Elsevier

Diabetes & Metabolism

Volume 41, Issue 6, December 2015, Pages 437-445
Diabetes & Metabolism

Review
Role of the autonomic nervous system in activation of human brown adipose tissue: A review of the literature

https://doi.org/10.1016/j.diabet.2015.08.005Get rights and content

Abstract

Brown adipose tissue (BAT) is able to convert calories into heat rather than storing them. Therefore, activated BAT could be a potential target in the battle against obesity and type 2 diabetes. This review focuses on the role of the autonomic nervous system in the activation of human BAT. Although the number of studies focusing on BAT in humans is limited, involvement of the sympathetic nervous system (SNS) in BAT activation is evident. Metabolic BAT activity can be visualized with 18F-fluorodeoxyglucose, whereas sympathetic activation of BAT can be visualized with nuclear-medicine techniques using different radiopharmaceuticals. Also, interruption of the sympathetic nerves leading to BAT activation diminishes sympathetic stimulation, resulting in reduced metabolic BAT activity. Furthermore, both β- and α-adrenoceptors might be important in the stimulation process of BAT, as pretreatment with propranolol or α-adrenoceptor blockade also diminishes BAT activity. In contrast, high catecholamine levels are known to activate and recruit BAT. There are several interventional studies in which BAT was successfully inhibited, whereas only one interventional study aiming to activate BAT resulted in the intended outcome. Most studies have focused on the SNS for activating BAT, although the parasympathetic nervous system might also be a target of interest. To better define the possible role of BAT in strategies to combat the obesity epidemic, it seems likely that future studies focusing on both histology and imaging are essential for identifying the factors and receptors critical for activation of human BAT.

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.

References (86)

  • M.K. Schafer et al.

    Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine transporter. II. The peripheral nervous system

    Neuroscience

    (1998)
  • J.T. Thackeray et al.

    Assessment of cardiac autonomic neuronal function using PET imaging

    J Nucl Cardiol

    (2013)
  • W.D. van Marken Lichtenbelt et al.

    Cold-activated brown adipose tissue in healthy men

    N Engl J Med

    (2009)
  • A.M. Cypess et al.

    Identification and importance of brown adipose tissue in adult humans

    N Engl J Med

    (2009)
  • K.A. Virtanen et al.

    Functional brown adipose tissue in healthy adults

    N Engl J Med

    (2009)
  • G.H. Vijgen et al.

    Brown adipose tissue in morbidly obese subjects

    PLoS One

    (2011)
  • C. Tsigos et al.

    Management of obesity in adults: European clinical practice guidelines

    Obes Facts

    (2008)
  • C.F. Runge

    Economic consequences of the obese

    Diabetes

    (2007)
  • K.F. Adams et al.

    Overweight, obesity, and mortality in a large prospective cohort of persons 50 to 71 years old

    N Engl J Med

    (2006)
  • A. Berrington de Gonzalez et al.

    Body-mass index and mortality among 1.46 million white adults

    N Engl J Med

    (2010)
  • A.A. van der Lans et al.

    Cold acclimation recruits human brown fat and increases nonshivering thermogenesis

    J Clin Invest

    (2013)
  • B. Cannon et al.

    Brown adipose tissue: function and physiological significance

    Physiol Rev

    (2004)
  • A. Bartelt et al.

    Brown adipose tissue activity controls triglyceride clearance

    Nat Med

    (2011)
  • M.C. Zingaretti et al.

    The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue

    Faseb j

    (2009)
  • J.D. Lever et al.

    Demonstration of a catecholaminergic innervation in human perirenal brown adipose tissue at various ages in the adult

    Anat Rec

    (1986)
  • S.F. Morrison

    2010 Carl Ludwig Distinguished lectureship of the APS neural control and autonomic regulation section: central neural pathways for thermoregulatory cold defense

    J Appl Physiol (1985)

    (2011)
  • S.F. Morrison et al.

    Central control of brown adipose tissue thermogenesis

    Front Endocrinol (Lausanne)

    (2012)
  • P. Pound et al.

    Is animal research sufficiently evidence based to be a cornerstone of biomedical research?

    BMJ

    (2014)
  • B.O. Roep et al.

    Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes

    Nat Rev Immunol

    (2004)
  • J. Seok et al.

    Genomic responses in mouse models poorly mimic human inflammatory diseases

    Proc Natl Acad Sci U S A

    (2013)
  • T. Yoneshiro et al.

    Recruited brown adipose tissue as an antiobesity agent in humans

    J Clin Invest

    (2013)
  • D.P. Blondin et al.

    Increased brown adipose tissue oxidative capacity in cold-acclimated humans

    J Clin Endocrinol Metab

    (2014)
  • G.H. Vijgen et al.

    Increase in brown adipose tissue activity after weight loss in morbidly obese subjects

    J Clin Endocrinol Metab

    (2012)
  • M.J. Gelfand

    123I-MIBG uptake in the neck and shoulders of a neuroblastoma patient: damage to sympathetic innervation blocks uptake in brown adipose tissue

    Pediatr Radiol

    (2004)
  • K. Fukuchi et al.

    Radionuclide imaging metabolic activity of brown adipose tissue in a patient with pheochromocytoma

    Exp Clin Endocrinol Diabetes

    (2004)
  • M. Hadi et al.

    Brown fat imaging with (18)F-6-fluorodopamine PET/CT, (18)F-FDG PET/CT, and (123)I-MIBG SPECT: a study of patients being evaluated for pheochromocytoma

    J Nucl Med

    (2007)
  • W. Cheng et al.

    Intense FDG activity in the brown adipose tissue in omental and mesenteric regions in a patient with malignant pheochromocytoma

    Clin Nucl Med

    (2012)
  • E. Søndergaard et al.

    Chronic adrenergic stimulation induces brown adipose tissue differentiation in visceral adipose tissue

    Diabet Med

    (2015)
  • C. Okuyama et al.

    (123)I- or (125)I-metaiodobenzylguanidine visualization of brown adipose tissue

    J Nucl Med

    (2002)
  • C. Okuyama et al.

    123I-Metaiodobenzylguanidine uptake in the nape of the neck of children: likely visualization of brown adipose tissue

    J Nucl Med

    (2003)
  • H.W. Yeung et al.

    Patterns of (18)F-FDG uptake in adipose tissue and muscle: a potential source of false-positives for PET

    J Nucl Med

    (2003)
  • W.M. Admiraal et al.

    Combining 123I-metaiodobenzylguanidine SPECT/CT and 18F-FDG PET/CT for the assessment of brown adipose tissue activity in humans during cold exposure

    J Nucl Med

    (2013)
  • W.M. Admiraal et al.

    Cold-induced activity of brown adipose tissue in young lean men of South-Asian and European origin

    Diabetologia

    (2013)
  • Cited by (21)

    • Fat biology and metabolic balance: On the significance of sex

      2021, Molecular and Cellular Endocrinology
      Citation Excerpt :

      Importantly, sympathetic nervous system innervation in WAT is required for browning during cold-induced thermogenesis (Cao et al., 2019). Interruption of the sympathetic nerves results in a reduced metabolic BAT activity in humans detected by PET/CT (Bahler et al., 2015). Knowledges of sex differences in the innervation-dependent adipose tissue activation is limited.

    • A<inf>2A</inf> Receptor Activation Attenuates Hypertensive Cardiac Remodeling via Promoting Brown Adipose Tissue-Derived FGF21

      2018, Cell Metabolism
      Citation Excerpt :

      Hypertension is normally associated with increased sympathetic activity and release of catecholamines (Esler, 2015). These can activate brown adipose tissue (BAT) (Bahler et al., 2015; Hankir et al., 2016). In contrast to white adipose tissue (WAT), BAT dissipates energy though uncoupled respiration and thermogenesis, and protects against metabolic disorders (Kozak, 2010; Sidossis and Kajimura, 2015).

    • Current Role of FDG-PET in Pediatric Hodgkin's Lymphoma

      2017, Seminars in Nuclear Medicine
      Citation Excerpt :

      A careful dose optimization for the CT part of the individual FDG-PET/CT scanners should be applied to achieve sufficient image quality in both the low-dose protocols and in the protocols using intravenous contrast agent. The activation of brown adipose tissue can be caused by a cold stimulus or a high level of activity of the sympathetic nervous system (eg, stress and pain) or by both.82-84 In the context of the FDG-PET study of young patients with lymphoma, activated brown adipose tissue can markedly affect the quality of the PET image through sometimes very pronounced and extended physiological enrichment of FDG (Fig. 9).

    View all citing articles on Scopus
    View full text