ReviewRole of the autonomic nervous system in activation of human brown adipose tissue: A review of the literature
Introduction
Brown adipose tissue (BAT) has the capacity to turn free fatty acids (FFAs) and glucose into heat. While BAT was thought to be present only in children, in 2009, it became clear that adults also have functional BAT following cold exposures [1], [2], [3]. Intriguingly, BAT was more often observed in lean than in obese individuals [1], [4]. These findings sparked interest in BAT activation as a potential treatment target for type 2 diabetes (T2D), one of the world's leading health problems in terms of both increased all-cause mortality as well as health costs [5], [6], [7], [8], [9]. Although interest in BAT has exponentially increased, there are still many uncertainties. It is not known, for example, whether the relatively small amount of BAT in humans is enough to correct body mass index (BMI) scores or metabolic imbalances. Furthermore, the exact workings and control mechanisms of BAT are yet to be unravelled.
Obesity reflects an imbalance between energy consumption and energy expenditure. Strategies to combat obesity focus on correcting this imbalance by decreasing energy intakes with dietary strategies and bariatric surgery, and increasing energy expenditures through physical-exercise programmes. However, energy expenditure is the sum of physical activity, diet-induced thermogenesis and resting energy expenditure, and cold-stimulated heat production by BAT increases resting energy expenditure [10], [11]. Thus, BAT may be an interesting option in the treatment of obesity and obesity-associated T2D.
BAT is able to convert excess calories into heat, whereas white adipose tissue (WAT) stores these excess calories. Brown adipocytes contain multiple lipid droplets in comparison to the large lipid droplets found in white adipocytes, and brown adipocytes also contain far more mitochondria, causing the typical brown color of BAT [12]. In addition, the mitochondria in brown adipocytes contain a unique mitochondrial inner membrane protein: uncoupling protein 1 (UCP1). UCP1 enables brown adipocytes to uncouple the respiratory chain, which means that BAT mitochondria are able to rapidly turn FFAs and glucose into heat instead of generating adenotriphosphate (ATP; Fig. 1) [12], [13]. In addition, BAT differs from WAT by having a greater degree of vascularization and a more pronounced sympathetic innervation [12], [14], [15]. The latter has raised the hypothesis that the sympathetic nervous system (SNS) plays a major role in the activation of BAT.
Indeed, the SNS appears to be involved in cold-activated BAT. Animal studies show that cold sensation in the skin, by cooling cutaneous thermal sensory receptors and lowering core body temperature, initiates peripheral vasoconstriction, resulting in the release of the sympathetic neurotransmitter norepinephrine in BAT to maintain normal body temperature [16], [17]. However, data derived from rodent research on the stimulating factors of BAT are not easily translated to humans, and it remains to be determined whether the same pathways are involved in human adults [18], [19], [20].
So far, only a few studies have shown that recruitment of BAT in human adults is possible by either bariatric surgery in obese subjects or repetitive cold exposure in lean subjects [10], [21], [22], [23]. However, most people will not tolerate cold exposure for the majority of the day. Therefore, alternative activators of BAT have to be investigated.
The present review discusses human BAT studies focused on factors that might influence the autonomic nervous system control of BAT in adult humans. A broader aim of this review is to identify gaps in our knowledge, thereby providing directions for future research.
Section snippets
Materials and methods
For our literature search on the autonomic nervous system and BAT in humans, MEDLINE was searched for studies on BAT published up to 16 March 2015, using the following text terms and medical subheadings: [(Brown Adipose Tissue [mesh] OR Brown Adipose Tissue [tiab] OR Brown Fat [tiab] OR Hibernating Gland [tiab]) NOT (animals [MeSH] NOT humans [MeSH]) OR (rat [ti] OR rats [ti] OR mouse [ti] OR mice [ti])]. A broad definition of entry terms was used to avoid missing potentially relevant articles.
Imaging studies highlighting the importance of the SNS in BAT activation
Several imaging studies provided evidence of the importance of sympathetic stimulation in the activation process of BAT. Most prospective BAT studies were performed, using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET–CT), to show the glucose metabolic activity of BAT. However, several tracers are now available with the ability to visualize sympathetic BAT activity.
The radiolabelled norepinephrine analogue 123I-meta-iodobenzylguanidine (123I-mIBG) can be
Interruption of sympathetic nerves
The actual causal relationship between sympathetic BAT innervation and BAT activity in humans has been nicely described in patients whose sympathetic nerves have been interrupted.
One case report describes a child with neuroblastoma in the right upper chest in the paraspinal region. Surgical removal of the neuroblastoma caused an interruption of the right upper thoracic and cervical sympathetic nerves, resulting in right-sided Horner's syndrome. After the operation, 123I-mIBG uptakes in BAT were
BAT activation through high catecholamine levels
Both α- and β-adrenergic agents are of potential interest in the search for activators of BAT. Indeed, extremely high BAT activity is often seen in patients with phaeochromocytoma, who are known to have elevated levels of catecholamines. The cause of such high catecholamine levels and BAT activity has been demonstrated in several ways. One case series described the positive relationship between plasma catecholamine levels and BAT activity in 14 patients with phaeochromocytoma and 14 healthy
Conclusion: clinical impact and future considerations
Our present review of the literature on human BAT activation clearly indicates the involvement of sympathetic stimuli through a number of findings (Table 1, Table 2). First, the uptake of the sympathetic tracers 123I-mIBG and 6-18F-FDA in BAT [27], [31], [33] and, second, interruption of the sympathetic nerves innervating BAT diminishes its metabolic activity [24], [40]. Third, β- and α-adrenergic receptor blockade are highly successful pretreatment strategies for reducing BAT activity [28],
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
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