Environmental temperature can have a major effect on whole-body and cellular energy expenditure (Fig.
1). When body heat loss is substantially increased by exposure to the cold, high rates of lipid and carbohydrate oxidation are essential to maintain an increased metabolic rate. Indeed, severe cold exposure in animals has been shown to increase lipolysis, lipid oxidation and NEFA turnover (among others: [
86]), as well as glucose oxidation and turnover, and thereby improves glucose tolerance and peripheral glucose uptake (Fig.
2) [
87,
88]. These findings indicate that an increase in cold-induced shivering thermogenesis can have pronounced effects on glucose homeostasis; however, these studies were conducted under severe cold exposure, a condition that cannot be sustained for long periods of time.
Role of NST
In contrast to extreme cold, mild cold exposure is an intervention that is feasible for application in humans for longer periods of time. When humans and animals are exposed to milder cold, NST increases to produce heat. Interestingly, this NST is blunted in obese individuals and is significantly reduced when compared with NST in lean counterparts [
89]. This relatively low NST may be related to body composition, as overweight and obese individuals have much more (subcutaneous) body fat and have more tissue insulation. Therefore, in daily (indoor) situations obese people experience much less cold than their lean counterparts, thereby triggering NST to a lesser extent. Indeed, after weight loss, morbidly obese patients show an increased NST capacity [
90]. In older people, NST is reduced and, together with reduced body temperatures in the cold, their net energy expenditure in the cold may even be lower than at thermoneutral conditions [
17]. The extent to which reduced NST in the elderly is caused by habituation or biological factors related to ageing is not known. Older people in western society generally tend to spend more time indoors in relatively warm and stable environments and are less tolerant of lower ambient temperatures. Therefore they may have lost their NST capacity. Both by living in such a protective stable environment and by increased body fat, NST and related metabolic processes are diminished. On the other hand, biological ageing itself may also affect their metabolic cold responses. Intriguingly, NST is also blunted in patients with type 2 diabetes [
91]. However, the lower NST in type 2 diabetes may be related to the fact that most type 2 diabetes patients are older and overweight. It is currently not known whether a low NST plays a role in the aetiology of type 2 diabetes.
Role of brown adipose tissue
In rodents the main tissue responsible for NST is brown adipose tissue (BAT) [
92]. Although NST in humans had been reported earlier, its relationship to functional BAT in adult humans was not revealed until 2009 [
93‐
96]. In contrast to white adipose tissue, BAT burns triacylglycerol and glucose to generate heat through mitochondrial uncoupling [
92]. Cold is the main stimulator of sympathetic nervous system-mediated BAT activation. Human brown fat is mainly studied by fluorodeoxyglucose–PET/CT imaging, which shows glucose uptake (rate) in those tissues that use glucose [
97]. BAT is not activated in fasting and thermoneutral conditions [
98], while it is activated by mild cold (i.e. without shivering) [
94]. Using the appropriate individual cooling protocols [
99], BAT glucose uptake was found to be significantly related to NST, indicating a role for BAT in whole-body thermogenesis, as shown in rodent studies. In parallel with NST, cold-induced BAT activation is reduced in obese and elderly individuals and those with type 2 diabetes [
91,
100,
101]. Only recently, studies on the effect of cold acclimation on NST and BAT activity have been performed. Cold acclimation by intermittent exposure to a cool (14–17°C), or cold (10°C) environment resulted in significant increases in NST capacity [
102]. A 10 day cold acclimation study with 6 h exposure to 14–15°C per day was enough to significantly increase NST by 65% on average [
103]. A 6 week mild cold acclimation study (daily 2 h cold exposure at 17°C) also resulted in an increase in NST together with a concomitant decrease in body fat mass [
104]. The latter two studies also revealed significant increases in BAT presence and activation [
103,
104]. All in all, cold-induced BAT activity is significant in adults and parallels NST. The actual quantitative contributions of BAT and of other tissues (e.g. skeletal muscle) to whole-body NST are, however, not elucidated and await further studies. Furthermore, more information is needed on the duration, timing and temperatures to find out which treatments are most effective with respect to increasing NST.
Whether activation of BAT (potentially via elevating NST) affects glucose homeostasis and insulin sensitivity has not been studied extensively. Thus, glucose is oxidised in high amounts by BAT when activated, although the direct contribution of glucose oxidation to total thermogenesis in BAT is believed to be relatively small compared with that of fat oxidation, somewhere in the range of 10–16% [
92,
105,
106]. It is likely that the glucose that is taken up is mainly used for the synthesis of glycerol-3-phosphate and triacylglycerols and also for the supply of extramitochondrial ATP through glycolysis to support fatty acid esterification to triacylglycerol and other cellular functions [
107]. A study on noradrenaline (norepinephrine) stimulation of rat brown adipocytes revealed that glucose uptake and oxygen consumption were related. It has also been shown that increasing BAT by transplantation in mice has advantageous effects on body composition, insulin sensitivity and glucose metabolism [
108].
In humans, retrospective patient studies show inverse relationships between BAT activity and diabetes and glycaemia [
96,
109]. Prospective cold exposure studies show, as mentioned above, that glucose uptake in BAT is positively related to NST [
103,
110]. These observations show that cold-induced thermogenesis goes hand in hand with increased glucose metabolism. The acute cold glucose uptake rate per unit of tissue mass as determined by dynamic PET/CT was higher in BAT than in skeletal muscle [
110,
111]. Interestingly, insulin-stimulated glucose uptake in BAT in humans was positively related to the
M value (a measure of whole-body insulin sensitivity derived from hyperinsulinaemic–euglycaemic clamps) [
112].
Whether the increased uptake of glucose by BAT significantly contributes to whole-body glucose metabolism in type 2 diabetes has not yet been substantiated, although it was recently shown that individuals with active BAT, when compared with individuals without BAT, showed significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation and insulin sensitivity [
113]. In another study, Lee et al [
114] showed that staying overnight in cold chambers (19°C) for 1 month increased BAT activity together with improved postprandial insulin sensitivity. In a recent study in individuals with type 2 diabetes we studied the effect of cold acclimation on BAT activity and insulin sensitivity using hyperinsulinaemic–euglycaemic clamp. The cold acclimation protocol was identical to that used by van der Lans et al [
103], where we found significant increases in BAT and NST. In type 2 diabetes patients the amount of BAT at baseline was significantly lower than that in healthy lean individuals [
91]. Acclimation increased BAT activity significantly but levels were still very low [
91]. Very interestingly, insulin sensitivity increased after cold acclimation by 43% on average [
91]. It is very unlikely that the small increase in BAT activity could be responsible for this improved insulin sensitivity. In fact, the study showed that the improved insulin sensitivity could be explained by enhanced GLUT4 translocation in skeletal muscle in the basal state, an effect that had been previously observed in cold-acclimated rats [
115] and has been confirmed in obese humans [
116]. Although the mechanisms responsible for GLUT4 translocation upon cold stimulation remain to be elucidated, these findings clearly demonstrate that the significant improvement in insulin sensitivity can be attributed to skeletal muscle tissue, rather than to BAT, and may involve increased energy turnover. However, since BAT increased in all participants after cold acclimation, an indirect role for BAT (e.g. by secreting BATokines) cannot be fully excluded.