Open access peer-reviewed chapter

Browning of Adipose Tissue and Sirtuin Involvement

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Gaia Favero, Kristína Krajčíková, Francesca Bonomini, Luigi Fabrizio Rodella, Vladimíra Tomečková and Rita Rezzani

Submitted: January 30th, 2018 Reviewed: February 1st, 2018 Published: May 30th, 2018

DOI: 10.5772/intechopen.74760

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Obesity is an important risk factor for many diseases, including cardiovascular diseases, metabolic syndrome and cancers. Excessive dietary intake of caloric food results in its accumulation in white adipose tissue (WAT), whereas energy expenditure by fat utilization and oxidation predominately occurs in brown adipose tissue (BAT). Reducing obesity has become an important prevention strategy of research interest, focusing in the recent years, mainly on browning of WAT, the process during which the enhance of the mitochondria biogenesis occurs and then white adipocytes are converted to metabolically active beige adipocytes. Sirtuin1 (SIRT1), the most known isoform of sirtuin deacetylases, is implied in the browning of WAT process. In fact, it is a sensitive sensor of cell energy metabolism and, together with other sirtuin isoforms, contributes to this differentiation process. This chapter provides an overview about SIRT1 involvement in browning of WAT as a target molecule that can thereby contrast obesity.


  • adipose tissue
  • browning
  • obesity
  • resveratrol
  • sirtuin1

1. Introduction

Lipids are stored in the body by two types of adipose tissue such as white adipose tissue (WAT) and brown adipose tissue (BAT) [1, 2, 3]; the main parenchymal cells of the adipose tissue are adipocytes, and so far two fat cell types, white and brown cells, have been reported, respectively [4, 5, 6]. The white and brown adipocytes arise from separate progenitor cell lines, present distinct structure, morphology, localization and functions [1, 5, 7] and these differences contribute to the maintenance and modulation of energy and of metabolic health [4, 8, 9]. Despite these differences, both types of adipocytes share the activity of accumulation and release of fatty acids and both express the rather specific adrenergic receptor β3 [10, 11].

The adipose tissue is highly dynamic in the sense that changes in mass of an order of magnitude can occur, this happen during physiological (like pregnancy/lactation or aging) and pathological states (like metabolic syndrome, obesity, etc.) [12, 13]. In physiological condition, functional WAT and BAT adipose tissues control and modulate the energy balance with important effects on metabolic health and longevity [6, 14]. Aging is typically associated with a body redistribution of adipose tissue (increased central, visceral and ectopic adiposity) [4, 6, 15, 16] and chronic low-grade inflammation [17, 18]. Aging is also related to an increase of lipotoxicity due to the reduced capacity of adipose depots to store free fatty acids [16, 19]. These conditions contribute to increased risk for metabolic perturbations such as insulin resistance, impaired glucose tolerance and diabetes [18, 20]. Of importance, key processes of adipose tissue physiology affect molecular pathways that regulate lifespan [21], such as sirtuins (SIRTs) levels decline with age in several tissues, including adipose tissue, and this reduction induces adipocyte dysfunctions leading to obesity [6, 22].

To date, in both advanced and developing countries, obesity has become a major health problem [7, 12, 23], mainly because it carries an increased risk of death for the associated disorders [24, 25]. In fact, excess WAT throughout the body is associated with an increased risk of cardiovascular diseases, breast, colon, oesophageal, gall bladder and pancreatic cancers, sleep apnea and physical disabilities, such as knee arthritis [26, 27, 28].

In the following sections, we present firstly the main differences between WAT and BAT and the WAT browning process and then we discuss the potential SIRT1 involvement in this process as a target molecule that can thereby contrast obesity, introducing also the effects of resveratrol as a SIRT1 exogenous inducer.


2. White adipose tissue

WAT is now known to be highly dynamic, synthesizing and secreting multiple lipids, proteins and autocrine, endocrine, paracrine and neuroendocrine factors which are involved in the regulation of a wide range of physiological and metabolic processes [4, 29]. In particular, white adipocytes, characterized by a large unilocular lipid droplet, have a low density of mitochondria and variable size (25–200 μm) [6, 7, 12, 29, 30] and they might secrete adipokines that are pro- and anti-inflammatory cytokines fundamental in the regulation of metabolic functions and also in the communication from adipose tissue to other tissues [7, 12, 31]. Other lipid molecules are also secreted by WAT, including prostanoids, cholesterol and retinol, which are stored in order to be subsequently released [4, 32].

The development of subcutaneous WAT begins in uterus, but primarily occurs after birth, when specialized fat storage cells are needed to provide fuel during fasting periods. Hyperplastic and hypertrophic white adipocyte processes occur during WAT development, throughout the organism’s lifespan and in conditions of positive energy balance [33, 34, 35]. If the caloric excess is not reconciled by increased energy utilization, cellular hypertrophy and hyperplasia occur and then lead to adipocytes dysfunctions and so obesity [36, 37].


3. Brown adipose tissue

Since the 1970s, BAT has been increasingly recognized as the main site of nonshivering thermogenesis in mammals [35, 38] and it is probably the outcome of a single evolutionary development, in fact, unlike WAT, BAT is only found in mammals [35]. BAT adipocytes are smaller (15–60 μm) than white adipocytes [39] and present a characteristic brown color due to its high content of mitochondria and a lobulated surface that is innervated and very well vascularized [6, 8, 30]. BAT has the physiological role of metabolizing fatty acids in order to produce heat [4, 26], that is why it is often referred to as “good” fat, since it helps burn, not store, calories. This specific role of BAT is supported by the high content in its mitochondria of uncoupling protein1 (UCP1), uniquely expressed in these cells [4, 8, 26, 40]. The activation of UCP1 and transcriptional induction of the genes encoding UCP1 induce uptake of lipids and glucose from the circulation to sustain oxidation and thermogenesis [35, 41].

Functional BAT is more common in women than men and its mass and activity are reduced in overweight, obese and aging people [4, 41, 42]. Thus recruitment and activation of BAT seem to be a good tool to counteract obesity and its related diseases.


4. Browning of white adipose tissue

Currently, the terms browning, britening and beiging are used as synonyms to describe the differentiation of white adipocytes from brown adipocytes, so defined beige fat cells [30, 39, 43, 44, 45]. Browning of WAT is an adaptive and reversible response to numerous stimuli, including noradrenaline stimulation by cold exposure, exercise, natriuretic peptides, thyroid hormones, bile acids and nutritional compounds (resveratrol, menthol, capsaicin, etc.) [46, 47]. Other stimuli are due to pharmacological molecules, such as β3-adrenergic agonists, peroxisome proliferator-activated receptor γ (PPARγ) agonists thiazolidinediones and cannabinoid antagonist (rimonabant) [30, 48]. As a result of these stimuli, the transcriptional machinery of the browning program activates the expression of characteristic thermogenic genes (such as UCP1), leading to a beige adipocyte phenotype [30, 45, 47].

Two theories exist about the origin of beige adipocytes: (1) de novo differentiation from resident progenitor cells and (2) transdifferentiation. In detail, beige adipocytes can originate from progenitors resident within WAT that are differentiated in response to browning stimuli [39, 49, 50, 51] or, alternatively, they can arise via transdifferentiation, a process that involves the direct conversion of existing white adipocytes into brown-like fat cells [50]. This capacity of transdifferentiation is highly dependent on environment stimuli and also on the physiopathology aging [30, 52].

Beige adipocytes have a predominant lipid vacuole in the cytoplasm and numerous mitochondria, so exhibiting several intermediate features between white and brown adipocytes [33, 36, 47] (Figure 1), but these cells expressed characteristic and distinct gene markers that distinguished them from both white and brown fat cells [30, 39, 53, 54]. These genes encode proteins with very distinct cellular functions, including transcription factors (Zic1, Tbx15, etc.), metabolism-related proteins (Slc27a1, etc.) and proteins associated with inflammatory pathways (CD40, CD137, etc.) [35, 53, 54, 55]. It has been proved that more than 50 transcriptional molecules have been identified and their action mechanisms have been defined necessary in the browning transcriptional process [35, 56]. Among these, it is important to mention: PPARγ [50, 57], several members of the bone morphogenic protein family (BMP) [35, 58, 59], peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), which is involved in mitochondrial biogenesis [30, 33, 35] and also some transcription factors, such as C/EBPα and PRDM16 [58, 60, 61]. Even though the current terminology stresses the differences in cell lineage and localization, the evidence suggests that the beige adipocytes function as true thermogenic brown adipocytes [35, 47]. However, there is not a precise bioenergetic analysis of beige fat cells.

Figure 1.

Main morphological characteristics of white, beige and brown adipocytes. UCP1: uncoupling protein 1.

To date, the metabolic benefits of browning of WAT in humans remain to be fully established and the safety is a concern that must first be addressed regarding any method used to induce WAT browning. Cold exposure is a classic and efficient way to induce browning [62, 63], but its obvious discomfort, together with risks of hypothermia, makes it almost impractical for clinical use [50]. Therefore, browning agents, either endogenous or exogenous, provide an attractive alternative for limiting metabolic diseases.

Following paragraphs describe the potential SIRT1 involvement as a target molecule that can thereby contrast obesity, introducing briefly the effects of resveratrol as a SIRT1 inducer.


5. Sirtuins

SIRTs are NAD+-dependent deacetylases present in all prokaryotic and eukaryotic cells (with the exception of several red algae and archaea) [64, 65]. Mammals possess seven isoforms, from 1 to 7, mainly known as anti-aging molecules [66, 67, 68, 69]; however they are involved also in the regulation of numerous other cellular processes, such as integrity of chromatin [70, 71], cell cycle [72, 73], apoptosis [74, 75], energy metabolism [76, 77, 78], inflammation [79, 80] or detoxification [81, 82]. Their expression occurs throughout whole body differing in their cellular localization (mitochondrion, cytoplasm or nucleus) and tissue distribution [81, 83, 84, 85, 86, 87, 88] (Table 1). Biochemically, SIRTs are a class of proteins that posses mainly NAD+-dependent lysine deacetylase activities [89, 90]; however, some particular isoforms, like SIRT4 or SIRT6, also hold ADP-ribosyl transfer activity [91, 92]. SIRT isoforms share a conserved core catalytic domain, a NAD+-binding place, consists of two subdomains [93]. SIRT isoforms’ structural differences are manifested at N- and C-terminal regions, which are variable among homologs and enable them to possess more than one type of catalytic activity [94].

SIRT1Nucleus, cytoplasmDeacetylase
SIRT2Nucleus, cytoplasmDeacetylase
SIRT3Mitochondria, nucleus, CytoplasmDeacetylase
SIRT4Mitochondria, cytoplasmADP-ribosyltransferase, lipoamidase, deacetylase
SIRT5Mitochondria, cytoplasm, nucleusMalonyl-, sukcinyl-, glutaryl-deacylase
SIRT6Nucleus, endoplasmatic reticulum, cytoplasmDeacetylase, ADP-ribozyltransferase, long-chain fatty acids deacylase
SIRT7Nucleus (nucleolus), cytoplasmDeacetylase

Table 1.

Localization and catalytic activity of mammalian sirtuin isoforms.

So far, more than 30 SIRTs substrates were identified and, in general, are divided into two groups: histones and non-histone substrates and deacetylation of both is a quick response to stress stimuli or activators [95, 96]. SIRTs also serve as the regulators of transcription of genes in complex with other transcription factors [97].

Among the SIRT isoforms, the most attention has been focused on SIRT1, the ortholog of yeast Sir2 [64, 98]. During aging, its levels decrease [99] and this reduction occurs also during age-associated diseases (like neurodegenerative pathologies, cardiovascular diseases, metabolic syndrome, etc.) [100, 101, 102] making SIRT1 a possible treatment target. In fact, the beneficial effects of SIRT1 activation have been shown on numerous animal models [103, 104, 105, 106] as well as humans [107, 108, 109]. Additionally, the positive effects of SIRT1 activation include also browning of WAT [110, 111, 112].

5.1. Sirtuin1 involvement in browning of white adipose tissue

All seven SIRT isoforms are expressed in adipose tissue [113, 114, 115, 116, 117, 118], where they hydrolyse acetyl- and/or other acyl-group from the lysine residue of target substrate [119, 120, 121]. After particular stimuli, as summarized in Figure 2, the activation of SIRT1 at WAT level occurs and leads to the modulation (deacetylation) of PPARγ [110, 122], that with PRDM16 and PGC-1α, promote transcription of genes specific of BAT [61, 123].

Figure 2.

Involvement of sirtuin1 in browning process of white adipocyte. Sirtuin1 deacetylates PPARγ which than create a transcription complex with PRDM16 and PGC-1α promoting the beige adipocyte formation. SIRT1: sirtuin1; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; PPARγ: peroxisome proliferator-activated receptor γ.

Furthermore, PPARγ induces binding of C/EBPα and carboxy-terminal binding proteins 1 and 2 (CtBP 1 and 2) and represses transcription of genes which are specific of WAT [61, 124]. Thus, through PPARγ, SIRT1 is involved not only in enhancement of transcription of BAT genes, but also in repression of WAT genes. Furthermore, SIRT1 promotes mitochondrial biogenesis by activating PGC-1α [125]. PGC-1α regulates also transcription of mitochondrial SIRT3, which is necessary for the full acquirement of BAT phenotype [117, 126]. In detail, PGC-1α promotes the transcription of SIRT3, which mediates the phosphorylation of CREB with subsequent enhanced expression of UCP1 and PGC-1α [117, 127] (Figure 3). Furthermore, SIRT3 is involved in the regulation of many steps of mitochondrial metabolism, such as deacetylation of subunits of electron transport chain, for maintaining mitochondria proper functions [127, 128, 129].

Figure 3.

Sirtuin1 and sirtuin3 involvement in browning process. Sirtuin1 deacetylates PPARγ, which subsequently activates brown adipose tissue gene transcription and represses white adipose tissue genes. Sirtuin1 deacetylates also PGC-1α, which enhances mitochondrial biogenesis and sirtuin3 transcription, that is involved in maintaining mitochondrial functions and transcription of brown adipose tissue genes. CtBP 1/2: carboxy-terminal binding proteins 1 and 2; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; PPARγ: peroxisome proliferatoractivated receptor γ; SIRT1: sirtuin1; SIRT3: sirtuin3; UCP1: uncoupling protein1; WAT: white adipose tissue.

Moreover, SIRT1 in adipose tissue might also decrease fat storage, promote lipolysis and protect against obesity-induced inflammation [130, 131]. Fang et al. [132] described a mechanism of regulation of SIRT1 activity by SIRT7, in detail, SIRT1 is able to augment its own catalytical activity by autodeacetylation and SIRT7 binds to SIRT1 and inhibits its activity. These data will help to clarify the mechanism of obesity in humans who showed decreased SIRT1 and increased SIRT7 in visceral adipose tissue in comparison to healthy normal-weight subjects [114]. However, Rappou et al. [133] investigated the subcutaneous adipose tissue changes of all SIRT isoforms in obese subject with respect to normal-weight individuals and found decrease not only in SIRT1 and SIRT7 expression, but also in SIRT3. Moreover, they observed in the obese group that the continuous weight losers showed higher levels of SIRT1 in comparison to weight maintainers, suggesting that the individuals with naturally higher level of SIRT1 could be helped in weight loss.

Taken together, these data suggest that SIRTs, mainly SIRT1, could be strategic target in prevention and treatment of obesity and relative diseases. In fact, SIRTs activation results in many health benefits, including repression of adipogenesis [134] and promotion of browning of WAT [135, 136].

Polyphenolic compounds, among which the most studied in relation with SIRTs is resveratrol, might be dietary activators of SIRT1 [137, 138, 139]. Resveratrol is present in foods, like black and red grapes, blueberries, dark chocolate and peanuts [140, 141, 142]. In humans, its consumption protects low-density lipoprotein particles against oxidation promoting vascular health, decreases inflammation reducing C-reactive protein, tumor necrosis factor-α and interleukin-6 and also inhibits reactive oxygen species production [143, 144, 145]. Remarkably, resveratrol supplementation induced browning of WAT not only in rodents [146, 147], but also in human [135]. SIRT1 activation by resveratrol decreased PPARγ acetylation in 3T3-L1 white adipocytes and in human subcutaneous adipose tissue [110]. Furthermore, the overexpression of SIRT1 did not affect adipogenesis, but selectively decreased representative WAT genes [110]. This is in accordance with observations of Andrade et al. [146] who used resveratrol as SIRT1 activator in diet and showed attenuated expression of PPARγ and increased in UCP1 expression, contributing to loss of fat mass in comparison with mice fed without resveratrol.

It is interesting to cite also capsaicin as an inducer of WAT browning process through SIRT1 activation. The capsaicin, an irritant component of chili peppers [148], is not a direct activator of SIRT1, but it activates AMPK which, in turn, activates SIRT1 [149]. It may relieve neuropathic pain [150], osteoarthritis [151], migraine, headaches [152] or psoriasis [153] and it was studied also as a potent inducer of browning process [149, 154, 155]. Baskaran et al. [119] showed that the addition of 0.01% of capsaicin to high fat diet suppressed weight-gain in mice together with decrease in lipid content of epididymal and subcutaneous adipocytes. Furthermore, significant increase of SIRT1 and then of UCP1, PPARγ, PGC-1α and PRDM16 expression, promotes browning of WAT. However, it is difficult to study the effects of capsaicin in human due to low tolerance to capsaicin.

Resveratrol and capsaicin, together with other natural compounds, for example, green tea extracts, curcumin, melatonin or ω-3 polyunsaturated fatty acids [156, 157] and non-dietary inducers, such as endurance training and cold exposure [158], may represent interesting and promising stimuli of WAT browning process.


6. Conclusion

In summary, SIRT1 will be considered as an essential regulatory protein in browning of WAT. As BAT amount and SIRT1 expression decreased with age, targeted activation of SIRT1 is a promising strategy to stimulate browning of WAT. Activation of SIRT1 could be a novel strategy in obesity treatment and related disorders. However, further studies are needed to better clarify the involvement of SIRT1 in the browning of WAT process and to identify more efficient SIRT1 inducers, which possess minimum side effects.


Conflict of interest

The Authors declare no conflict of interest.


  1. 1. Kuda O, Rossmeisl M, Kopecky J. Omega-3 fatty acids and adipose tissue biology. Molecular Aspects of Medicine. 2018. [Epub ahead of print]. DOI: 10.1016/j.mam.2018.01.004
  2. 2. Obregon MJ. Adipose tissues and thyroid hormones. Frontiers in Physiology. 2014;5:479. DOI: 10.3389/fphys.2014.00479
  3. 3. Scheja L, Heeren J. Metabolic interplay between white, beige, brown adipocytes and the liver. Journal of Hepatology. 2016;64:1176-1186. DOI: 10.1016/j.jhep.2016.01.025
  4. 4. Esteve Ràfols M. Adipose tissue: Cell heterogeneity and functional diversity. Endocrinología y Nutrición. 2014;61:100-112. DOI: 10.1016/j.endonu.2013.03.011
  5. 5. Gaggini M, Carli F, Gastaldelli A. The color of fat and its central role in the development and progression of metabolic diseases. Hormone Molecular Biology and Clinical Investigation. 2017;31(1):1-14. DOI: 10.1515/hmbci-2017-0060
  6. 6. Schosserer M, Grillari J, Wolfrum C, Scheideler M. Age-induced changes in white, brite, and brown adipose depots: A mini-review. Gerontology. 2017. [Epub ahead of print]. DOI: 10.1159/000485183
  7. 7. Mathew H, Castracane VD, Mantzoros C. Adipose tissue and reproductive health. Metabolism. 2017. [Epub ahead of print]. DOI: 10.1016/j.metabol.2017.11.006
  8. 8. Cinti S. The adipose organ. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2005;73:9-15
  9. 9. Koppen A, Kalkhoven E. Brown vs white adipocytes: The PPARgamma coregulator story. FEBS Letters. 2010;584:3250-3259. DOI: 10.1016/j.febslet.2010.06.035
  10. 10. Decara J, Rivera P, Arrabal S, Vargas A, Serrano A, Pavón FJ, Dieguez C, Nogueiras R, Rodríguez de Fonseca F, Suárez J. Cooperative role of the glucagon-like peptide-1 receptor and β3-adrenergic-mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats. Acta Physiologica (Oxford, England). 2017. [Epub ahead of print]. DOI: 10.1111/apha.13008
  11. 11. Mund RA, Frishman WH. Brown adipose tissue thermogenesis: β3-adrenoreceptors as a potential target for the treatment of obesity in humans. Cardiology in Review. 2013;21:265-269. DOI: 10.1097/CRD.0b013e31829cabff
  12. 12. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiological Reviews. 2013;93:1-21. DOI: 10.1152/physrev.00017.2012
  13. 13. Trayhurn P. Hypoxia and adipocyte physiology: Implications for adipose tissue dysfunction in obesity. Annual Review of Nutrition. 2014;34:207-236. DOI: 10.1146/annurev-nutr-071812-161156
  14. 14. Charles KN, Li MD, Engin F, Arruda AP, Inouye K, Hotamisligil GS. Uncoupling of metabolic health from longevity through genetic alteration of adipose tissue lipid-binding proteins. Cell Reports. 2017;21:393-402. DOI: 10.1016/j.celrep.2017.09.051
  15. 15. Sakuma K, Yamaguchi A. Molecular mechanisms in aging and current strategies to counteract sarcopenia. Current Aging Science. 2010;3:90-101
  16. 16. Pararasa C, Bailey CJ, Griffiths HR. Ageing, adipose tissue, fatty acids and inflammation. Biogerontology. 2015;16:235-248. DOI: 10.1007/s10522-014-9536-x
  17. 17. Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, Furusawa J, Ohtani M, Fujii H, Koyasu S. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2010;463(7280):540-544. DOI: 10.1038/nature08636
  18. 18. Stout MB, Justice JN, Nicklas BJ, Kirkland JL. Physiological aging: Links among adipose tissue dysfunction, diabetes, and frailty. Physiology (Bethesda, Md.). 2017;32:9-19
  19. 19. Huffman DM, Barzilai N. Contribution of adipose tissue to health span and longevity. Interdisciplinary Topics in Gerontology. 2010;37:1-19. DOI: 10.1159/000319991
  20. 20. Morley JE. The metabolic syndrome and aging. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2004;59:139-142
  21. 21. Lettieri Barbato D, Aquilano K. Feast and famine: Adipose tissue adaptations for healthy aging. Ageing Research Reviews. 2016;28:85-93. DOI: 10.1016/j.arr.2016.05.007
  22. 22. Gong H, Pang J, Han Y, Dai Y, Dai D, Cai J, Zhang TM. Age-dependent tissue expression patterns of Sirt1 in senescence-accelerated mice. Molecular Medicine Reports. 2014;10:3296-3302. DOI: 10.3892/mmr.2014.2648
  23. 23. Withrow D, Alter DA. The economic burden of obesity worldwide: A systematic review of the direct costs of obesity. Obesity Reviews. 2011;12:131-141. DOI: 10.1111/j.1467-789X.2009.00712.x
  24. 24. Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, Cinti S. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. Journal of Lipid Research. 2008;49:1562-1568. DOI: 10.1194/jlr.M800019-JLR200
  25. 25. Upadhyay J, Farr O, Perakakis N, Ghaly W, Mantzoros C. Obesity as a disease. The Medical Clinics of North America. 2018;102:13-33. DOI: 10.1016/j.mcna.2017.08.004
  26. 26. Batta A. How brown fat interacts with white fat. Medico Research Chronicles. 2016;3:341-351
  27. 27. Bertolini F. Adipose tissue and breast cancer progression: A link between metabolism and cancer. Breast. 2013;22(Suppl 2):S48-S49. DOI: 10.1016/j.breast.2013.07.009
  28. 28. Jordan BF, Gourgue F, Cani PD. Adipose tissue metabolism and cancer progression: Novel insights from gut microbiota? Current Pathobiology Reports. 2017;5:315-322. DOI: 10.1007/s40139-017-0154-6
  29. 29. Chen Y, Pan R, Pfeifer A. Fat tissues, the brite and the dark sides. Pflügers Archiv. 2016;468:1803-1807
  30. 30. Vargas-Castillo A, Fuentes-Romero R, Rodriguez-Lopez LA, Torres N, Tovar AR. Understanding the biology of thermogenic fat: Is browning a new approach to the treatment of obesity? Archives of Medical Research. 2017;48:401-413. DOI: 10.1016/j.arcmed.2017.10.002
  31. 31. Favero G, Stacchiotti A, Castrezzati S, Bonomini F, Albanese M, Rezzani R, Rodella LF. Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice. Nutrition Research. 2015;35:891-900. DOI: 10.1016/j.nutres.2015.07.001
  32. 32. Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. European Journal of Cell Biology. 2013;92:229-236. DOI: 10.1016/j.ejcb.2013.06.001
  33. 33. Cinti S. Transdifferentiation properties of adipocytes in the adipose organ. American Journal of Physiology. Endocrinology and Metabolism. 2009;297:E977-E986. DOI: 10.1152/ajpendo.00183.2009
  34. 34. Cinti S. The adipose organ at a glance. Disease Models & Mechanisms. 2012;5:588-594. DOI: 10.1242/dmm.009662
  35. 35. Giralt M, Villarroya F. White, brown, beige/brite: Different adipose cells for different functions? Endocrinology. 2013;154:2992-3000. DOI: 10.1210/en.2013-1403
  36. 36. Aldiss P, Betts J, Sale C, Pope M, Symonds ME. Exercise-induced ‘browning’ of adipose tissues. Metabolism. 2017. [Epub ahead of print]. DOI: 10.1016/j.metabol.2017.11.009
  37. 37. Haczeyni F, Bell-Anderson KS, Farrell GC. Causes and mechanisms of adipocyte enlargement and adipose expansion. Obesity Reviews. 2018;19:406-420. DOI: 10.1111/obr.12646
  38. 38. Gao W, Kong X, Yang Q. Isolation, primary culture, and differentiation of preadipocytes from mouse brown adipose tissue. Methods in Molecular Biology. 2017;1566:3-8. DOI: 10.1007/978-1-4939-6820-6_1
  39. 39. Jeanson Y, Carrière A, Casteilla L. A new role for browning as a redox and stress adaptive mechanism? Frontiers in Endocrinology (Lausanne). 2015;6:158. DOI: 10.3389/fendo.2015.00158
  40. 40. Cannon B, Nedergaard J. Brown adipose tissue: Function and physiological significance. Physiological Reviews. 2004;84:277-359
  41. 41. Marlatt KL, Ravussin E. Brown adipose tissue: An update on recent findings. Current Obesity Reports. 2017;6:389-396. DOI: 10.1007/s13679-017-0283-6
  42. 42. Dong M, Lin J, Lim W, Jin W, Lee HJ. Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia. Frontiers in Medicine. 2017. [Epub ahead of print]. DOI: 10.1007/s11684-017-0555-2
  43. 43. Fenzl A, Kiefer FW. Brown adipose tissue and thermogenesis. Hormone Molecular Biology and Clinical Investigation. 2014;19:25-37. DOI: 10.1515/hmbci-2014-0022
  44. 44. Stanford KI, Middelbeek RJ, Goodyear LJ. Exercise effects on white adipose tissue: Beiging and metabolic adaptations. Diabetes. 2015;64:2361-2368. DOI: 10.2337/db15-0227. Erratum in: Diabetes. 2015;64:3334
  45. 45. Stanford KI, Goodyear LJ. Exercise regulation of adipose tissue. Adipocytes. 2016;5:153-162. DOI: 10.1080/21623945.2016.1191307
  46. 46. Azhar Y, Parmar A, Miller CN, Samuels JS, Rayalam S. Phytochemicals as novel agents for the induction of browning in white adipose tissue. Nutrition & Metabolism (London). 2016;13:89. DOI: 10.1186/s12986-016-0150-6
  47. 47. Castro É, Silva TEO, Festuccia WT. Critical review of beige adipocyte thermogenic activation and contribution to whole-body energy expenditure. Hormone Molecular Biology and Clinical Investigation. 2017;31(2). DOI: 10.1515/hmbci-2017-0042
  48. 48. Horder J, Browning M, Di Simplicio M, Cowen PJ, Harmer CJ. Effects of 7 days of treatment with the cannabinoid type 1 receptor antagonist, rimonabant, on emotional processing. Journal of Psychopharmacology. 2012;26:125-132
  49. 49. Smorlesi A, Frontini A, Giordano A, Cinti S. The adipose organ: White-brown adipocyte plasticity and metabolic inflammation. Obesity Reviews. 2012;13(Suppl 2):83-96. DOI: 10.1111/j.1467-789X.2012.01039.x
  50. 50. Tamucci KA, Namwanje M, Fan L, Qiang L. The dark side of browning. Protein & Cell. 2018;9:152-163. DOI: 10.1007/s13238-017-0434-2
  51. 51. Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nature Medicine. 2013;19:1338-1344. DOI: 10.1038/nm.3324
  52. 52. Kajimura S, Spiegelman BM, Seale P. Brown and beige fat: Physiological roles beyond heat generation. Cell Metabolism. 2015;22:546-559. DOI: 10.1016/j.cmet.2015.09.007
  53. 53. Waldén TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. American Journal of Physiology. Endocrinology and Metabolism. 2012;302:E19-E31. DOI: 10.1152/ajpendo.00249.2011
  54. 54. Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366-376
  55. 55. Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One. 2012;7:e49452. DOI: 10.1371/journal.pone.0049452
  56. 56. Wu H, Deng X, Shi Y, Su Y, Wei J, Huan H. PGC-1α, glucose metabolism and type 2 diabetes mellitus. The Journal of Endocrinology. 2016;229:99-115. DOI: 10.1530/JOE-16-0021
  57. 57. Farmer SR. Transcriptional control of adipocyte formation. Cell Metabolism. 2006;4:263-273
  58. 58. Kim E, Lim SM, Kim MS, Yoo SH, Kim Y. Phyllodulcin, a natural sweetener, regulates obesity-related metabolic changes and fat Browning-related genes of subcutaneous white adipose tissue in high-fat diet-induced obese mice. Nutrients. 2017;9(10):1-15
  59. 59. Poher AL, Altirriba J, Veyrat-Durebex C, Rohner-Jeanrenaud F. Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance. Frontiers in Physiology. 2015;6:4. DOI: 10.3389/fphys.2015.00004
  60. 60. Bargut TCL, Souza-Mello V, Aguila MB, Mandarim-de-Lacerda CA. Browning of white adipose tissue: Lessons from experimental models. Hormone Molecular Biology and Clinical Investigation. 2017;31(1). DOI: 10.1515/hmbci-2016-0051
  61. 61. Lo KA, Sun L. Turning WAT into BAT: A review on regulators controlling the browning of white adipocytes. Bioscience Reports. 2013;33:711-719. DOI: 10.1042/BSR20130046
  62. 62. Bartness TJ, Ryu V. Neural control of white, beige and brown adipocytes. International Journal of Obesity Supplements. 2015;5(Suppl 1):S35-S39. DOI: 10.1038/ijosup.2015.9
  63. 63. Kiefer FW. The significance of beige and brown fat in humans. Endocrine Connections. 2017;6:R70-R79. DOI: 10.1530/EC-17-0037
  64. 64. Greiss S, Gartner A. Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation. Molecules and Cells. 2009;28:407-415. DOI: 10.1007/s10059-009-0169-x
  65. 65. Min J, Landry J, Sternglanz R, Xu R-M. Crystal structure of a SIR2 homolog-NAD complex. Cell. 2010;105:269-279. DOI: 10.1016/S0092-8674(01)00317-8
  66. 66. Favero G, Franceschetti L, Rodella LF, Rezzani R. Sirtuins, aging, and cardiovascular risks. Age (Dordrecht, Netherlands). 2015;37:9804. DOI: 10.1007/s11357-015-9804-y
  67. 67. Guarente L. Calorie restriction and sirtuins revisited. Genes & Development. 2013;27:2072-2085. DOI: 10.1101/gad.227439.113
  68. 68. North BJ, Rosenberg MA, Jeganathan KB, Hafner AV, Michan S, Dai J, Baker DJ, Cen Y, Wu LE, Sauve AA, van Deursen JM, Rosenzweig A, Sinclair DA. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO Journal. 2014;33:1438-1453. DOI: 10.15252/embj.201386907
  69. 69. Satoh A, Brace CS, Rensing N, Clifton P, Wozniak DF, Herzog ED, Yamada KA, Imai S. Sirt1 extends life span and delays aging in mice trough regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metabolism. 2013;18:416-430. DOI: 10.1016/j.cmet.2013.07.013
  70. 70. De Bonis MJ, Ortega S, Blasco MA. SIRT1 is necessary for proficient telomere elongation and genomic stability of induced pluripotent stem cells. Stem Cell Reports. 2014;2:690-706. DOI: 10.1016/j.stemcr.2014.03.002
  71. 71. Dobbin MM, Madabushi R, Pan L, Chen Y, Kim D, Gao J, Ahanonu B, Pao PC, Qiu Y, Zhao Y, Tsai LH. SIRT1 collaborates with ATM and HDAC1 to maintain genetic stability in neurons. Nature Neuroscience. 2013;16:1008-1015. DOI: 10.1038/nn.3460
  72. 72. Sasaki T, Maier B, Koclega KD, Chruszcz M, Gluba W, Stukenberg PT. Phosphorylation regulates SIRT1 function. PLoS One. 2008;3:e4020. DOI: 10.1371/journal.pone.0004020
  73. 73. Wang R-H, Lahusen TJ, Chen Q, Xu X, Jenkins LMM, Leo E, Fu H, Aladjem M, Pommier Y, Appella E, Deng C-X. SIRT1 Deacetylates TopBP1 and modulates intra-S-phase checkpoint and DNA replication origin firing. International Journal of Biological Sciences. 2014;10:1193-1202. DOI: 10.7150/ijbs.11066
  74. 74. Chao S-C, Chen Y-J, Huang K-H, Kuo K-L, Yang T-H, Huang K-Y, Wang C-C, Tang C-H, Yang R-S, Liu S-H. Induction of sirtuin-1 signaling by resveratrol induces human chondrosarcoma cell apoptosis and exhibits antitumor activity. Scientific Reports. 2017;7:3180. DOI: 10.1038/s41598-017-03635-7
  75. 75. Jiang W, Zhang X, Hao J, Shen J, Fang J, Dong W, Wang D, Zhang X, Shui W, Luo Y, Lin L, Qiu Q, Liu B, Hu Z. SIRT1 protects against apoptosis by promoting autophagy in degenerative human disc nucleus pulposus cells. Scientific Reports. 2014;4:7456. DOI: 10.1038/srep07456
  76. 76. Liu TF, Vachharajani VT, Yoza BK, McCall CE. NAD+ -dependent Sirtuin 1 and 6 proteins coordinate a switch from glucose to fatty acid oxidation during the acute inflammatory response. The Journal of Biological Chemistry. 2012;287:25758-25769. DOI: 10.1074/jbc.M112.362343
  77. 77. Sodhi K, Puri N, Favero G, Stevens S, Meadows C, Abraham NG, Rezzani R, Ansinelli H, Lebovics E, Shapiro JI. Fructose mediated non-alcoholic fatty liver is attenuated by HO-1-SIRT1 module in murine hepatocytes and mice fed a high fructose diet. PLoS One. 2015;10:e0128648. DOI: 10.1371/journal.pone.0128648
  78. 78. Stacchiotti A, Favero G, Lavazza A, Golic I, Aleksic M, Korac A, Rodella JF, Rezzani R. Hepatic macrosteatosis is partially converted to microsteatosis by melatonin supplementation in ob/ob mice non-alcoholic fatty liver disease. PLoS One. 2016;11:e0148115. DOI: 10.1371/journal.pone.0148115
  79. 79. Balestieri ML, Rizzo MR, Barbieri M, Paolisso P, D’Onofrio N, Giovane A, Siniscalchi M, Minicucci F, Sardu C, D’Andrea D, Mauro C, Ferraccio F, Servillo L, Chirico F, Calazzo P, Paolisso G, Marfella R. Sirtuin 6 expression and inflammation in diabetic atherosclerotic plaques: Effects of incretin treatment. Diabetes 2015;64:1395-1406. DOI: 10.2337/db14-1149
  80. 80. Hou KL, Lin SK, Chao LH, Hsiang-Hua Lai E, Chang CC, Shun CT, Lu WY, Wang JH, Hsiao M, Hong CY, Kok SH. Sirtuin 6 supresses hypoxia-induced inflammatory response in human osteoblasts via inhibition of reactive oxygen species production and glycolysis-A therapeutic implication in inflammatory bone resorption. BioFactors. 2017;43:170-180. DOI: 10.1002/biof.1320
  81. 81. Mendes KL, Lelis DF, Santos SHS. Nuclear sirtuins and inflammatory signalling pathways. Cytokine & Growth Factor Reviews. 2017;38:98-105. DOI: 10.1016/j.cytogfr.2017.11.001
  82. 82. Tao R, Vassilopoulos A, Parisiadou L, Yan Y, Gius D. Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxidants & Redox Signaling. 2014;20:1646-1654. DOI: 10.1089/ars.2013.5482
  83. 83. Chen Y-R, Fang S-R, Fu Y-C, Zhou X-H, Xu MY, Xu W-C. Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochemistry and Cell Biology. 2010;88:715-722. DOI: 10.1139/O10-010
  84. 84. Iwahara T, Bonasio R, Narendra V, Reinberg D. SIRT3 functions in the nucleus in the control of stress-related gene expression. Molecular and Cellular Biology. 2012;32:5022-5034. DOI: 10.1128/MCB.00822-12
  85. 85. Jedrusik-Bode M, Studencka M, Smolka C, Baumann T, Schmidt H, Kampf J, Paap F, Martin S, Tazi J, Müller KM, Krüger M, Braun T, Bober E. The sirtuin SIRT6 regulates stress granule formation in C. elegans and mammals. Journal of Cell Science. 2013;126:5166-5177. DOI: 10.1242/jcs.130708
  86. 86. Kiran S, Chatterjee N, Singh S, Kaul SC, Wadhwa R, Ramakrishna G. Intracellular distribution of human SIRT7 and mapping of the nuclear/nucleolar localization signal. FEBS Journal. 2013;280:3451-3466. DOI: 10.1111/febs.12346
  87. 87. Kupis W, Pałyga J, Tomal E, Niewiadomska E. The role of sirtuins in cellular homeostasis. Journal of Physiology and Biochemistry. 2016;72:371-380. DOI: 10.1007/s13105-016-0492-6
  88. 88. Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Molecular and Cellular Biology. 2008;28:6384-6401. DOI: 10.1128/MCB.00426-08
  89. 89. Buck SW, Gallo CM, Smith JS. Diversity in the Sir2 family of protein deacetylases. Journal of Leukocyte Biology. 2004;75:939-950
  90. 90. Li Y, Liu T, Liao S, Li Y, Lan Y, Wang A, Wang Y, He B. A mini-review on sirtuin activity assays. Biochemical and Biophysical Research Communications. 2015;467:459-466. DOI: 10.1016/j.bbrc.2015.09.172
  91. 91. Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A, Seluanov A, Gorbunova V. SIRT6 promotes DNA repair under stress by activating PARP1. Science. 2011;332:1443-1446. DOI: 10.1126/science.1202723
  92. 92. Mathias RA, Greco TM, Oberstein A, Budayeva HG, Chakrabarti R, Rowland EA, Kang Y, Shenk T, Cristea IM. Sirtuin4 is a lipoamidase regulate pyruvate dehydrogenase complex activity. Cell. 2014;159:1615-1625. DOI: 10.1016/j.cell.2014.11.046
  93. 93. Davenport AM, Huber FM, Hoelz A. Structural and functional analysis of human SIRT1. Journal of Molecular Biology. 2014;426:526-541. DOI: 10.1016/j.jmb.2013.10.009
  94. 94. Haigis MC, Sinclair DA. Mammalian sirtuins: Biological insights and disease relevance. Annual Review of Pathology. 2010;5:253-295. DOI: 10.1146/annurev.pathol.4.110807.092250
  95. 95. Li XY, Han X, Zhang HM, Tan H, Han SF. SIRT1 signaling pathway mediated the protective effects on myocardium of rats after endurance training and acute exhaustive exercise. Zhonghua Xin Xue Guan Bing Za Zhi 2017;45:501-506. DOI: 10.3760/cma.j.issn.0253-3758.2017.06.012
  96. 96. Mansur AP, Roggerio A, Goes MFS, Avakian SD, Leal DP, Maranhão RC, Strunz CMC. Serum concentrations and gene expression of sirtuin 1 in healthy and slightly overweight subjects after caloric restriction or resveratrol supplementation: A randomized trial. International Journal of Cardiology. 2017;227:788-794. DOI: 10.1016/j.ijcard.2016.10.058
  97. 97. Tasseli L, Xi Y, Zheng W, Tennen RI, Odrowaz Z, Simeoni F, Li W, Chua KF. SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence. Nature Structural & Molecular Biology. 2016;23:434-440. DOI: 10.1038/nsmb.3202
  98. 98. Wolf G. Calorie restriction increases life span: A molecular mechanism. Nutrition Reviews. 2006;64(2 Pt 1):89-92
  99. 99. Owczarz M, Budzinska M, Domaszewska-Szostek A, Borkowska J, Polosak J, Gewartowska M, Slusarczyk P, Puzianowska-Kuznicka M. miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans. Experimental Biology and Medicine. 2017;242:1453-1461. DOI: 10.1177/1535370217720884
  100. 100. Lu T-M, Tsai J-Y, Chen Y-C, Huang C-Y, Hsu H-L, Weng C-F, Shih C-C, Hsu C-P. Downregulation of Sirt1 as aging change in advanced heart failure. Journal of Biomedical Science. 2014;21:57. DOI: 10.1186/1423-0127-21-57
  101. 101. Mariani S, Fiore D, Basciani S, Persichetti A, Contini S, Lubrano C, Salvatori L, Lenzi A, Gnessi L. Plasma levels of SIRT1 associate with non-alcoholic fatty liver disease in obese patients. Endocrine. 2015;49:711-716. DOI: 10.1007/s12020-014-0465-x
  102. 102. Singh P, Hanson PS, Morris CM. SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson’s disease. BMC Neuroscience. 2017;18:46. DOI: 10.1186/s12868-017-0364-1
  103. 103. Huang XZ, Wen D, Zhang M, Xie Q, Ma L, Guan Y, Ren Y, Chen J, Hao CM. Sirt1 activation ameliorates renal fibrosis by inhibiting the TGF-β/Smad3 pathway. Journal of Cellular Biochemistry. 2014;115:996-1005. DOI: 10.1002/jcb.24748
  104. 104. Gilbert RE, Thai K, Advani SL, Cummins CL, Kepecs DM, Schroer SA, Woo M, Zhang Y. SIRT1 activation ameliorates hyperglycaemia by inducing a torpor-like state in an obese mouse model of type 2 diabetes. Diabetologia. 2015;58:819-827. DOI: 10.1007/s00125-014-3485-4
  105. 105. Kuno A, Tanno M, Horio Y. The effects of resveratrol and SIRT1 activation on dystrophic cardiomyopathy. Annal of the New York Academy of Sciences. 2015;1348:46-54. DOI: 10.1111/nyas.12812
  106. 106. Sin TK, Yu AP, Yung BY, Yip SP, Chan LW, Wong CS, Rudd JA, Siu PM. Effects of long-term resveratrol-induced SIRT1 activation on insulin and apoptotic signaling in aged skeletal muscle. Acta Diabetologica. 2015;52:1063-1075. DOI: 10.1007/s00592-015-0767-3
  107. 107. Timmers S, Konnings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MKC, Kunz I, Schrauwen-Hinderlink VB, Blaak E, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metabolism 2011;14:612-622. DOI: 10.1016/j.cmet.2011.10.002
  108. 108. Goh KP, Lee HY, Lau DP, Supaat W, Chan YH, Koh AFY. Effects of resveratrol in patients with type 2 diabetes mellitus on skeletal muscle SIRT1 expression and energy expenditure. International Journal of Sport Nutrition and Exercise Metabolism. 2014;24:2-13. DOI: 10.1123/ijsnem.2013-0045
  109. 109. van der Meer AJ, Scicluna BP, Moerland PD, Lin J, Jacobson EW, Vlasuk GP, vad der Poll T. The selective Sirtuin 1 activator SRT2104 reduces endotoxin-induced cytokine release and coagulation activation in humans. Critical Care Medicine. 2015;43:199-202. DOI: 10.1097/CCM.0000000000000949
  110. 110. Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, Rosenbaum M, Zhao Y, Gu W, Farmer SR, Accili D. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of PPARγ. Cell. 2012;150:620-632. DOI: 10.1016/j.cell.2012.06.027
  111. 111. Wang H, Liu L, Lin JZ, Aprahamian TR, Farmer SR. Browning of white adipose tissue with roscovitine induces a distinct population of UCP1(+) adipocytes. Cell Metabolism. 2016;24:835-847. DOI: 10.1016/j.cmet.2016.10.005
  112. 112. Xing T, Kang Y, Xu X, Wang B, Du M, Zhu MJ. Raspberry supplementation improves insulin signaling and promotes brown-like adipocyte development in white adipose tissue of obese mice. Molecular Nutrition & Food Research. 2018. [Epub ahead of print]. DOI: 10.1002/ mnfr.201701035
  113. 113. Jukarainen S, Heinonen S, Rämö JT, Rinnankoski-Tuikka R, Rappou E, Tummers M, Muniandy M, Hakkarainen A, Lundbom J, Lundbom N, Kaprio J, Rissanen A, Pirinen E, Pietiläinen KH. Obesity is associated with low NAD+/SIRT pathway expression in adipose tissue of BMI-discordant monozygotic twins. The Journal of Clinical Endocrinology and Metabolism. 2016;101:275-283. DOI: 10.1210/jc.2015-3095
  114. 114. Kurylowicz A, Owczarz M, Polosak J, Jonas MI, Lisik W, Joans M, Chmura A, Puzianowska-Kuznicka M. SIRT1 and SIRT7 expression in adipose tissue of obese and normal-weight individuals is regulated by microRNAs but not by methylation status. International Journal of Obesity. 2016;40:1635-1642. DOI: 10.1038/ijo.2016.131
  115. 115. Laurent G, German NJ, Saha AK, de Boer VCJ, Davies M, Koves TR, Dephoure N, Fischer F, Boanca G, Vaitheesvaran B, Lovitch SB, Sharpe AH, Kurland IJ, Steegborn C, Gygi SP, Muoio DM, Ruderman NB, Haigis MC. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl-CoA decarboxylase. Molecular Cell. 2013;50:686-698. DOI: 10.1016/j.molcel.2013.05.012
  116. 116. Peredo-Escárcega AE, Guarner-Lans V, Pérez-Torres I, Ortega-Ocampo S, Carreón-Torres E, Castrejón-Tellez V, Díaz-Diáz E, Rubio-Ruiz ME. The combination of resveratrol and quercetin attenuates metabolic syndrome in rats by modifying the serum fatty acid composition and by upregulating SIRT 1 and SIRT 2 expression in white adipose tissue. Evidence-based Complementary and Alternative Medicine. 2015;2015:474032. DOI: 10.1155/2015/474032
  117. 117. Shi T, Wang F, Stieren E, Tong Q. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. The Journal of Biological Chemistry. 2005;280:13560-13567. DOI: 10.1074/jbc.M414670200
  118. 118. Yao L, Cui X, Chen Q, Yang X, Fang F, Zhang J, Liu G, Jin W, Chang Y. Cold-inducible SIRT6 regulates thermognesis of brown and beige fat. Cell Reports. 2017;20:641-654. DOI: 10.1016/j.celrep.2017.06.069
  119. 119. Baskaran P, Krishnan V, Fettel K, Gao P, Zhu Z, Ren J, Thyagarajan B. TRPV1 activation counters diet-induced obesity trough sirtuin-1 activation and PRDM-16 deacetylation in brown adipose tissue. International Journal of Obesity. 2017;41:739-749. DOI: 10.1038/ijo.2017.16
  120. 120. Jinag H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature. 2013;496:110-113. DOI: 10.1038/nature12038
  121. 121. Xiong X, Zhang C, Zhang Y, Fan R, Qian X, Dong XC. Fabp-4-Cre-mediated Sirt6 deletion impairs adipose tissue function and metabolic homeostasis in mice. The Journal of Endocrinology. 2017;233:307-314. DOI: 10.1530/JOE-17-0033
  122. 122. Han L, Zhou R, Niu J, McNutt MA, Wang P, Tong T. SIRT1 is regulated by a PPARγ-SIRT1 negative feedback loop associated with senescence. Nucleic Acids Research. 2010;38:7458-7471. DOI: 10.1093/nar/gkq609
  123. 123. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scimè A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961-967. DOI: 10.1038/nature07182
  124. 124. Vernochet C, Peres SB, Davis KE, McDonald ME, Qiang L, Wang H, Scherer PE, Farmer SR. C/EBPα and the Corepressors CtBP1 and CtBP2 regulate repression of select Viscelar white adipose genes during induction od the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor γ agonists. Molecular and Cellular Biology. 2009;29:4714-4728. DOI: 10.1128/MCB.01899-08
  125. 125. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98:115-124
  126. 126. Giralt A, Hondares E, Villena JA, Ribas F, Díaz-Delfín J, Giralt M, Iglesias R, Villarroya F. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha controls transcription of the Sirt3 gene, an essential component of the thermogenic brown adipocyte phenotype. The Journal of Biological Chemistry. 2011;286:16958-16966. DOI: 10.1074/jbc.M110.202390
  127. 127. Brenmoehl J, Hoeflich A. Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3. Mitochondrion. 2013;13:755-761. DOI: 10.1016/j.mito.2013.04.002
  128. 128. Anamika KA, Acharjee P, Acharjee A, Trigun SK. Mitochondrial SIRT3 and neurodegenerative brain disorders. Journal of Chemical Neuroanatomy. 2017. [Epub ahead of print]. DOI: 10.1016/j. jchemneu.2017.11.009
  129. 129. Tang X, Chen XF, Chen HZ, Liu DP. Mitochondrial sirtuins in cardiometabolic diseases. Clinical Science (London, England). 2017;131:2063-2078. DOI: 10.1042/CS20160685
  130. 130. Lone J, Parray HA, Yun JW. Nobiletin induces brown adipocyte-like phenotype and ameliorates stress in 3T3-L1 adipocytes. Biochimie. 2018;146:97-104. DOI: 10.1016/j.biochi.2017.11.021
  131. 131. Nillni EA. The metabolic sensor Sirt1 and the hypothalamus: Interplay between peptide hormones and pro-hormone convertases. Molecular and Cellular Endocrinology. 2016;438:77-88. DOI: 10.1016/j.mce.2016.09.002
  132. 132. Fang J, Ianni A, Smolka C, Vakhrusheva O, Nolte H, Krüger M, Wietelmann A, Simonet NG, Adrian-Segarra JM, Vaquero A, Braun T, Bober E. Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1. Proceedings of the National Academy of Sciences of the United States of America. 2017;114:8352-8361. DOI: 10.1073/pnas.1706945114
  133. 133. Rappou E, Jukarainen S, Rinnankoski-Tuikka R, Kave S, Heinonen S, Hakkarainen A, Lunborn J, Lunborn N, Saunavaara V, Rissanen A, Virtanen KA, Pirinen E, Pietiläinen KH. Weight loss is associated with increased NAD+/SIRT1 expression but reduced PARP activity in white adipose tissue. The Journal of Clinical Endocrinology and Metabolism. 2016;101:1263-1273
  134. 134. Mayoral R, Osborn O, McNelis J, Johnson AM, Oh DY, Izquierdo CL, Chung H, Li P, Traves PG, Bandyopadhyay G, Pessentheiner AR, Ofrecio JM, Cook JR, Qiang L, Accili D, Olefsky JM. Adipocyte SIRT1 knouckout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Molecular Metabolism. 2015;4:378-391. DOI: 10.1016/j.molmet.2015.02.007
  135. 135. Gospin R, Sandu O, Gambina K, Tiwari A, Bonkowski M, Hawkins M. Resveratrol improves insulin resistance with anti-inflammatory and “browning” effects in adipose tissue of overweight humans. Journal of Investigative Medicine. 2016;64:814.2-81815. DOI: 10.1136/jim-2016-000080.35
  136. 136. Jiménez-Aeanda A, Fernándes-Vázquez G, Campos D, Tassi M, Velasco-Perez L, Tan DX, Reiter RJ, Aqil A. Melatonin induces browning of inguinal white adipose tissue in Zucker diabetic fatty rats. Pineal Research. 2013;55:416-423. DOI: 10.1111/jpi.12089
  137. 137. Modi S, Yaluri N, Kokkola T, Laakso M. Plant-derived compounds strigolactone GR24 and pinosylvin activate SIRT1 and enhance glucose uptake in rat skeletal muscle cells. Scientific Reports. 2017;7(1):17606. DOI: 10.1038/s41598-017-17840-x
  138. 138. Safaeinejad Z, Nabiuni M, Peymani M, Ghaedi K, Nasr-Esfahani MH, Baharvand H. Resveratrol promotes human embryonic stem cells self-renewal by targeting SIRT1-ERK signaling pathway. European Journal of Cell Biology. 2017;96:665-672. DOI: 10.1016/j.ejcb.2017.08.002
  139. 139. Sarubbo F, Ramis MR, Kienzer C, Aparicio S, Esteban S, Miralles A, Moranta D. Chronic silymarin, quercetin and naringenin treatments increase monoamines synthesis and hippocampal Sirt1 levels improving cognition in aged rats. Journal of Neuroimmune Pharmacology. 2018;13:24-38. DOI: 10.1007/s11481-017-9759-0
  140. 140. Chedea VS, Vicaş SI, Sticozzi C, Pessina F, Frosini M, Maioli E, Valacchi G. Resveratrol: From diet to topical usage. Food & Function. 2017;8(11):3879-3892. DOI: 10.1039/c7fo01086a
  141. 141. Stephan LS, Almeida ED, Markoski MM, Garavaglia J, Marcadenti A. Red wine, resveratrol and atrial fibrillation. Nutrients. 2017;9(11):1-8. DOI: 10.3390/nu9111190
  142. 142. Truong VL, Jun M, Jeong WS. Role of resveratrol in regulation of cellular defense systems against oxidative stress. BioFactors. 2018;44:36-49. DOI: 10.1002/biof.1399
  143. 143. Novelle MG, Wahl D, Diéguez C, Bernier M, de Cabo R. Resveratrol supplementation: Where are we now and where should we go? Ageing Research Reviews. 2015;21:1-15. DOI: 10.1016/j.arr.2015.01.002
  144. 144. Rodella LF, Vanella L, Peterson SJ, Drummond G, Rezzani R, Falck JR, Abraham NG. Heme oxygenase-derived carbon monoxide restores vascular function in type 1 diabetes. Drug Metabolism Letters. 2008;2:290-300
  145. 145. Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health – A comprehensive review of human clinical trials. Molecular Nutrition and Food Research. 2011;55:1129-1141. DOI: 10.1002/mnfr.201100143
  146. 146. Andrade JMO, Frade ACM, Giumarãea JB, Freitas KM, Lopes MT, Guimarães AL, de Paula AM, Coimbra CC, Santos SH. Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed with standard diet. European Journal of Nutrition. 2014;53:1503-1510. DOI: 10.1007/s00394-014-0655-6
  147. 147. Wang S, Liang X, Yang Q, Fu X, Rogers CJ, Zhu M, Rodgers BD, Jiang Q, Dodson MV, Du M. Resveratrol induces brown-like adipocyte formation in white fat trough activation of AMP-activated protein kinase (AMPK) α1. International Journal of Obesity. 2015;39:967-976. DOI: 10.1038/ijo.2015.23
  148. 148. Victoria-Campos CI, Ornelas-Paz JJ, Ramos-Aguilar OP, Faillia ML, Chitchumroonchokchai C, Ibarra-Junquera V, Pérez-Martínez J. The effect of ripening, heat processing and frozen storage on the in vitro bioaccessibility of capsaicin and dihydrocapsaicin from Jalapeño peppers in absence and presence of two dietary fat types. Food Chemistry. 2015;181:325-332. DOI: 10.1016/j.foodchem.2015.02.119
  149. 149. Baskaran P, Krishnan V, Ren J, Thyagarajan B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. British Journal of Pharmacology. 2016;173:2369-2389. DOI: 10.1111/bph.13514
  150. 150. Derry S, Sven-Rice A, Cole P, Tan T, Moore RA. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. The. Cochrane Database of Systematic Reviews. 2017;1:CD007393. DOI: 10.1002/14651858
  151. 151. Persson M, Fu Y, Bhattacharya A, Goh SL, van Middelkoop M, Bierma-Zeinstra SM, Walsh D, Doherty M, Zhang W. Relative efficacy of topical non-steroidal inflammatory drugs and topical capsaicin in osteoarthritis: Protocol for an individual patient data meta-analysis. Systematic Reviews. 2016;5:165. DOI: 10.1186/s13643-016-0348-8
  152. 152. Alexianu M, Chatterjee A. Intranasal Capsaicin (IC) rapidly relieves the pain of migraine and other severe headaches. Neurology. 2014;82:P7.179
  153. 153. Gupta R, Gupta M, Mangal S, Agrawal U, Vyas SP. Capsaicin-loaded vesicular systems designed for enhancing localized delivery for psoriasis therapy. Artificial Cells, Nanomedicine, and Biotechnology. 2016;44:825-834. DOI: 10.3109/21691401.2014.984301
  154. 154. Baboota RK, Singh DP, Sarma DP, Kaur J, Sandhir R, Boparai RK, Kondepudi KK, Bishnoi M. Capsaicin induces “Brite” phenotype in differentiating 3T3-L1 Preadipocytes. PLoS One 2014;9:e103093. DOI: 10.1371/journal.pone.0103093
  155. 155. Yoshida T, Yoshioka K, Wakabayashi Y, Nishioka H, Kondo M. Effects of capsaicin and isothiocyanate on thermogenesis of interscapular brown adipose tissue in rats. Journal of Nutritional Science and Vitaminology. 1988;34:587-594. DOI: 10.3177/jnsv.34.587
  156. 156. Neyrinck AM, Bindels LB, Geurts L, Van Hul M, Cani PD, Delzenne NM. A polyphenolic extract from green tea leaves activates fat browning in high-fat-diet-induced obese mice. The Journal of Nutritional Biochemistry. 2017;49:15-21. DOI: 10.1016/j.jnutbio.2017.07.008
  157. 157. Okla M, Kim J, Koehler K, Chung S. Dietary factors promoting Brown and Beige fat development and thermogenesis. Advances in Nutrition. 2017;8:473-483. DOI: 10.3945/an.116.014332
  158. 158. Kim SH, Plutzky J. Brown fat and Browning for the treatment of obesity and related metabolic disorders. Diabetes and Metabolism Journal. 2016;40:12-21. DOI: 10.4093/dmj.2016.40.1.12

Written By

Gaia Favero, Kristína Krajčíková, Francesca Bonomini, Luigi Fabrizio Rodella, Vladimíra Tomečková and Rita Rezzani

Submitted: January 30th, 2018 Reviewed: February 1st, 2018 Published: May 30th, 2018