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Regulation of energy balance by brown adipose tissue: at least three potential roles for physical activity
  1. Jonatan R Ruiz1,
  2. Borja Martinez-Tellez1,
  3. Guillermo Sanchez-Delgado1,
  4. Concepcion M Aguilera2,
  5. Angel Gil2
  1. 1 PROFITH “PROmoting FITness and Health through physical activity” Research Group, Faculty of Sport Sciences, Department of Physical Education and Sport, University of Granada, Granada, Spain
  2. 2 Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, Centre for Biomedical Research, University of Granada, Granada, Spain
  1. Correspondence to Dr Jonatan R Ruiz, PROFITH “PROmoting FITness and Health through physical activity” Research Group, Faculty of Sport Sciences, Department of Physical Education and Sport, University of Granada, Carretera de Alfacar s/n, Granada 18071, Spain; ruizj{at}

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Brown adipose tissue (BAT) has the ability to oxidise glucose and lipids, and dissipate energy in the form of heat.1 Thus, it could provide one method to influence energy balance—and therefore, be a player in the fight against obesity and type 2 diabetes.

BAT is highly regulated by the sympathetic nervous system (SNS) to increase body temperature when mammals are exposed to cold. The heat production is mediated by uncoupling protein 1 (UCP-1), an inner-membrane mitochondrial protein exclusively expressed in BAT.1 Dogma was that BAT was only present in newborns. However, radiologists using the radiotracer 18F-fluorodeoxyglucose in positron emission tomography (PET)/computed tomography to detect metabolically active tumours, found competing areas in the supraclavicular, thoracic spine and neck regions with high rates of glucose uptake. The significance of BAT for human physiology was recognised in 2007.2

Recently, another type of cells called brown-in-white (BRITE) or beige cells, in white adipose tissue (WAT) have been found.3 BRITE cells possess a multilocular morphology, enriched mitochondria and express the brown adipocyte-specific UCP-1.

Importance of activating BAT

A potential clinical implication of activating BAT relates to the stimulation of resting energy expenditure and diet-induced thermogenesis. In humans, the thermogenic response to a meal is higher in those possessing BAT. It has been estimated that 50 g of activated BAT might translate to increase ∼5% of resting energy expenditure. A 5% chronic increase in resting energy expenditure turns to ∼75–100 kcal/day, which over the course of a year might translate into a loss of ∼4–4.7 kg of fat.

Sympathetic nervous system

Following the exposure to cold temperatures or acute food intake, the brain coordinates the activation of SNS. In the mature brown adipocytes, released catecholamines activate hormone sensitive lipase, and stimulate lipolysis. The resulting increase in free fatty acids activates UCP-1. Catecholamines also stimulates glucose uptake into brown adipocytes, and this is why BAT is visible to PET/CT.

Exercise stimulates SNS and catecholamines release. Exercise-induced SNS stimulation might have both acute (lipolysis and activation of UCP-1) and chronic (UCP-1 gene transcription, mitochondrial biogenesis, hyperplasia of BAT, recruitment of brown adipocytes in WAT) effects on BAT.

Interestingly, recent findings have shown a group of novel myokines (cytokines or other peptides that are produced, expressed and released by skeletal muscle) that act independently of the stimulation of the SNS (eg, irisin4 and β-aminoisobutyric acid5 (BAIBA)), and that are released into the circulation during exercise.

Myokines: irisin and BAIBA

Murine (mouse) exercising skeletal muscles, on increased levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), induce the expression of fibronectin type III domain containing 5 (FNDC5), which after cleavage is secreted into the blood stream as irisin.4 Irisin induces the expression of UCP-1 in WAT, and triggers the browning process, that is, the transformation of white adipocytes into BRITE cells. This change is accompanied by an increase in total body energy expenditure, modest weight loss, and modest improvements in glucose intolerance. Irisin levels are also increased after exercising at moderate intensity in humans.6 Irisin appears to be influenced by a number of phenotypic traits including increased adiposity, lean mass and fasting plasma glucose that may partially explain the conflicting results emerged in human studies.

BAIBA was identified early in 2014.5 BAIBA concentration increases after exercise training, induces browning of WAT, and is inversely associated with metabolic risk factors.

Cardiac natriuretic peptides

Natriuretic peptides are hormones produced by the heart. Receptors for the natriuretic peptides are in the kidneys and vasculature, as well as in fat tissue. In human adipocytes, natriuretic peptides induced lipolysis and UCP-1 expression.7 Brain type natriuretic peptide treatment in mice enhanced energy expenditure and increased thermogenic protein levels in WAT and BAT.7

Exercise increases the secretion of natriuretic peptides. The impacts of long-term exercise effects on atrial natriuretic peptides in adults, and its role on human BAT activity and recruitment could be studied. Moreover, whether the potential effects attributed to natriuretic peptides might be additive to, and perhaps synergistic with those increases seen with classical β-adrenergic stimulation would be a valuable experiment.

In summary, exercise might activate and recruit BAT through three different players, namely (1) the SNS, (2) skeletal muscle and (3) cardiac muscle (figure 1). Well-controlled studies in humans are needed to elucidate whether and how exercise is able to (1) activate and recruit BAT, (2) induce the specific gene programme to favour white-to-brown adipocyte transformation and (3) stimulate other potential BAT precursors. Studies investigating the optimal exercise dose in terms of duration and intensity able to stimulate activate and recruit BAT are also warranted. Such studies will improve our understanding of exercise and its protective effects against the development of obesity and type 2 diabetes. Pharmaceutical companies are rushing to design pills to activate BAT with no side effects. The magic pill, the one with multiorganic effects is already invented—physical activity.8

Figure 1

Potential mechanisms for exercise on activation and recruitment of brown adipose tissue (BAT) through the sympathetic nervous system (SNS), skeletal muscle, and heart. Exercise stimulates SNS and catecholamines release. Released catecholamines induce fibroblast growth factor 21 (FGF21) gene transcription and release in BAT, which subsequently activates hormone sensitive lipase (HSL) and consequently stimulates lipolysis. The resulting increase in free fatty acids activates uncoupling protein 1 (UCP-1), and activates the thermogenesis machinery. Exercise also increases the secretion of cardiac natriuretic peptides. The stimulus for their secretion is the increase in heart rate. Therefore cardiac natriuretic peptides increase rapidly after the initiation of exercise. Natriuretic peptides induce lipolysis and UCP-1 expression, induce mitochondriogenesis, and increased thermogenesis. Skeletal muscle is an endocrine organ capable of communicating with other tissues through myokines, which are released into the circulation during exercise. Exercising skeletal muscle induces the expression of myokines such as irisin and β-aminoisobutyric acid (BAIBA) that binds to the surface of white adipocytes and induces the expression of UCP-1, which triggers the browning process (transformation of white adipocytes into brown-in-white (BRITE) cells). Dash lines suggest an indirect effect of FGF21 released in BAT on the UCP-1 expression in white adipose tissue (WAT). Moreover, cardiac natriuretic peptides activate UCP-1 expression and browning in WAT.



  • Contributors JRR wrote the first draft of the manuscript. All authors contributed to the interpretation and discussion of the content, and critically revised the drafted manuscript.

  • Funding The study was supported by the Spanish Ministry of Economy and Competitiveness, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III (PI13/01393) Fondos Estructurales de la Unión Europea (FEDER), Spanish Ministry of Science and Innovation (RYC-2010–05957) by the Spanish Ministry of Education (FPU 13/04365). This study is part of a Ph.D. thesis conducted in the Biomedicine Doctoral Studies of the University of Granada, Spain.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.