from substrate oxidation directly into heat through the action of uncoupling protein 1, thereby contributing to the maintenance of a constant internal body temperature upon exposure to cold. Because of this "energy-wasting" process, BAT activation results in increased EE, which could reverse or protect against obesity. Indeed, several rodent studies have demonstrated that BAT activation and recruitment by prolonged exposure to cold or β-adrenergic stimulation ameliorates diet-induced obesity and improves its associated complications, such as disturbed glucose and lipid homeostasis.[5,6] In animals, prolonged cold stimulation also induces browning of distinct white adipose tissue (WAT) depots, likely contributing to improved substrate metabolism.[7] This phenomenon also has recently been observed in human subcutaneous WAT upon severe and prolonged adrenergic stress.[8]

In humans, as in mice, exposure to cold is one of the most powerful physiological stimuli for activation of BAT.[9] As such, using dedicated cooling protocols to activate BAT, we have shown that BAT is present and active upon acute exposure to cold in 90–100% of lean, young adults and that BAT activity is related to nonshivering thermogenesis (NST).[10,11] In addition, several studies have reported negative relations between BAT activity and age and body fatness in humans,[3,12] likely the result of the "whitening" of classical BAT depots,[13] most notably the supraclavicular BAT depot. Interestingly, both older age[14] and obesity[15] are also associated with a blunted NST response upon exposure to mild cold. This has led to the hypothesis that recruitment of BAT by cold acclimatization could enhance cold-induced EE, thereby counteracting WAT accumulation and its possible negative metabolic consequences. We[11] and others[16–18] recently showed that BAT can be effectively recruited in lean individuals by means of prolonged intermittent exposure to cold, that is, cold acclimation. Interestingly, BAT recruitment was indeed paralleled by enhanced cold-induced NST.[11,16] Moreover, Yoneshiro et al.[16] showed a negative relation between changes in BAT activity and whole-body fat mass after daily 2-h exposure to cold (17°C) for 6 weeks, suggesting an antiobesity effect of BAT recruitment in humans. Importantly, these studies were all performed in young, lean, and healthy subjects. A 10-day cold acclimation period in patients with type 2 diabetes resulted in only a minor increase in metabolic activity of the supraclavicular BAT region.[19] However, in addition to being overweight, these patients were also older and presented already very low activity of this BAT region at baseline. Therefore, it remains to be established whether significant amounts of BAT can be recruited in obese subjects within a wide age range and whether this is associated with enhanced NST.

In addition to BAT, skeletal muscle (SM) and visceral and subcutaneous adipose tissue metabolism also may be affected by prolonged exposure to cold, as has been suggested by animal studies[7,20,21] and our recent observation of enhanced basal GLUT4 translocation upon cold acclimation in patients with type 2 diabetes.[19] However, it is not known whether prolonged, intermittent exposure to cold can elicit such improvements in metabolically healthy obese subjects as well. Therefore, we studied here changes in NST, BAT presence and activity, browning of WAT, and SM metabolic parameters after a 10-day cold acclimation period in healthy obese males.

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