Buscar en
Porto Biomedical Journal
Toda la web
Inicio Porto Biomedical Journal The impact of exercise training on adipose tissue remodelling in cancer cachexia
Journal Information
Vol. 2. Issue 6.
Pages 333-339 (November - December 2017)
Download PDF
More article options
Vol. 2. Issue 6.
Pages 333-339 (November - December 2017)
Review article
DOI: 10.1016/j.pbj.2017.02.006
Open Access
The impact of exercise training on adipose tissue remodelling in cancer cachexia
Rita Ferreiraa, Rita Nogueira-Ferreiraa,b, Rui Vitorinob,c, Lúcio Lara Santosd,e,f, Daniel Moreira-Gonçalvesa,g,
Corresponding author

Corresponding author.
a QOPNA, Departamento de Química, Universidade de Aveiro, Aveiro, Portugal
b Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
c iBiMED, Departamento de Ciências Médicas, Universidade de Aveiro, Aveiro, Portugal
d Experimental Pathology and Therapeutics Group – Research Center, IPO-Porto, Porto, Portugal
e Health School of University of Fernando Pessoa, Porto, Portugal
f Department of Surgical Oncology, IPO-Porto, Porto, Portugal
g CIAFEL, Faculdade de Desporto, Universidade do Porto, Porto, Portugal
Article information
Full Text
Download PDF
Figures (1)
Tables (1)
Table 1. Circulating mediators modulated by cancer cachexia (CC) and/or exercise training.

Cachexia affects the majority of patients with advanced cancer and no effective treatment is currently available to address this paraneoplastic syndrome. It is characterized by a reduction in body weight due to the loss of white adipose tissue (WAT) and skeletal muscle. The loss of WAT seems to occur at an earlier time point than skeletal muscle proteolysis, with recent evidence suggesting that the browning of WAT may be a major contributor to this process. Several factors seem to modulate WAT browning including pro-inflammatory cytokines; however, the underlying molecular pathways are poorly characterized.

Exercise training is currently recommended for the clinical management of low-grade inflammatory conditions as cancer cachexia. While it seems to counterbalance the impairment of skeletal muscle function and attenuate the loss of muscle mass, little is known regarding its effects in adipose tissue. The browning of WAT is one of the mechanisms through which exercise improves body composition in overweight/obese individuals. While this effect is obviously advantageous in this clinical setting, it remains to be clarified if exercise training could protect or exacerbate the cachexia-related catabolic phenotype occurring in adipose tissue of cancer patients. Herein, we overview the molecular players involved in adipose tissue remodelling in cancer cachexia and in exercise training and hypothesize on the mechanisms modulated by the synergetic effect of these conditions. A better understanding of how physical activity regulates body composition will certainly help in the development of successful multimodal therapeutic strategies for the clinical management of cancer cachexia.

Body wasting
WAT browning
Exercise training
Full Text

Cancer cachexia (CC) is a syndrome associated with poor prognosis, being responsible for about 20% of deaths in cancer patients.1 This paraneoplastic syndrome is characterized by a hypermetabolic state that leads to the loss of adipose tissue and skeletal muscle.2,3 Hormones, cytokines and other factors secreted by the tumour have been suggested to cause unbalanced energy expenditure, negative protein balance and increased lipolysis.4–6 Deregulation of hypothalamic mechanisms controlling energy wasting, hunger and satiety have also been associated with CC, suggesting that neuroendocrine processes can regulate adipose tissue and skeletal muscle wasting.1,4 Remodelling of adipose tissue seems to occur at an earlier time point than muscle proteolysis in CC. This is characterized by the browning of white adipose tissue (WAT) that leads to lipid mobilization/oxidation and heat production.1,7,8 Whereas increased proteolysis seems to explain muscle wasting, elevated lipolysis has been reported to be the main cause of adipose tissue loss in cancer patients.9 Nevertheless, the molecular pathways behind WAT adaptation to CC are poorly characterized.

Exercise training has been suggested as a preventive and therapeutic strategy for CC mostly because it prevents or counteracts muscle loss.10,11 However, the impact of exercise training on CC-related WAT remodelling is poorly comprehended. In this review we overview the molecular pathways involved in CC-related WAT remodelling and the putative impact of exercise training on this process.

WAT remodelling in cancer and involved molecular players

The CC-related alterations in the metabolism of adipose tissue include changes in the expression of genes with regulatory roles in the browning of WAT, a process by which WAT is converted into brown adipose tissue (BAT).12 Both WAT and BAT participate in the regulation of energy balance but while WAT is mainly involved in the maintenance of energy homeostasis by storing energy in the form of triglycerides, BAT is responsible for thermogenesis through lipid oxidation.13

Until recently, BAT was believed to be only present in neonatal and childhood periods whereas WAT is distributed all over the body.14 Nowadays, depots of BAT are recognized to persist in adults which correlates with their leanness.15 In CC, the presence of BAT was firstly noted when the use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning was introduced in the routine clinical practice for cancer staging.16,17 This methodological approach works by monitoring glucose uptake and so it is not surprising that some non-tumour tissues utilizing glucose are also labelled. In fact, besides the labelling of brain, heart and bladder, some additional areas of glucose uptake were observed by PET, particularly in the neck and shoulder area. This was later attributed to BAT.18 FDG uptake by BAT in adulthood implies the existence of thermogenically active adipose tissue, suggesting its involvement in energy wasting. So, FDG-PET seems an attractive non-invasive approach to determine BAT activity, supporting routinely employed clinical PET imaging to be extended to the diagnosis of patients at risk of CC.

WAT adipocytes are bigger than BAT adipocytes and have an unilocular morphology while BAT adipocytes present a multilocular morphology.19,20 BAT has a large density of mitochondria and is among the most vascularized tissues of the body, which confer its characteristic brown colour.19 Another type of adipocytes named brite (or beige) adipose cells were recently reported. These cells are located in WAT tissue in both subcutaneous and trunk compartments, and have the same thermogenic function of BAT cells. While brite adipocytes could be perceived as the result of ‘transdifferentiation’ of WAT to BAT in response to certain stimuli, there is also the suggestion that beige adipocytes are a new type of adipocytes derived from progenitors distinct from WAT and BAT.21,22

Browning of WAT in CC can be triggered by several factors, including sympathetic nervous system (SNS) signals that activate β3 adrenoceptors.13,23,24 Consequently, there is an overexpression of zinc-α2-glycoprotein (ZAG), which activates a G-coupled receptor with the consequent activation of hormone sensitive lipase (HSL) and the release of glycerol and free fatty acids (FFAs) from adipocytes.23 ZAG is one of the best described adipokines involved in CC-related WAT browning.4,24 Other adipokines are secreted by BAT such as leptin, adiponectin and resistin.25 The role of leptin in CC is not clear. In most studies the levels of this adipokine are positively correlated with body mass index (BMI), suggesting that low levels simply reflect diminished fat mass.26 However, these low leptin levels did not seem to result in increased appetite and decreased energy expenditure as expected. Thus, hypothalamic insensitivity to the low circulating levels of leptin have been speculated to occur in CC.27 Circulating adiponectin concentrations were inversely correlated with both free and total leptin concentrations in cancer patients suggesting that adiponectin antagonizes the effect of leptin after weight loss.28 Indeed, adiponectin concentration was reported to be significantly higher in cachectic patients when compared with stable weight patients.29 Higher production of adiponectin in CC seems to contribute to the wasting process, as adiponectin administration in experimental animal models was shown to increase energy expenditure.30 However, some authors have suggested that catabolic reactions and uncontrolled energy consumption in CC may contribute to adipose tissue degradation and to the reduction of adiponectin expression.31 Resistin is an adipose tissue derived hormone, also termed “adipocyte secreted factor” (ADSF) or “found in inflammatory zone” (FIZZ3).32 Despite its association to a variety of inflammatory and autoimmune processes, and to increased cancer risk, the association of resistin with body weight, appetite and insulin resistance is not clear.27 Indeed, the majority of the studies on CC did not report a correlation between resistin and fat mass.33,34

BAT also produces other substances as a result of its endocrine activity, such as vascular endothelial growth factor (VEGF).25 By promoting a dense vascular network, VEGF, particularly VEGF-A, indirectly supports the high-energy consumption of BAT.35,36 Fibroblast growth factor (FGF) 21, a protein originally known to be expressed by the liver in response to fasting, is secreted by BAT, especially during thermogenic activation.25 Parathyroid-hormone related protein (PTHrP) was also involved in WAT browning.37 Indeed, higher serum levels of this protein were associated with weight loss in cancer patients.38 Fat-specific knockout of PTHrP was reported to prevent adipose browning and also to preserve muscle mass and improve muscle strength.39

WAT is a contributor to systemic inflammation, as adipocytes and infiltrating inflammatory cells, primarily macrophages, produce inflammatory mediators, initiating a negative set of effects in the adipose tissue function, including the death of adipocytes.40 For instance, TNF-α inhibits lipoprotein lipase (LPL) activity, increases HSL mRNA expression and reduces GLUT4 expression, leading to reduced glucose transport and consequently to a decline in glucose availability for lipogenesis.41 TNF-α also increases the expression of chemoattractant protein 1, attracting monocytes to the adipose tissue.42 The resulting inflammatory response leads to the recruitment of macrophages that produce TNF-α, IL-6 and IL-1β, increasing macrophage recruitment, perpetuating this vicious cycle.42 IL-6 might enhance thermogenesis acting directly on BAT or indirectly through the stimulation of the sympathetic nervous system.2 The cytokine TNF-related weak inducer of apoptosis (TWEAK) secreted by the tumour was also associated to cachexia.43,44 However, inconsistent results have been reported regarding the CC-related levels of pro-inflammatory cytokines, which might be justified by the transient nature of its secretion, cancer stage or distinct assays sensitivities. Besides cytokines, inflammatory-induced prostaglandins have also been proposed as key mediators of CC. Among prostaglandins, prostaglandin E2 (PGE2) seems to be involved in CC once inhibition of the inducible cyclooxygenase (COX-2) prevents body weight loss.45. Indeed, higher levels of PGE2 were reported in cancer patients with cachexia.46. Table 1 overviews the most described circulating mediators involved in CC-related WAT remodelling.

Table 1.

Circulating mediators modulated by cancer cachexia (CC) and/or exercise training.

Mediator  Content variation in CC  Ref.  Content variation in CC following exercise training  Ref.  Content variation promoted by exercise training in health  Ref. 
47  ⇑  47,48 
CRP  ⇑  29,49  ⇓  49 
GDF15  ⇑  52  –    ⇑  53 
Ghrelin  ⇑  26  –    ⇓  54,55 
IL-15  ⇓  56  ⇑  56  ⇑  56 
IL-1β  ⇑  3,52  –    57,58 
IL-6  ⇑  2,59  49 
IL-8  ⇑  52,59  –    ⇑  57 
Irisin  ⇑  60  –    ⇑  61 
Leptin  ⇓  26  ⇓  62  ⇓  48 
Myostatin  ⇑  43  43 
PGE2  ⇑  46  –    ⇑  66 
PTHrP  ⇑  38  –    67 
Resistin  33,34  –    68 
TNF-α  ⇑  59  ⇓  40  57,58 
TWEAK  ⇑  69  ⇓  69     
VEGF-A  ⇑  59  –    ⇑  70 

⇑ higher content; ⇓ lower content; = no content alterations; – not known.

Cellular events underlying the browning of WAT

The main molecular sign of WAT browning is the overexpression of uncoupling protein 1 (UCP1). The brite cells formed in WAT are capable of performing thermogenesis because they contain pockets of UCP1-expressing multilocular cells.25,37 UCP1 is a long chain fatty acid-activated protein, highly selective for brown and beige adipose cells, that sits in the inner membrane of mitochondria.20 The thermogenic effect of this protein is due to the deviation of mitochondria from its function of ATP production by mediating proton leakage across the inner mitochondrial membrane71, not allowing the protons to be used in the process of ATP synthesis.20 Consequently, there is a decrease in energy production and an increase in heat production triggered by increased lipid mobilization, oxidation and energy expenditure.13 Released FFAs are used not only as oxidative substrates to lipogenesis but are also potent activators of UCP1 expression, which is mediated by PKA-p38 mitogen-activated protein kinase (MAPK) signalling pathway.25

The overexpression of UCP1 that characterizes browning of WAT goes together with mitochondrial biogenesis, which is mediated by the transcriptional coactivator PPARγ coactivator 1α (PGC-1α) (Fig. 1). PGC-1α might be activated by the PKA/CREB pathway or by the β-adrenergic/cAMP pathway through p38 MAPK, which counteracts p160-mediated repression and increases PGC-1α stability.72,73 Several other factors positively regulate PGC-1α transcription such as forkhead box protein C2 (FOXC2) and sirtuin 3 (SIRT3).74 SIRT3 is overexpressed in BAT, in contrast to its low expression in WAT, being required for brown adipocytes to respond to PGC1α-related thermogenic activation. Indeed, PGC-1α/SIRT3 axis seems to be important for brown adipocytes, similarly to what has been observed in other cell types with high mitochondrial plasticity.75 In addition, PGC-1α coactivates nuclear respiratory factors 1 and 2 (NRF1 and NRF2), with the consequent overexpression of genes encoding for respiratory chain subunits and other factors important for mitochondrial functionality.72 PGC-1α also increases the expression and activation of peroxisome proliferator-activated receptors (PPARs) and other transcriptional factors that regulate the expression of genes involved in oxidative phosphorylation and thermogenesis.76,77 The stimulation of PPARγ was reported to enhance fatty acid transport into the mitochondrial matrix, fatty acid oxidation and oxygen consumption, which occurs in tandem with increased mitochondrial density.78 PPARα seems to act as a key component of brown fat thermogenesis by the induction not only of PGC-1α but also of PR- (PRD1-BF-1-RIZ1 homologous) domain containing protein (PRDM16).76 PRDM16 is a transcriptional regulator that stimulates brown adipogenesis by activating a broad program of brown fat differentiation.79,80 Indeed, PRDM16-expressing cells consume very high oxygen amounts due to uncoupled respiration, the classic hallmark of BAT.80 Other regulators of BAT differentiation include p53, pRB and C/EBPβ.81 Whereas pRB and C/EBPβ are required for adipogenesis and regulation of mitochondrial capacity, p53 seems to inhibit adipose conversion.82,83

Fig. 1.

Overview of the mediators and signalling pathways underlying WAT browning in cancer cachexia.

Abbreviations: AR, adrenergic receptor; CREB, cAMP response element-binding protein; FA, fatty acid; FOXC2, forkhead box protein C2; HSL, hormone sensitive lipase; IL, interleukin; MAPK, mitogen activated kinase; NA, noradrenaline; OXPHOS, oxidative phosphorylation; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PKA, protein kinase A; PPAR, peroxisome proliferator-activated receptor; PRDM16, PR- (PRD1-BF-1-RIZ1 homologous) domain containing protein 16; PTHrP, parathyroid-hormone related protein; TCA, tricarboxylic acid; TNF-α, tumour necrosis factor alpha; TWEAK, tumour necrosis factor-like weak inducer of apoptosis; UCP1, uncoupling protein 1; VEGF, vascular endothelial growth factor.

How exercise training modulates WAT remodelling

Physical activity has been reported to prevent and even counteract cachexia by improving whole-body metabolic status and modulating the inflammatory response.10 Consequently, skeletal muscle proteolysis is prevented, protein synthesis is stimulated and muscle mass is preserved.10,69 Indeed, adaptations in skeletal muscle are considered central to the anti-CC effect of exercise training. Less characterized are the mechanisms underlying the remodelling of adipose tissue promoted by exercise training in CC. In fact, if exercise training promotes remodelling of WAT in CC by the same mechanisms observed in obesity, exercise training is expected to potentiate CC-related WAT browning with impact on body weight.

Repeated bouts of exercise over a period of days, weeks, or even years, were reported to modulate WAT morphology and biochemical properties, independently of significant changes in weight loss. The adipocyte size and lipid content decreases following exercise training, resulting in reduced adiposity.84 However, these changes promoted by exercise training are dependent on WAT depots’ location, being subcutaneous WAT more responsive to physical activity. Indeed, Stanford et al.85 found that only 11 days of voluntary wheel running increased UCP1 content and resulted in the presence of multilocular cells in the subcutaneous WAT, which is consistent with tissue beiging. The number of blood vessels and the content of markers of vascularization as VEGFA and PGDF also increased in the subcutaneous WAT from exercised animals. This effect was hypothesized to be mediated by increased sympathetic innervation or by the interplay with other tissues responsive to exercise training. Indeed, moderate to high intensity endurance training leads to increased activity of SNS, resulting in higher levels of catecholamines and, consequently, in a marked increase of the thermogenic capacity of adipose tissue.86 Moreover, during exercise training, irisin is released from skeletal muscle by myocytes and leads to thermogenesis by promoting the browning of WAT. Exercise increases irisin by up-regulating PGC-1α expression in skeletal muscle.62 However, the role of irisin is still of great controversy because its precursor, the fibronectin domain containing protein 5 (FNDC5), and circulating irisin have not been consistently increased with endurance exercise in humans. This might be somehow related to a number of drawbacks in the detection of irisin with ELISA kits.87 Myostatin, initially characterized as a potent inhibitor of skeletal muscle growth, seems to regulate the metabolic phenotype of other tissues as adipose tissue.88 Loss of myostatin signalling in white adipocytes promotes the development of a brown adipose tissue-like phenotype through enhancing FNDC5 expression in these cells.89 Likewise, leptin has been shown to negatively regulate irisin-induced WAT browning.90 Musclin, also known as “exercise hormone” is a peptide secreted to bloodstream by skeletal muscle in response to exercise. It has been suggested that musclin activates PPAR?? and mitochondrial biogenesis, which induces WAT browning.7 Indeed, several reports highlight the impact of exercise training on mitochondria biogenesis and functionality. For instance, 8 weeks of swimming promoted the increase of respiratory chain complex cytochrome c oxidase and of the tricarboxylic acid cycle enzyme malate dehydrogenase in visceral WAT.91 Eleven days of voluntary wheel running was reported to increase basal rates of oxygen consumption rates in subcutaneous WAT.85 Changes in mitochondrial gene expression in subcutaneous WAT occur in response to several modalities of exercise, as well as to various training program durations ranging from as few as 11 days to up to 8 weeks.84

The interplay between cancer cachexia and exercise training

In the set of cancer cachexia, the therapeutic effect of exercise training has been mostly associated to its anti-inflammatory role.11,92 Substantial evidences collectively demonstrate the positive effects of exercise training on chronic inflammation through a reduction in circulating pro-inflammatory biomarkers. The anti-inflammatory ratio IL-10/TNF-α was reported to increase following exercise training in tumour-bearing animals, favouring an anti-inflammatory environment in adipose tissue.47,56 The levels of IL-15 also increased in these animals following 6-weeks of treadmill exercise training with consequent anabolic effects.56 Lifelong moderate intensity exercise training was shown to reduce C-reactive protein (CRP) in a preclinical model of mammary tumourigenesis, though without substantial evidences of modulation of other pro-inflammatory markers, including IL-6 and TNF-α (Table 1).49 The circulating levels of IL-6 are expected to increase following exercise and the magnitude of change on its levels is related to exercise intensity, duration and endurance capacity.58 The major contributor to this IL-6 increase after exercise are not monocytes93 but contracting skeletal muscle and, in smaller amounts, adipose tissue and brain.58,94,95 Nevertheless, IL-6 responsive to exercise training has an anti-inflammatory effect once inhibits TNF-α and IL-1 production96 and increases IL-1ra and IL-10.97 Chronic exercise training was also reported to prevent the mammary tumourigenesis-related increase of the pro-inflammatory cytokine TWEAK, with impact in body wasting.69 This positive effect of exercise training was associated to decreased tumour weight98 and less malignant lesions in rats.49 So, the enhancement of immune system in tumour-bearing animals seems to be among the mechanisms regulated by exercise training with impact on tumour growth and malignancy.

The anti-inflammatory effect of exercise training might also counteract or prevent anorexia that accompanies cachexia syndrome, improving body composition. This effect is reflected in the circulating levels of appetite-regulating hormones such as ghrelin. Ghrelin is an orexigenic hormone mostly synthesized in the stomach and activated by acylation through the addition of an octanoyl group in the stomach and small intestine.55 Exercise training reduces or circumvents the cachexia-related ghrelin resistance by promoting positive changes in the intracellular signalling pathways, especially in the hypothalamus and pituitary gland. So, ghrelin becomes more effective in enhancing growth hormone release and stimulating central appetite drive.55,99 Ghrelin also inhibits pro-inflammatory cytokines expression in endothelial cells.100 It has been hypothesized that the combination of pharmacological ghrelin with exercise training might exert an anabolic role or, at least, arrest cachexia-related catabolism.99 Exercise training also increased the circulating levels of anorexigenic hormones such as the gut hormone peptide tyrosine tyrosine (PYY3–36), in an intensity-dependent manner.55 Nevertheless, the mechanisms underlying the effect of exercise training on these appetite-regulating hormones are not well understood and even less in the set of cancer cachexia.


There is a general awareness of the health benefits of physical activity, evidenced by ongoing clinical trials that include exercise programs in multimodal management of cachexia along with pharmacological approaches. Despite the protective effect of exercise training against low-grade chronic inflammatory conditions as cancer cachexia, the synergy between these two conditions in the modulation of adipose tissue remodelling and, consequently, in the regulation of body composition remains elusive. Indeed, both conditions promote WAT browning but distinct mechanisms are probably involved. Whereas cancer cachexia-related beiging occurs in an inflammatory milieu, exercise-induced browning is associated with lower circulating levels of pro-inflammatory cytokines. So, one might suspect on the activation of distinct signalling pathways in adipocytes. Future studies should address this issue by starting to characterize and compare the signalling pathways involved in adipose tissue remodelling in cancer setting and cancer plus exercise training. A better understanding of how exercise intensity and workload regulate body composition across sexes, life stages and disease grades will certainly help in the development of more successful therapeutic strategies for the clinical management of this paraneoplasic syndrome.

Conflicts of interest

The authors declare no conflicts of interest.


This work was supported by Portuguese Foundation for Science and Technology (FCT), European Union, QREN, FEDER and COMPETE for funding the QOPNA (UID/QUI/00062/2013), CIAFEL (UID/DTP/00617/2013), UnIC (UID/IC/00051/2013) research units, R.V. (IF/00286/2015), R.N.F (SFRH/BD/91067/2012) and D.M.G (SFRH/BPD/90010/2012).

J.M. Argiles, S. Busquets, B. Stemmler, F.J. Lopez-Soriano.
Cancer cachexia: understanding the molecular basis.
Nat Rev Cancer, 14 (2014), pp. 754-762
M. Tsoli, M. Moore, D. Burg, A. Painter, R. Taylor, S.H. Lockie, et al.
Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice.
Cancer Res, 72 (2012), pp. 4372-4382
A.I. Padrao, P. Oliveira, R. Vitorino, B. Colaco, M.J. Pires, M. Marquez, et al.
Bladder cancer-induced skeletal muscle wasting: disclosing the role of mitochondria plasticity.
Int J Biochem Cell Biol, 45 (2013), pp. 1399-1409
M.C. Mendes, G.D. Pimentel, F.O. Costa, J.B. Carvalheira.
Molecular and neuroendocrine mechanisms of cancer cachexia.
J Endocrinol, 226 (2015), pp. R29-R43
M.J. Tisdale.
Mechanisms of cancer cachexia.
Physiol Rev, 89 (2009), pp. 381-410
K.C. Fearon, D.J. Glass, D.C. Guttridge.
Cancer cachexia: mediators, signaling, and metabolic pathways.
Cell Metab, 16 (2012), pp. 153-166
N. Jeremic, P. Chaturvedi, S.C. Tyagi.
Browning of white fat: novel insight into factors, mechanisms, and therapeutics.
J Cell Physiol, 232 (2017), pp. 61-68
K.C. Fearon.
Cancer cachexia and fat-muscle physiology.
N Engl J Med, 365 (2011), pp. 565-567
M. Ebadi, V.C. Mazurak.
Evidence and mechanisms of fat depletion in cancer.
Nutrients, 6 (2014), pp. 5280-5297
J.M. Argilés, S. Busquets, F.J. López-Soriano, P. Costelli, F. Penna.
Are there any benefits of exercise training in cancer cachexia?.
J Cachexia Sarcopenia Muscle, 3 (2012), pp. 73-76
R. Vitorino, D. Moreira-Goncalves, R. Ferreira.
Mitochondrial plasticity in cancer-related muscle wasting: potential approaches for its management.
Curr Opin Clin Nutr Metab Care, 18 (2015), pp. 226-233
T. Agustsson, P. Wikrantz, M. Rydén, T. Brismar, B. Isaksson.
Adipose tissue volume is decreased in recently diagnosed cancer patients with cachexia.
Nutrition, 28 (2012), pp. 851-855
M. Petruzzelli, M. Schweiger, R. Schreiber, R. Campos-Olivas, M. Tsoli, J. Allen, et al.
A switch from white to brown fat increases energy expenditure in cancer-associated cachexia.
Cell Metab, 20 (2014), pp. 433-447
A. Park, W.K. Kim, K.H. Bae.
Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells.
World J Stem Cells, 6 (2014), pp. 33-42
J. Ishibashi, P. Seale.
Beige can be slimming.
Science, 328 (2010), pp. 1113-1114
R.M. Kwee.
Prediction of tumor response to neoadjuvant therapy in patients with esophageal cancer with use of 18F FDG PET: a systematic review.
Radiology, 254 (2010), pp. 707-717
A.M. Cypess, S. Lehman, G. Williams, I. Tal, D. Rodman, A.B. Goldfine, et al.
Identification and importance of brown adipose tissue in adult humans.
N Engl J Med, 360 (2009), pp. 1509-1517
J. Nedergaard, T. Bengtsson, B. Cannon.
Unexpected evidence for active brown adipose tissue in adult humans.
Am J Physiol Endocrinol Metab, 293 (2007), pp. E444-E452
H-S. Park, S-G. Cho, C.K. Kim, H.S. Hwang, K.T. Noh, M-S. Kim, et al.
Heat shock protein Hsp72 is a negative regulator of apoptosis signal-regulating kinase 1.
Mol Cell Biol, 22 (2002), pp. 7721-7730
J. Wu, P. Cohen, B.M. Spiegelman.
Adaptive thermogenesis in adipocytes: is beige the new brown?.
Genes Dev, 27 (2013), pp. 234-250
A. Smorlesi, A. Frontini, A. Giordano, S. Cinti.
The adipose organ: white-brown adipocyte plasticity and metabolic inflammation.
J. Wu, P. Bostrom, L.M. Sparks, L. Ye, J.H. Choi, A.H. Giang, et al.
Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human.
S.T. Russell, K. Hirai, M.J. Tisdale.
Role of beta3-adrenergic receptors in the action of a tumour lipid mobilizing factor.
Br J Cancer, 86 (2002), pp. 424-428
A. Cabassi, S. Tedeschi.
Zinc-α2-glycoprotein as a marker of fat catabolism in humans.
Curr Opin Clin Nutr Metab Care, 16 (2013), pp. 267-271
Y. Jeanson, A. Carrière, L. Casteilla.
A new role for browning as a redox and stress adaptive mechanism?.
Front Endocrinol, 6 (2015), pp. 158
P. Mondello, A. Lacquaniti, S. Mondello, D. Bolignano, V. Pitini, C. Aloisi, et al.
Emerging markers of cachexia predict survival in cancer patients.
BMC Cancer, 14 (2014), pp. 828
E. Ntikoudi, M. Kiagia, P. Boura, K.N. Syrigos.
Hormones of adipose tissue and their biologic role in lung cancer.
Cancer Treat Rev, 40 (2014), pp. 22-30
N.B. Jamieson, D.J. Brown, A. Michael Wallace, D.C. McMillan.
Adiponectin and the systemic inflammatory response in weight-losing patients with non-small cell lung cancer.
Cytokine, 27 (2004), pp. 90-92
M.L. Batista Jr., M. Olivan, P.S.M. Alcantara, R. Sandoval, S.B. Peres, R.X. Neves, et al.
Adipose tissue-derived factors as potential biomarkers in cachectic cancer patients.
Cytokine, 61 (2013), pp. 532-539
J. Fruebis, T.S. Tsao, S. Javorschi, D. Ebbets-Reed, M.R. Erickson, F.T. Yen, et al.
Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.
Proc Natl Acad Sci U S A, 98 (2001), pp. 2005-2010
D. Diakowska, K. Markocka-Maczka, P. Szelachowski, K. Grabowski.
Serum levels of resistin, adiponectin, and apelin in gastroesophageal cancer patients.
Dis Markers, 2014 (2014), pp. 619649
I.N. Holcomb, R.C. Kabakoff, B. Chan, T.W. Baker, A. Gurney, W. Henzel, et al.
FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family.
EMBO J, 19 (2000), pp. 4046-4055
J. Smiechowska, A. Utech, G. Taffet, T. Hayes, M. Marcelli, J.M. Garcia.
Adipokines in patients with cancer anorexia and cachexia.
J Investig Med, 58 (2010), pp. 554-559
T.E. Nakajima, Y. Yamada, T. Hamano, K. Furuta, T. Gotoda, H. Katai, et al.
Adipocytokine levels in gastric cancer patients: resistin and visfatin as biomarkers of gastric cancer.
J Gastroenterol, 44 (2009), pp. 685-690
I. Shimizu, K. Walsh.
The whitening of brown fat and its implications for weight management in obesity.
Curr Obes Rep, 4 (2015), pp. 224-229
Y. Xue, N. Petrovic, R. Cao, O. Larsson, S. Lim, S. Chen, et al.
Hypoxia-independent angiogenesis in adipose tissues during cold acclimation.
Cell Metab, 9 (2009), pp. 99-109
S. Kir, J.P. White, S. Kleiner, L. Kazak, P. Cohen, V.E. Baracos, et al.
Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia.
Nature, 513 (2014), pp. 100-104
N. Hong, H.J. Yoon, Y.H. Lee, H.R. Kim, B.W. Lee, Y. Rhee, et al.
Serum PTHrP predicts weight loss in cancer patients independent of hypercalcemia, inflammation, and tumor burden.
J Clin Endocrinol Metab, 101 (2016), pp. 1207-1214
S. Kir, H. Komaba, A.P. Garcia, K.P. Economopoulos, W. Liu, B. Lanske, et al.
PTH/PTHrP receptor mediates cachexia in models of kidney failure and cancer.
Cell Metab, 23 (2016), pp. 315-323
F.S. Lira, J.C. Rosa, N.E. Zanchi, A.S. Yamashita, R.D. Lopes, A.C. Lopes, et al.
Regulation of inflammation in the adipose tissue in cancer cachexia: effect of exercise.
Cell Biochem Funct, 27 (2009), pp. 71-75
H.H. Zhang, M. Halbleib, F. Ahmad, V.C. Manganiello, A.S. Greenberg.
Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP.
Diabetes, 51 (2002), pp. 2929-2935
N. Kamei, K. Tobe, R. Suzuki, M. Ohsugi, T. Watanabe, N. Kubota, et al.
Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance.
J Biol Chem, 281 (2006), pp. 26602-26614
A.I. Padrao, D. Moreira-Goncalves, P.A. Oliveira, C. Teixeira, A.I. Faustino-Rocha, L. Helguero, et al.
Endurance training prevents TWEAK but not myostatin-mediated cardiac remodelling in cancer cachexia.
Arch Biochem Biophys, 567 (2015), pp. 13-21
A.J. Johnston, K.T. Murphy, L. Jenkinson, D. Laine, K. Emmrich, P. Faou, et al.
Targeting of Fn14 prevents cancer-induced cachexia and prolongs survival.
Cell, 162 (2015), pp. 1365-1378
J. Ruud, A. Nilsson, L. Engstrom Ruud, W. Wang, C. Nilsberth, B.M. Iresjo, et al.
Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.
Brain Behav Immun, 29 (2013), pp. 124-135
J. Faber, M.J. Uitdehaag, M. Spaander, S. van Steenbergen-Langeveld, P. Vos, M. Berkhout, et al.
Improved body weight and performance status and reduced serum PGE2 levels after nutritional intervention with a specific medical food in newly diagnosed patients with esophageal cancer or adenocarcinoma of the gastro-esophageal junction.
J Cachexia Sarcopenia Muscle, 6 (2015), pp. 32-44
F.F. Donatto, R.X. Neves, F.O. Rosa, R.G. Camargo, H. Ribeiro, E.M. Matos-Neto, et al.
Resistance exercise modulates lipid plasma profile and cytokine content in the adipose tissue of tumour-bearing rats.
Cytokine, 61 (2013), pp. 426-432
A. Bouassida, K. Chamari, M. Zaouali, Y. Feki, A. Zbidi, Z. Tabka.
Review on leptin and adiponectin responses and adaptations to acute and chronic exercise.
Br J Sports Med, 44 (2010), pp. 620-630
A.I. Faustino-Rocha, A. Gama, P.A. Oliveira, A. Alvarado, M.J. Neuparth, R. Ferreira, et al.
Effects of lifelong exercise training on mammary tumorigenesis induced by MNU in female Sprague-Dawley rats.
Clin Exp Med, (2016),
[Epub ahead of print]
U.R. Mikkelsen, C. Couppe, A. Karlsen, J.F. Grosset, P. Schjerling, A.L. Mackey, et al.
Life-long endurance exercise in humans: circulating levels of inflammatory markers and leg muscle size.
Mech Ageing Dev, 134 (2013), pp. 531-540
T. Nakajima, M. Kurano, T. Hasegawa, H. Takano, H. Iida, T. Yasuda, et al.
Pentraxin3 and high-sensitive C-reactive protein are independent inflammatory markers released during high-intensity exercise.
Eur J Appl Physiol, 110 (2010), pp. 905-913
L. Lerner, T.G. Hayes, N. Tao, B. Krieger, B. Feng, Z. Wu, et al.
Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients.
J Cachexia Sarcopenia Muscle, 6 (2015), pp. 317-324
E. Galliera, G. Lombardi, M.G. Marazzi, D. Grasso, E. Vianello, R. Pozzoni, et al.
Acute exercise in elite rugby players increases the circulating level of the cardiovascular biomarker GDF-15.
Scand J Clin Lab Invest, 74 (2014), pp. 492-499
C. Kojima, A. Ishibashi, K. Ebi, K. Goto.
The effect of a 20km run on appetite regulation in long distance runners.
Nutrients, 8 (2016), pp. 672
T.J. Hazell, H. Islam, L.K. Townsend, M.S. Schmale, J.L. Copeland.
Effects of exercise intensity on plasma concentrations of appetite-regulating hormones: potential mechanisms.
M. Molanouri Shamsi, S. Chekachak, S. Soudi, L.S. Quinn, K. Ranjbar, J. Chenari, et al.
Combined effect of aerobic interval training and selenium nanoparticles on expression of IL-15 and IL-10/TNF-alpha ratio in skeletal muscle of 4T1 breast cancer mice with cachexia.
Cytokine, 90 (2017), pp. 100-108
J.M. Peake, P. Della Gatta, K. Suzuki, D.C. Nieman.
Cytokine expression and secretion by skeletal muscle cells: regulatory mechanisms and exercise effects.
Exerc Immunol Rev, 21 (2015), pp. 8-25
A.M. Petersen, B.K. Pedersen.
The anti-inflammatory effect of exercise.
J Appl Physiol, 98 (2005), pp. 1154-1162
M. Krzystek-Korpacka, M. Matusiewicz, D. Diakowska, K. Grabowski, K. Blachut, I. Kustrzeba-Wojcicka, et al.
Acute-phase response proteins are related to cachexia and accelerated angiogenesis in gastroesophageal cancers.
Clin Chem Lab Med, 46 (2008), pp. 359-364
D. Us Altay, E.E. Keha, S. Ozer Yaman, I. Ince, A. Alver, B. Erdogan, et al.
Investigation of the expression of irisin and some cachectic factors in mice with experimentally induced gastric cancer.
QJM Int J Med, 109 (2016), pp. 785-790
P. Boström, J. Wu, M.P. Jedrychowski, A. Korde, L. Ye, J.C. Lo, et al.
A PGC1α-dependent myokine that drives browning of white fat and thermogenesis.
Nature, 481 (2012), pp. 463-468
M. Ost, V. Coleman, J. Kasch, S. Klaus.
Regulation of myokine expression: role of exercise and cellular stress.
Free Radic Biol Med, 98 (2016), pp. 78-89
K.S. Walker, R. Kambadur, M. Sharma, H.K. Smith.
Resistance training alters plasma myostatin but not IGF-1 in healthy men.
Med Sci Sports Exerc, 36 (2004), pp. 787-793
A. Saremi, R. Gharakhanloo, S. Sharghi, M.R. Gharaati, B. Larijani, K. Omidfar.
Effects of oral creatine and resistance training on serum myostatin and GASP-1.
Mol Cell Endocrinol, 317 (2010), pp. 25-30
J.S. Kim, J.K. Petrella, J.M. Cross, M.M. Bamman.
Load-mediated downregulation of myostatin mRNA is not sufficient to promote myofiber hypertrophy in humans: a cluster analysis.
J Appl Physiol, 103 (2007), pp. 1488-1495
J.F. Markworth, L. Vella, B.S. Lingard, D.L. Tull, T.W. Rupasinghe, A.J. Sinclair, et al.
Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment.
Am J Physiol Regul Integr Comp Physiol, 305 (2013), pp. R1281-R1296
H. Rong, U. Berg, O. Torring, C.J. Sundberg, B. Granberg, E. Bucht.
Effect of acute endurance and strength exercise on circulating calcium-regulating hormones and bone markers in young healthy males.
Scand J Med Sci Sports, 7 (1997), pp. 152-159
O.S. Gondim, V.T. de Camargo, F.A. Gutierrez, P.F. Martins, M.E. Passos, C.M. Momesso, et al.
Benefits of regular exercise on inflammatory and cardiovascular risk markers in normal weight, overweight and obese adults.
PLoS ONE, 10 (2015), pp. e0140596
A.I. Padrao, A.C. Figueira, A.I. Faustino-Rocha, A. Gama, M.M. Loureiro, M.J. Neuparth, et al.
Long-term exercise training prevents mammary tumorigenesis-induced muscle wasting in rats through the regulation of TWEAK signalling.
Acta Physiol, (2016),
[Epub ahead of print]
M.D. Ross, A.L. Wekesa, J.P. Phelan, M. Harrison.
Resistance exercise increases endothelial progenitor cells and angiogenic factors.
Med Sci Sports Exerc, 46 (2014), pp. 16-23
E. Beijer, J. Schoenmakers, G. Vijgen, F. Kessels, A.M. Dingemans, P. Schrauwen, et al.
A role of active brown adipose tissue in cancer cachexia?.
Oncol Rev, 6 (2012), pp. e11
B.K. Sharma, M. Patil, A. Satyanarayana.
Negative regulators of brown adipose tissue (BAT)-mediated thermogenesis.
J Cell Physiol, 229 (2014), pp. 1901-1907
W. Cao, K.W. Daniel, J. Robidoux, P. Puigserver, A.V. Medvedev, X. Bai, et al.
p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene.
Mol Cell Biol, 24 (2004), pp. 3057-3067
P. Seale, S. Kajimura, B.M. Spiegelman.
Transcriptional control of brown adipocyte development and physiological function – of mice and men.
Genes Dev, 23 (2009), pp. 788-797
A. Giralt, E. Hondares, J.A. Villena, F. Ribas, J. Diaz-Delfin, M. Giralt, et al.
Peroxisome proliferator-activated receptor-gamma coactivator-1alpha controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype.
J Biol Chem, 286 (2011), pp. 16958-16966
B. Zafrir.
Brown adipose tissue: research milestones of a potential player in human energy balance and obesity.
Horm Metab Res, 45 (2013), pp. 774-785
S. Kajimura, P. Seale, T. Tomaru, H. Erdjument-Bromage, M.P. Cooper, J.L. Ruas, et al.
Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex.
Genes Dev, 22 (2008), pp. 1397-1409
L. Wilson-Fritch, S. Nicoloro, M. Chouinard, M.A. Lazar, P.C. Chui, J. Leszyk, et al.
Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone.
J Clin Invest, 114 (2004), pp. 1281-1289
P. Seale, B. Bjork, W. Yang, S. Kajimura, S. Chin, S. Kuang, et al.
PRDM16 controls a brown fat/skeletal muscle switch.
Nature, 454 (2008), pp. 961-967
P. Seale, S. Kajimura, W. Yang, S. Chin, L.M. Rohas, M. Uldry, et al.
Transcriptional control of brown fat determination by PRDM16.
Cell Metab, 6 (2007), pp. 38-54
M. Rosell, M. Kaforou, A. Frontini, A. Okolo, Y.W. Chan, E. Nikolopoulou, et al.
Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice.
Am J Physiol Endocrinol Metab, 306 (2014), pp. E945-E964
P. Hallenborg, S. Feddersen, L. Madsen, K. Kristiansen.
The tumor suppressors pRB and p53 as regulators of adipocyte differentiation and function.
Expert Opin Ther Targets, 13 (2009), pp. 235-246
Q.Q. Tang, M.D. Lane.
Adipogenesis: from stem cell to adipocyte.
Annu Rev Biochem, 81 (2012), pp. 715-736
K.I. Stanford, R.J. Middelbeek, L.J. Goodyear.
Exercise effects on white adipose tissue: beiging and metabolic adaptations.
Diabetes, 64 (2015), pp. 2361-2368
K.I. Stanford, R.J. Middelbeek, K.L. Townsend, M.Y. Lee, H. Takahashi, K. So, et al.
A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis.
Diabetes, 64 (2015), pp. 2002-2014
D.M. Sepa-Kishi, R.B. Ceddia.
Exercise-mediated effects on white and brown adipose tissue plasticity and metabolism.
Exerc Sport Sci Rev, 44 (2016), pp. 37-44
F. Sanchis-Gomar, R. Alis, G. Lippi.
Circulating irisin detection: does it really work?.
Trends Endocrinol Metab, 26 (2015), pp. 335-336
S. Kirk, J. Oldham, R. Kambadur, M. Sharma, P. Dobbie, J. Bass.
Myostatin regulation during skeletal muscle regeneration.
X. Ge, D. Sathiakumar, B.J.G. Lua, H. Kukreti, M. Lee, C. McFarlane.
Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes.
Int J Obes, 41 (2017), pp. 137-148
A. Rodriguez, S. Ezquerro, L. Mendez-Gimenez, S. Becerril, G. Fruhbeck.
Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism.
Am J Physiol Endocrinol Metab, 309 (2015), pp. E691-E714
B. Stallknecht, J. Vinten, T. Ploug, H. Galbo.
Increased activities of mitochondrial enzymes in white adipose tissue in trained rats.
Am J Physiol, 261 (1991), pp. E410-E414
F.S. Lira, J.C.R. Neto, M. Seelaender.
Exercise training as treatment in cancer cachexia.
Appl Physiol Nutr Metab, 39 (2014), pp. 679-686
R.L. Starkie, J. Rolland, D.J. Angus, M.J. Anderson, M.A. Febbraio.
Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-α levels after prolonged running.
Am J Physiol Cell Physiol, 280 (2001), pp. C769-C774
D. Lyngso, L. Simonsen, J. Bulow.
Interleukin-6 production in human subcutaneous abdominal adipose tissue: the effect of exercise.
J Physiol, 543 (2002), pp. 373-378
L. Nybo, B. Nielsen, B.K. Pedersen, K. Moller, N.H. Secher.
Interleukin-6 release from the human brain during prolonged exercise.
J Physiol, 542 (2002), pp. 991-995
R. Schindler, J. Mancilla, S. Endres, R. Ghorbani, S.C. Clark, C.A. Dinarello.
Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF.
Blood, 75 (1990), pp. 40-47
A. Steensberg, C.P. Fischer, C. Keller, K. Moller, B.K. Pedersen.
IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans.
Am J Physiol Endocrinol Metab, 285 (2003), pp. E433-E437
F.S. Lira, F.L. Tavares, A.S. Yamashita, C.H. Koyama, M.J. Alves, E.C. Caperuto, et al.
Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats.
Cell Biochem Funct, 26 (2008), pp. 701-708
D. Fuoco, R.D. Kilgour, A. Vigano.
A hypothesis for a possible synergy between ghrelin and exercise in patients with cachexia: biochemical and physiological bases.
Med Hypotheses, 85 (2015), pp. 927-933
M. Invernizzi, S. Carda, C. Cisari.
Possible synergism of physical exercise and ghrelin-agonists in patients with cachexia associated with chronic heart failure.
Aging Clin Exp Res, 26 (2014), pp. 341-351
Copyright © 2017. PBJ-Associação Porto Biomedical/Porto Biomedical Society
Article options
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos