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Natural Bioactive Compounds as Potential Browning Agents in White Adipose Tissue

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Abstract

The epidemic of overweight and obesity underlies many common metabolic diseases. Approaches aimed to reduce energy intake and/or stimulate energy expenditure represent potential strategies to control weight gain. Adipose tissue is a major energy balancing organ. It can be classified as white adipose tissue (WAT) and brown adipose tissue (BAT). While WAT stores excess metabolic energy, BAT dissipates it as heat via adaptive thermogenesis. WAT also participates in thermogenesis by providing thermogenic fuels and by directly generating heat after browning. Browned WAT resembles BAT morphologically and metabolically and is classified as beige fat. Like BAT, beige fat can produce heat. Human adults have BAT-like or beige fat. Recruitment and activation of this fat type have the potential to increase energy expenditure, thereby countering against obesity and its metabolic complications. Given this, agents capable of inducing WAT browning have recently attracted broad attention from biomedical, nutritional and pharmaceutical societies. In this review, we summarize natural bioactive compounds that have been shown to promote beige adipocyte recruitment and activation in animals and cultured cells. We also discuss potential molecular mechanisms for each compound to induce adipose browning and metabolic benefits.

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Abbreviations

AMPK:

5’ AMP-activated protein kinase

ArtC:

Artepillin C

BAT:

Brown adipose tissue

BDNF:

Brain-derived neurotrophic factor

BMPs:

Bone morphogenetic proteins

C3G:

Cyanidin-3-O-β-glucoside

CPT1α:

Carnitine Palmitoyltransferase 1α

Dio2:

Iodothyronine Deiodinase 2

Elovl3:

ELOVL Fatty Acid Elongase 3

EPI:

(−)-Epicatechin

eWAT:

Epididymal white adipose tissue

FGF21:

Fibroblast growth factor 21

GTC:

Green tea catechins

HFD:

High-fat diet

iWAT:

Inguinal subcutaneous WAT

LCA:

Lithocholic acid

mTOR:

Mammalian target of rapamycin

NE:

Norepinephrine

PDEs:

Phosphodiesterases

PGC-1α:

PPARγ co-activator-1α

PKA:

Protein kinase A

PPARγ:

Peroxisome proliferator-activated receptor γ

PRDM16:

PR domain zinc finger protein 16

RSV:

Resveratrol

SIRT1:

Sirtuin-1

SVCs:

Stromal vascular cells

Tbx1:

T-Box Transcription Factor 1

Tfam:

Mitochondrial transcription factor A

TG:

Triglyceride

TMEM26:

Transmembrane protein 26

TRPM8:

Transient Receptor Potential Cation Channel Subfamily M Member 8

TRPV1:

Transient Receptor Potential Cation Channel Subfamily V Member 1

UCP-1:

Uncoupling protein-1

WAT:

White adipose tissue

β3-AR:

Beta-3 adrenergic receptor

References

  1. Caballero B. Humans against Obesity: Who Will Win? Adv Nutr. 2019;10(suppl_1):S4–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–62.

    Article  CAS  PubMed  Google Scholar 

  3. Saltiel AR. New therapeutic approaches for the treatment of obesity. Sci Transl Med. 2016;8(323):323rv322.

    Article  CAS  Google Scholar 

  4. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84(1):277–359.

    Article  CAS  PubMed  Google Scholar 

  5. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360(15):1500–8.

    Article  PubMed  Google Scholar 

  6. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360(15):1518–25.

    Article  CAS  PubMed  Google Scholar 

  7. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360(15):1509–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Denjean F, Lachuer J, Geloen A, Cohen-Adad F, Moulin C, Barre H, et al. Differential regulation of uncoupling protein-1, −2 and −3 gene expression by sympathetic innervation in brown adipose tissue of thermoneutral or cold-exposed rats. FEBS Lett. 1999;444(2–3):181–5.

    Article  CAS  PubMed  Google Scholar 

  9. Ikeda K, Maretich P, Kajimura S. The common and distinct features of Brown and Beige adipocytes. Trends Endocrinol Metab. 2018;29(3):191–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 2013;5(5):1196–203.

    Article  CAS  PubMed  Google Scholar 

  11. Fenzl A, Kiefer FW. Brown adipose tissue and thermogenesis. Horm Mol Biol Clin Investig. 2014;19(1):25–37.

    CAS  PubMed  Google Scholar 

  12. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150(2):366–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19(10):1252–63.

    Article  CAS  PubMed  Google Scholar 

  14. Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol. 2014;10(1):24–36.

    Article  CAS  PubMed  Google Scholar 

  15. Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest. 2015;125(2):478–86.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liu X, Rossmeisl M, McClaine J, Riachi M, Harper ME, Kozak LP. Paradoxical resistance to diet-induced obesity in UCP1-deficient mice. J Clin Invest. 2003;111(3):399–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bertholet AM, Kazak L, Chouchani ET, Bogaczynska MG, Paranjpe I, Wainwright GL, et al. Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile Creatine cycling. Cell Metab. 2017;25(4):811–22 e814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell. 2015;163(3):643–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ikeda K, Kang Q, Yoneshiro T, Camporez JP, Maki H, Homma M, et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med. 2017;23(12):1454–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cao W, Daniel KW, Robidoux J, Puigserver P, Medvedev AV, Bai X, 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. 2004;24(7):3057–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121(1):96–105.

    Article  CAS  PubMed  Google Scholar 

  22. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454(7207):961–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009;460(7259):1154–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 2007;6(1):38–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mulligan JD, Gonzalez AA, Stewart AM, Carey HV, Saupe KW. Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. J Physiol. 2007;580(Pt. 2):677–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hutchinson DS, Chernogubova E, Dallner OS, Cannon B, Bengtsson T. Beta-adrenoceptors, but not alpha-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1. Diabetologia. 2005;48(11):2386–95.

    Article  CAS  PubMed  Google Scholar 

  27. Vila-Bedmar R, Lorenzo M, Fernandez-Veledo S. Adenosine 5′-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation. Endocrinology. 2010;151(3):980–92.

    Article  CAS  PubMed  Google Scholar 

  28. Baskaran P, Krishnan V, Ren J, Thyagarajan B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. Br J Pharmacol. 2016;173(15):2369–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-1alpha and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 2012;26(3):271–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Keipert S, Kutschke M, Ost M, Schwarzmayr T, van Schothorst EM, Lamp D, et al. Long-term cold adaptation does not require FGF21 or UCP1. Cell Metab. 2017;26(2):437–46 e435.

    Article  CAS  PubMed  Google Scholar 

  31. Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vazquez MJ, et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell. 2012;149(4):871–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim S, Choe S, Lee DK. BMP-9 enhances fibroblast growth factor 21 expression and suppresses obesity. Biochim Biophys Acta. 2016;1862(7):1237–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454(7207):1000–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature. 2013;495(7441):379–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kuo MM, Kim S, Tseng CY, Jeon YH, Choe S, Lee DK. BMP-9 as a potent brown adipogenic inducer with anti-obesity capacity. Biomaterials. 2014;35(10):3172–9.

    Article  CAS  PubMed  Google Scholar 

  36. Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppargamma. Cell. 2012;150(3):620–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rachid TL, Penna-de-Carvalho A, Bringhenti I, Aguila MB, Mandarim-de-Lacerda CA, Souza-Mello V. Fenofibrate (PPARalpha agonist) induces beige cell formation in subcutaneous white adipose tissue from diet-induced male obese mice. Mol Cell Endocrinol. 2015;402:86–94.

    Article  CAS  PubMed  Google Scholar 

  38. Liu D, Bordicchia M, Zhang C, Fang H, Wei W, Li JL, et al. Activation of mTORC1 is essential for beta-adrenergic stimulation of adipose browning. J Clin Invest. 2016;126(5):1704–16.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bargut TCL, Souza-Mello V, Aguila MB, Mandarim-de-Lacerda CA. Browning of white adipose tissue: lessons from experimental models. Horm Mol Biol Clin Investig. 2017;31(1).

  40. Schlessinger K, Li W, Tan Y, Liu F, Souza SC, Tozzo E, et al. Gene expression in WAT from healthy humans and monkeys correlates with FGF21-induced browning of WAT in mice. Obesity (Silver Spring). 2015;23(9):1818–29.

    Article  CAS  Google Scholar 

  41. Spiegelman BM. Banting lecture 2012: regulation of adipogenesis: toward new therapeutics for metabolic disease. Diabetes. 2013;62(6):1774–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 2013;27(3):234–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Veeresham C. Natural products derived from plants as a source of drugs. J Adv Pharm Technol Res. 2012;3(4):200–1.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Mele L, Bidault G, Mena P, Crozier A, Brighenti F, Vidal-Puig A, et al. Dietary (poly)phenols, Brown adipose tissue activation, and energy expenditure: a narrative review. Adv Nutr. 2017;8(5):694–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Concha F, Prado G, Quezada J, Ramirez A, Bravo N, Flores C, et al. Nutritional and non-nutritional agents that stimulate white adipose tissue browning. Rev Endocr Metab Disord. 2019;20(2):161–71.

    Article  CAS  PubMed  Google Scholar 

  46. Kang HW, Lee SG, Otieno D, Ha K. Flavonoids, Potential Bioactive Compounds, and Non-Shivering Thermogenesis. Nutrients. 2018;10(9).

  47. Zhang X, Li X, Fang H, Guo F, Li F, Chen A, et al. Flavonoids as inducers of white adipose tissue browning and thermogenesis: signalling pathways and molecular triggers. Nutr Metab (Lond). 2019;16:47.

    Article  CAS  Google Scholar 

  48. Del Rio D, Rodriguez-Mateos A, Spencer JP, Tognolini M, Borges G, Crozier A. Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal. 2013;18(14):1818–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Silvester AJ, Aseer KR, Yun JW. Dietary polyphenols and their roles in fat browning. J Nutr Biochem. 2019;64:1–12.

    Article  CAS  PubMed  Google Scholar 

  50. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127(6):1109–22.

    Article  CAS  PubMed  Google Scholar 

  52. Um JH, Park SJ, Kang H, Yang S, Foretz M, McBurney MW, et al. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 2010;59(3):554–63.

    Article  CAS  PubMed  Google Scholar 

  53. Bhatt JK, Thomas S, Nanjan MJ. Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res. 2012;32(7):537–41.

    Article  CAS  PubMed  Google Scholar 

  54. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011;14(5):612–22.

    Article  CAS  PubMed  Google Scholar 

  55. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15(5):675–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mitterberger MC, Zwerschke W. Mechanisms of resveratrol-induced inhibition of clonal expansion and terminal adipogenic differentiation in 3T3-L1 preadipocytes. J Gerontol A Biol Sci Med Sci. 2013;68(11):1356–76.

    Article  CAS  PubMed  Google Scholar 

  57. Wang S, Liang X, Yang Q, Fu X, Rogers CJ, Zhu M, et al. Resveratrol induces brown-like adipocyte formation in white fat through activation of AMP-activated protein kinase (AMPK) alpha1. Int J Obes. 2015;39(6):967–76.

    Article  CAS  Google Scholar 

  58. Lasa A, Schweiger M, Kotzbeck P, Churruca I, Simon E, Zechner R, et al. Resveratrol regulates lipolysis via adipose triglyceride lipase. J Nutr Biochem. 2012;23(4):379–84.

    Article  CAS  PubMed  Google Scholar 

  59. Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytother Res. 2008;22(10):1367–71.

    Article  CAS  PubMed  Google Scholar 

  60. Alberdi G, Rodriguez VM, Miranda J, Macarulla MT, Churruca I, Portillo MP. Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. Food Chem. 2013;141(2):1530–5.

    Article  CAS  PubMed  Google Scholar 

  61. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, et al. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell. 2012;148(3):421–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hui S, Liu Y, Huang L, Zheng L, Zhou M, Lang H, et al. Resveratrol enhances brown adipose tissue activity and white adipose tissue browning in part by regulating bile acid metabolism via gut microbiota remodeling. Int J Obes. 2020;44(8):1678–90.

    Article  CAS  Google Scholar 

  63. Liao W, Yin X, Li Q, Zhang H, Liu Z, Zheng X, Zheng L, Feng X. Resveratrol-Induced White Adipose Tissue Browning in Obese Mice by Remodeling Fecal Microbiota. Molecules. 2018;23(12).

  64. Velazquez-Villegas LA, Perino A, Lemos V, Zietak M, Nomura M, Pols TWH, et al. TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat Commun. 2018;9(1):245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–9.

    Article  CAS  PubMed  Google Scholar 

  66. Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014;30(3):332–8.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Chiang JYL. The gut's feeling on bile acid signaling in NAFLD. Hepatobiliary Surg Nutr. 2018;7(2):151–3.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Russell DW, Setchell KD. Bile acid biosynthesis. Biochemistry. 1992;31(20):4737–49.

    Article  CAS  PubMed  Google Scholar 

  69. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005;49(5):472–81.

    Article  CAS  PubMed  Google Scholar 

  70. Wang P, Sang S. Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors. 2018;44(1):16–25.

    Article  CAS  PubMed  Google Scholar 

  71. Serrano A, Asnani-Kishnani M, Rodriguez AM, Palou A, Ribot J, Bonet ML. Programming of the beige phenotype in white adipose tissue of adult mice by mild resveratrol and nicotinamide riboside supplementations in early postnatal life. Mol Nutr Food Res. 2018;62(21):e1800463.

    Article  PubMed  CAS  Google Scholar 

  72. Serrano A, Asnani-Kishnani M, Couturier C, Astier J, Palou A, Landrier JF, Ribot J, Bonet ML. DNA Methylation Changes are Associated with the Programming of White Adipose Tissue Browning Features by Resveratrol and Nicotinamide Riboside Neonatal Supplementations in Mice. Nutrients. 2020;12(2).

  73. Liu Z, Liao W, Yin X, Zheng X, Li Q, Zhang H, et al. Resveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway. Food Nutr Res. 2020;64.

  74. Imamura H, Nagayama D, Ishihara N, Tanaka S, Watanabe R, Watanabe Y, et al. Resveratrol attenuates triglyceride accumulation associated with upregulation of Sirt1 and lipoprotein lipase in 3T3-L1 adipocytes. Mol Genet Metab Rep. 2017;12:44–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Andrade JMO, Barcala-Jorge AS, Batista-Jorge GC, Paraiso AF, Freitas KM, Lelis DF, et al. Effect of resveratrol on expression of genes involved thermogenesis in mice and humans. Biomed Pharmacother. 2019;112:108634.

    Article  CAS  PubMed  Google Scholar 

  76. Nijveldt RJ, van Nood E, van Hoorn DE, Boelens PG, van Norren K, van Leeuwen PA. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr. 2001;74(4):418–25.

    Article  CAS  PubMed  Google Scholar 

  77. Rivera L, Moron R, Sanchez M, Zarzuelo A, Galisteo M. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity (Silver Spring). 2008;16(9):2081–7.

    Article  CAS  Google Scholar 

  78. Kobori M, Takahashi Y, Sakurai M, Akimoto Y, Tsushida T, Oike H, et al. Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice. Mol Nutr Food Res. 2016;60(2):300–12.

    Article  CAS  PubMed  Google Scholar 

  79. Dong J, Zhang X, Zhang L, Bian HX, Xu N, Bao B, et al. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKalpha1/SIRT1. J Lipid Res. 2014;55(3):363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–7.

    Article  CAS  PubMed  Google Scholar 

  83. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840–6.

    Article  CAS  PubMed  Google Scholar 

  84. Henagan TM, Cefalu WT, Ribnicky DM, Noland RC, Dunville K, Campbell WW, et al. In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. Genes Nutr. 2015;10(1):451.

    Article  CAS  PubMed  Google Scholar 

  85. Kuipers EN, Dam ADV, Held NM, Mol IM, Houtkooper RH, Rensen PCN, Boon MR. Quercetin Lowers Plasma Triglycerides Accompanied by White Adipose Tissue Browning in Diet-Induced Obese Mice. Int J Mol Sci. 2018;19(6).

  86. Lee SG, Parks JS, Kang HW. Quercetin, a functional compound of onion peel, remodels white adipocytes to brown-like adipocytes. J Nutr Biochem. 2017;42:62–71.

    Article  CAS  PubMed  Google Scholar 

  87. Khan N, Mukhtar H. Tea Polyphenols in Promotion of Human Health. Nutrients. 2018;11(1).

  88. Yang CS, Chen G, Wu Q. Recent scientific studies of a traditional chinese medicine, tea, on prevention of chronic diseases. J Tradit Complement Med. 2014;4(1):17–23.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ueda-Wakagi M, Nagayasu H, Yamashita Y, Ashida AH. Green Tea Ameliorates Hyperglycemia by Promoting the Translocation of Glucose Transporter 4 in the Skeletal Muscle of Diabetic Rodents. Int J Mol Sci. 2019;20(10).

  90. Wang LC, Pan TM, Tsai TY. Lactic acid bacteria-fermented product of green tea and Houttuynia cordata leaves exerts anti-adipogenic and anti-obesity effects. J Food Drug Anal. 2018;26(3):973–84.

    Article  CAS  PubMed  Google Scholar 

  91. Yan J, Zhao Y, Zhao B. Green tea catechins prevent obesity through modulation of peroxisome proliferator-activated receptors. Sci China Life Sci. 2013;56(9):804–10.

    Article  CAS  PubMed  Google Scholar 

  92. Gutierrez-Salmean G, Ortiz-Vilchis P, Vacaseydel CM, Garduno-Siciliano L, Chamorro-Cevallos G, Meaney E, et al. Effects of (−)-epicatechin on a diet-induced rat model of cardiometabolic risk factors. Eur J Pharmacol. 2014;728:24–30.

    Article  CAS  PubMed  Google Scholar 

  93. Nirengi S, Amagasa S, Homma T, Yoneshiro T, Matsumiya S, Kurosawa Y, et al. Daily ingestion of catechin-rich beverage increases brown adipose tissue density and decreases extramyocellular lipids in healthy young women. Springerplus. 2016;5(1):1363.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Weisberg SP, Leibel R, Tortoriello DV. Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology. 2008;149(7):3549–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Quiles JL, Aguilera C, Mesa MD, Ramirez-Tortosa MC, Baro L, Gil A. An ethanolic-aqueous extract of Curcuma longa decreases the susceptibility of liver microsomes and mitochondria to lipid peroxidation in atherosclerotic rabbits. Biofactors. 1998;8(1–2):51–7.

    Article  CAS  PubMed  Google Scholar 

  96. Rao DS, Sekhara NC, Satyanarayana MN, Srinivasan M. Effect of curcumin on serum and liver cholesterol levels in the rat. J Nutr. 1970;100(11):1307–15.

    Article  CAS  PubMed  Google Scholar 

  97. Alappat L, Awad AB. Curcumin and obesity: evidence and mechanisms. Nutr Rev. 2010;68(12):729–38.

    Article  PubMed  Google Scholar 

  98. Wang S, Wang X, Ye Z, Xu C, Zhang M, Ruan B, et al. Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way. Biochem Biophys Res Commun. 2015;466(2):247–53.

    Article  CAS  PubMed  Google Scholar 

  99. Nedergaard J, Cannon B. The browning of white adipose tissue: some burning issues. Cell Metab. 2014;20(3):396–407.

    Article  CAS  PubMed  Google Scholar 

  100. Song Z, Revelo X, Shao W, Tian L, Zeng K, Lei H, et al. Dietary curcumin intervention targets mouse white adipose tissue inflammation and Brown adipose tissue UCP1 expression. Obesity (Silver Spring). 2018;26(3):547–58.

    Article  CAS  Google Scholar 

  101. Lone J, Choi JH, Kim SW, Yun JW. Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J Nutr Biochem. 2016;27:193–202.

    Article  CAS  PubMed  Google Scholar 

  102. Matsuda AH, de Almeida-Muradian LB. Validated method for the quantification of artepillin-C in Brazilian propolis. Phytochem Anal. 2008;19(2):179–83.

    Article  CAS  PubMed  Google Scholar 

  103. Simoes LM, Gregorio LE, Da Silva Filho AA, de Souza ML, Azzolini AE, Bastos JK, et al. Effect of Brazilian green propolis on the production of reactive oxygen species by stimulated neutrophils. J Ethnopharmacol. 2004;94(1):59–65.

    Article  CAS  PubMed  Google Scholar 

  104. Cheung KW, Sze DM, Chan WK, Deng RX, Tu W, Chan GC. Brazilian green propolis and its constituent, Artepillin C inhibits allogeneic activated human CD4 T cells expansion and activation. J Ethnopharmacol. 2011;138(2):463–71.

    Article  CAS  PubMed  Google Scholar 

  105. Szliszka E, Helewski KJ, Mizgala E, Krol W. The dietary flavonol fisetin enhances the apoptosis-inducing potential of TRAIL in prostate cancer cells. Int J Oncol. 2011;39(4):771–9.

    CAS  PubMed  Google Scholar 

  106. Nishikawa S, Aoyama H, Kamiya M, Higuchi J, Kato A, Soga M, et al. Artepillin C, a typical Brazilian Propolis-derived component, induces Brown-like adipocyte formation in C3H10T1/2 cells, primary inguinal white adipose tissue-derived adipocytes, and mice. PLoS One. 2016;11(9):e0162512.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Kreft S, Knapp M, Kreft I. Extraction of rutin from buckwheat (Fagopyrum esculentumMoench) seeds and determination by capillary electrophoresis. J Agric Food Chem. 1999;47(11):4649–52.

    Article  CAS  PubMed  Google Scholar 

  108. Huang WY, Zhang HC, Liu WX, Li CY. Survey of antioxidant capacity and phenolic composition of blueberry, blackberry, and strawberry in Nanjing. J Zhejiang Univ Sci B. 2012;13(2):94–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Korkmaz A, Kolankaya D. Protective effect of rutin on the ischemia/reperfusion induced damage in rat kidney. J Surg Res. 2010;164(2):309–15.

    Article  CAS  PubMed  Google Scholar 

  110. Stanley Mainzen Prince P, Kamalakkannan N. Rutin improves glucose homeostasis in streptozotocin diabetic tissues by altering glycolytic and gluconeogenic enzymes. J Biochem Mol Toxicol. 2006;20(2):96–102.

    Article  CAS  PubMed  Google Scholar 

  111. Gao M, Ma Y, Liu D. Rutin suppresses palmitic acids-triggered inflammation in macrophages and blocks high fat diet-induced obesity and fatty liver in mice. Pharm Res. 2013;30(11):2940–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yuan X, Wei G, You Y, Huang Y, Lee HJ, Dong M, et al. Rutin ameliorates obesity through brown fat activation. FASEB J. 2017;31(1):333–45.

    Article  CAS  PubMed  Google Scholar 

  113. Lopez-Lazaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem. 2009;9(1):31–59.

    Article  CAS  PubMed  Google Scholar 

  114. Qian LB, Wang HP, Chen Y, Chen FX, Ma YY, Bruce IC, et al. Luteolin reduces high glucose-mediated impairment of endothelium-dependent relaxation in rat aorta by reducing oxidative stress. Pharmacol Res. 2010;61(4):281–7.

    Article  CAS  PubMed  Google Scholar 

  115. El-Bassossy HM, Abo-Warda SM, Fahmy A. Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation: effect on lipid profile. AGEs and NO generation Phytother Res. 2013;27(11):1678–84.

    Article  CAS  PubMed  Google Scholar 

  116. Xu N, Zhang L, Dong J, Zhang X, Chen YG, Bao B, et al. Low-dose diet supplement of a natural flavonoid, luteolin, ameliorates diet-induced obesity and insulin resistance in mice. Mol Nutr Food Res. 2014;58(6):1258–68.

    Article  CAS  PubMed  Google Scholar 

  117. Kwon EY, Jung UJ, Park T, Yun JW, Choi MS. Luteolin attenuates hepatic steatosis and insulin resistance through the interplay between the liver and adipose tissue in mice with diet-induced obesity. Diabetes. 2015;64(5):1658–69.

    Article  CAS  PubMed  Google Scholar 

  118. Zhang X, Zhang QX, Wang X, Zhang L, Qu W, Bao B, et al. Dietary luteolin activates browning and thermogenesis in mice through an AMPK/PGC1alpha pathway-mediated mechanism. Int J Obes. 2016;40(12):1841–9.

    Article  CAS  Google Scholar 

  119. Harnly JM, Doherty RF, Beecher GR, Holden JM, Haytowitz DB, Bhagwat S, et al. Flavonoid content of U.S. fruits, vegetables, and nuts. J Agric Food Chem. 2006;54(26):9966–77.

    Article  CAS  PubMed  Google Scholar 

  120. Chen W, Li Y, Li J, Han Q, Ye L, Li A. Myricetin affords protection against peroxynitrite-mediated DNA damage and hydroxyl radical formation. Food Chem Toxicol. 2011;49(9):2439–44.

    Article  CAS  PubMed  Google Scholar 

  121. Lu J, Papp LV, Fang J, Rodriguez-Nieto S, Zhivotovsky B, Holmgren A. Inhibition of mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. Cancer Res. 2006;66(8):4410–8.

    Article  CAS  PubMed  Google Scholar 

  122. Chen W, Feng L, Shen Y, Su H, Li Y, Zhuang J, et al. Myricitrin inhibits acrylamide-mediated cytotoxicity in human Caco-2 cells by preventing oxidative stress. Biomed Res Int. 2013;2013:724183.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Chen W, Zhuang J, Li Y, Shen Y, Zheng X. Myricitrin protects against peroxynitrite-mediated DNA damage and cytotoxicity in astrocytes. Food Chem. 2013;141(2):927–33.

    Article  CAS  PubMed  Google Scholar 

  124. Ong KC, Khoo HE. Effects of myricetin on glycemia and glycogen metabolism in diabetic rats. Life Sci. 2000;67(14):1695–705.

    Article  CAS  PubMed  Google Scholar 

  125. Liu IM, Liou SS, Lan TW, Hsu FL, Cheng JT. Myricetin as the active principle of Abelmoschus moschatus to lower plasma glucose in streptozotocin-induced diabetic rats. Planta Med. 2005;71(7):617–21.

    Article  CAS  PubMed  Google Scholar 

  126. Liu IM, Tzeng TF, Liou SS, Lan TW. Myricetin, a naturally occurring flavonol, ameliorates insulin resistance induced by a high-fructose diet in rats. Life Sci. 2007;81(21–22):1479–88.

    Article  CAS  PubMed  Google Scholar 

  127. Hu T, Yuan X, Wei G, Luo H, Lee HJ, Jin W. Myricetin-induced brown adipose tissue activation prevents obesity and insulin resistance in db/db mice. Eur J Nutr. 2018;57(1):391–403.

    Article  CAS  PubMed  Google Scholar 

  128. Yuasa K, Tada K, Harita G, Fujimoto T, Tsukayama M, Tsuji A. Sudachitin, a polymethoxyflavone from Citrus sudachi, suppresses lipopolysaccharide-induced inflammatory responses in mouse macrophage-like RAW264 cells. Biosci Biotechnol Biochem. 2012;76(3):598–600.

    Article  CAS  PubMed  Google Scholar 

  129. Tsutsumi R, Yoshida T, Nii Y, Okahisa N, Iwata S, Tsukayama M, et al. Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle. Nutr Metab (Lond). 2014;11:32.

    Article  CAS  Google Scholar 

  130. Olivas-Aguirre FJ, Rodrigo-Garcia J, Martinez-Ruiz ND, Cardenas-Robles AI, Mendoza-Diaz SO, Alvarez-Parrilla E, Gonzalez-Aguilar GA, de la Rosa LA, Ramos-Jimenez A, Wall-Medrano A. Cyanidin-3-O-glucoside: Physical-Chemistry, Foodomics and Health Effects. Molecules. 2016;21(9).

  131. Wang Y, Zhao L, Wang D, Huo Y, Ji B. Anthocyanin-rich extracts from blackberry, wild blueberry, strawberry, and chokeberry: antioxidant activity and inhibitory effect on oleic acid-induced hepatic steatosis in vitro. J Sci Food Agric. 2016;96(7):2494–503.

    Article  CAS  PubMed  Google Scholar 

  132. Guo H, Xia M, Zou T, Ling W, Zhong R, Zhang W. Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1. J Nutr Biochem. 2012;23(4):349–60.

    Article  CAS  PubMed  Google Scholar 

  133. Liu Y, Li D, Zhang Y, Sun R, Xia M. Anthocyanin increases adiponectin secretion and protects against diabetes-related endothelial dysfunction. Am J Physiol Endocrinol Metab. 2014;306(8):E975–88.

    Article  CAS  PubMed  Google Scholar 

  134. Sasaki R, Nishimura N, Hoshino H, Isa Y, Kadowaki M, Ichi T, et al. Cyanidin 3-glucoside ameliorates hyperglycemia and insulin sensitivity due to downregulation of retinol binding protein 4 expression in diabetic mice. Biochem Pharmacol. 2007;74(11):1619–27.

    Article  CAS  PubMed  Google Scholar 

  135. You Y, Yuan X, Liu X, Liang C, Meng M, Huang Y, Han X, Guo J, Guo Y, Ren C, Zhang Q, Sun X, Ma T, Liu G, Jin W, Huang W, Zhan J. Cyanidin-3-glucoside increases whole body energy metabolism by upregulating brown adipose tissue mitochondrial function. Mol Nutr Food Res. 2017;61(11).

  136. Swiezewska E, Danikiewicz W. Polyisoprenoids: structure, biosynthesis and function. Prog Lipid Res. 2005;44(4):235–58.

    Article  CAS  PubMed  Google Scholar 

  137. van den Brink DM, Wanders RJ. Phytanic acid: production from phytol, its breakdown and role in human disease. Cell Mol Life Sci. 2006;63(15):1752–65.

    Article  PubMed  CAS  Google Scholar 

  138. Santos CC, Salvadori MS, Mota VG, Costa LM, de Almeida AA, de Oliveira GA, et al. Antinociceptive and antioxidant activities of phytol in vivo and in vitro models. Neurosci J. 2013;2013:949452.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Elmazar MM, El-Abhar HS, Schaalan MF, Farag NA. Phytol/Phytanic acid and insulin resistance: potential role of phytanic acid proven by docking simulation and modulation of biochemical alterations. PLoS One. 2013;8(1):e45638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Goto T, Takahashi N, Kato S, Egawa K, Ebisu S, Moriyama T, et al. Phytol directly activates peroxisome proliferator-activated receptor alpha (PPARalpha) and regulates gene expression involved in lipid metabolism in PPARalpha-expressing HepG2 hepatocytes. Biochem Biophys Res Commun. 2005;337(2):440–5.

    Article  CAS  PubMed  Google Scholar 

  141. Zhang F, Ai W, Hu X, Meng Y, Yuan C, Su H, et al. Phytol stimulates the browning of white adipocytes through the activation of AMP-activated protein kinase (AMPK) alpha in mice fed high-fat diet. Food Funct. 2018;9(4):2043–50.

    Article  CAS  PubMed  Google Scholar 

  142. Maeda H, Hosokawa M, Sashima T, Miyashita K. Dietary combination of fucoxanthin and fish oil attenuates the weight gain of white adipose tissue and decreases blood glucose in obese/diabetic KK-ay mice. J Agric Food Chem. 2007;55(19):7701–6.

    Article  CAS  PubMed  Google Scholar 

  143. Sangeetha RK, Bhaskar N, Baskaran V. Comparative effects of beta-carotene and fucoxanthin on retinol deficiency induced oxidative stress in rats. Mol Cell Biochem. 2009;331(1–2):59–67.

    Article  CAS  PubMed  Google Scholar 

  144. Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS, et al. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Mol Cells. 2003;16(1):97–105.

    Article  CAS  PubMed  Google Scholar 

  145. Maeda H. Nutraceutical effects of fucoxanthin for obesity and diabetes therapy: a review. J Oleo Sci. 2015;64(2):125–32.

    Article  CAS  PubMed  Google Scholar 

  146. Gammone MA, D'Orazio N. Anti-obesity activity of the marine carotenoid fucoxanthin. Mar Drugs. 2015;13(4):2196–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Maeda H, Hosokawa M, Sashima T, Funayama K, Miyashita K. Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues. Biochem Biophys Res Commun. 2005;332(2):392–7.

    Article  CAS  PubMed  Google Scholar 

  148. Rebello CJ, Greenway FL, Johnson WD, Ribnicky D, Poulev A, Stadler K, et al. Fucoxanthin and its metabolite Fucoxanthinol do not induce Browning in human adipocytes. J Agric Food Chem. 2017;65(50):10915–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Yang F, Shi H, Zhang X, Yu LL. Two novel anti-inflammatory 21-nordammarane saponins from tetraploid Jiaogulan ( Gynostemma pentaphyllum ). J Agric Food Chem. 2013;61(51):12646–52.

    Article  CAS  PubMed  Google Scholar 

  150. Yang F, Shi H, Zhang X, Yang H, Zhou Q, Yu LL. Two new saponins from tetraploid jiaogulan (Gynostemma pentaphyllum), and their anti-inflammatory and alpha-glucosidase inhibitory activities. Food Chem. 2013;141(4):3606–13.

    Article  CAS  PubMed  Google Scholar 

  151. Megalli S, Davies NM, Roufogalis BD. Anti-hyperlipidemic and hypoglycemic effects of Gynostemma pentaphyllum in the Zucker fatty rat. J Pharm Pharm Sci. 2006;9(3):281–91.

    PubMed  Google Scholar 

  152. Hu Y, Ip FC, Fu G, Pang H, Ye W, Ip NY. Dammarane saponins from Gynostemma pentaphyllum. Phytochemistry. 2010;71(10):1149–57.

    Article  CAS  PubMed  Google Scholar 

  153. Yeo J, Kang YJ, Jeon SM, Jung UJ, Lee MK, Song H, et al. Potential hypoglycemic effect of an ethanol extract of Gynostemma pentaphyllum in C57BL/KsJ-db/db mice. J Med Food. 2008;11(4):709–16.

    Article  CAS  PubMed  Google Scholar 

  154. Gauhar R, Hwang SL, Jeong SS, Kim JE, Song H, Park DC, et al. Heat-processed Gynostemma pentaphyllum extract improves obesity in Ob/Ob mice by activating AMP-activated protein kinase. Biotechnol Lett. 2012;34(9):1607–16.

    Article  CAS  PubMed  Google Scholar 

  155. Liu J, Li Y, Yang P, Wan J, Chang Q, Wang TTY, et al. Gypenosides reduced the risk of overweight and insulin resistance in C57BL/6J mice through modulating adipose thermogenesis and gut microbiota. J Agric Food Chem. 2017;65(42):9237–46.

    Article  CAS  PubMed  Google Scholar 

  156. Mu Q, Fang X, Li X, Zhao D, Mo F, Jiang G, et al. Ginsenoside Rb1 promotes browning through regulation of PPARgamma in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2015;466(3):530–5.

    Article  CAS  PubMed  Google Scholar 

  157. Almeida MC, Hew-Butler T, Soriano RN, Rao S, Wang W, Wang J, et al. Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature. J Neurosci. 2012;32(6):2086–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448(7150):204–8.

    Article  CAS  PubMed  Google Scholar 

  159. McKemy DD, Neuhausser WM, Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416(6876):52–8.

    Article  CAS  PubMed  Google Scholar 

  160. Colburn RW, Lubin ML, Stone DJ Jr, Wang Y, Lawrence D, D'Andrea MR, et al. Attenuated cold sensitivity in TRPM8 null mice. Neuron. 2007;54(3):379–86.

    Article  CAS  PubMed  Google Scholar 

  161. Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A. TRPM8 is required for cold sensation in mice. Neuron. 2007;54(3):371–8.

    Article  CAS  PubMed  Google Scholar 

  162. Voets T, Owsianik G, Janssens A, Talavera K, Nilius B. TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli. Nat Chem Biol. 2007;3(3):174–82.

    Article  CAS  PubMed  Google Scholar 

  163. Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y, et al. Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. J Mol Cell Biol. 2012;4(2):88–96.

    Article  CAS  PubMed  Google Scholar 

  164. Sakellariou P, Valente A, Carrillo AE, Metsios GS, Nadolnik L, Jamurtas AZ, et al. Chronic l-menthol-induced browning of white adipose tissue hypothesis: a putative therapeutic regime for combating obesity and improving metabolic health. Med Hypotheses. 2016;93:21–6.

    Article  CAS  PubMed  Google Scholar 

  165. Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, et al. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 2014;383(1–2):137–46.

    Article  CAS  PubMed  Google Scholar 

  166. Jiang C, Zhai M, Yan D, Li D, Li C, Zhang Y, et al. Dietary menthol-induced TRPM8 activation enhances WAT "browning" and ameliorates diet-induced obesity. Oncotarget. 2017;8(43):75114–26.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Kannaiyan R, Shanmugam MK, Sethi G. Molecular targets of celastrol derived from thunder of god vine: potential role in the treatment of inflammatory disorders and cancer. Cancer Lett. 2011;303(1):9–20.

    Article  CAS  PubMed  Google Scholar 

  168. Salminen A, Lehtonen M, Paimela T, Kaarniranta K. Celastrol: molecular targets of thunder god vine. Biochem Biophys Res Commun. 2010;394(3):439–42.

    Article  CAS  PubMed  Google Scholar 

  169. Ng SW, Chan Y, Chellappan DK, Madheswaran T, Zeeshan F, Chan YL, et al. Molecular modulators of celastrol as the keystones for its diverse pharmacological activities. Biomed Pharmacother. 2019;109:1785–92.

    Article  CAS  PubMed  Google Scholar 

  170. Liu J, Lee J, Salazar Hernandez MA, Mazitschek R, Ozcan U. Treatment of obesity with celastrol. Cell. 2015;161(5):999–1011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Hu M, Luo Q, Alitongbieke G, Chong S, Xu C, Xie L, et al. Celastrol-induced Nur77 interaction with TRAF2 alleviates inflammation by promoting mitochondrial ubiquitination and autophagy. Mol Cell. 2017;66(1):141–53 e146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ma X, Xu L, Alberobello AT, Gavrilova O, Bagattin A, Skarulis M, et al. Celastrol protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1alpha transcriptional Axis. Cell Metab. 2015;22(4):695–708.

    Article  CAS  PubMed  Google Scholar 

  173. Pfuhlmann K, Schriever SC, Baumann P, Kabra DG, Harrison L, Mazibuko-Mbeje SE, et al. Celastrol-induced weight loss is driven by Hypophagia and independent from UCP1. Diabetes. 2018;67(11):2456–65.

    Article  CAS  PubMed  Google Scholar 

  174. Enerback S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 1997;387(6628):90–4.

    Article  CAS  PubMed  Google Scholar 

  175. Chouchani ET, Kazak L, Spiegelman BM. New advances in adaptive thermogenesis: UCP1 and beyond. Cell Metab. 2019;29(1):27–37.

    Article  CAS  PubMed  Google Scholar 

  176. Al Othman ZA, Ahmed YB, Habila MA, Ghafar AA. Determination of capsaicin and dihydrocapsaicin in Capsicum fruit samples using high performance liquid chromatography. Molecules. 2011;16(10):8919–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Dairam A, Fogel R, Daya S, Limson JL. Antioxidant and iron-binding properties of curcumin, capsaicin, and S-allylcysteine reduce oxidative stress in rat brain homogenate. J Agric Food Chem. 2008;56(9):3350–6.

    Article  CAS  PubMed  Google Scholar 

  178. Zheng L, Chen J, Ma Z, Liu W, Yang F, Yang Z, et al. Capsaicin enhances anti-proliferation efficacy of pirarubicin via activating TRPV1 and inhibiting PCNA nuclear translocation in 5637 cells. Mol Med Rep. 2016;13(1):881–7.

    Article  CAS  PubMed  Google Scholar 

  179. Narang N, Jiraungkoorskul W, Jamrus P. Current understanding of Antiobesity property of capsaicin. Pharmacogn Rev. 2017;11(21):23–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Janssens PL, Hursel R, Martens EA, Westerterp-Plantenga MS. Acute effects of capsaicin on energy expenditure and fat oxidation in negative energy balance. PLoS One. 2013;8(7):e67786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Baboota RK, Murtaza N, Jagtap S, Singh DP, Karmase A, Kaur J, et al. Capsaicin-induced transcriptional changes in hypothalamus and alterations in gut microbial count in high fat diet fed mice. J Nutr Biochem. 2014;25(9):893–902.

    Article  CAS  PubMed  Google Scholar 

  182. Baboota RK, Singh DP, Sarma SM, Kaur J, Sandhir R, Boparai RK, et al. Capsaicin induces "brite" phenotype in differentiating 3T3-L1 preadipocytes. PLoS One. 2014;9(7):e103093.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Chow YL, Sogame M, Sato F. 13-Methylberberine, a berberine analogue with stronger anti-adipogenic effects on mouse 3T3-L1 cells. Sci Rep. 2016;6:38129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Zhang WL, Zhu L, Jiang JG. Active ingredients from natural botanicals in the treatment of obesity. Obes Rev. 2014;15(12):957–67.

    Article  CAS  PubMed  Google Scholar 

  185. Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N, et al. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab. 2008;93(7):2559–65.

    Article  CAS  PubMed  Google Scholar 

  186. Li Y, Wang P, Zhuang Y, Lin H, Li Y, Liu L, et al. Activation of AMPK by berberine promotes adiponectin multimerization in 3T3-L1 adipocytes. FEBS Lett. 2011;585(12):1735–40.

    Article  CAS  PubMed  Google Scholar 

  187. Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006;55(8):2256–64.

    Article  CAS  PubMed  Google Scholar 

  188. Sun Y, Xia M, Yan H, Han Y, Zhang F, Hu Z, et al. Berberine attenuates hepatic steatosis and enhances energy expenditure in mice by inducing autophagy and fibroblast growth factor 21. Br J Pharmacol. 2018;175(2):374–87.

    Article  CAS  PubMed  Google Scholar 

  189. Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10(12):1344–51.

    Article  CAS  PubMed  Google Scholar 

  190. Hu Y, Davies GE. Berberine inhibits adipogenesis in high-fat diet-induced obesity mice. Fitoterapia. 2010;81(5):358–66.

    Article  CAS  PubMed  Google Scholar 

  191. Wang L, Ye X, Hua Y, Song Y. Berberine alleviates adipose tissue fibrosis by inducing AMP-activated kinase signaling in high-fat diet-induced obese mice. Biomed Pharmacother. 2018;105:121–9.

    Article  CAS  PubMed  Google Scholar 

  192. Xu JH, Liu XZ, Pan W, Zou DJ. Berberine protects against diet-induced obesity through regulating metabolic endotoxemia and gut hormone levels. Mol Med Rep. 2017;15(5):2765–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun. 2014;5:5493.

    Article  CAS  PubMed  Google Scholar 

  194. Wu L, Xia M, Duan Y, Zhang L, Jiang H, Hu X, et al. Berberine promotes the recruitment and activation of brown adipose tissue in mice and humans. Cell Death Dis. 2019;10(6):468.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Rein MJ, Renouf M, Cruz-Hernandez C, Actis-Goretta L, Thakkar SK, da Silva Pinto M. Bioavailability of bioactive food compounds: a challenging journey to bioefficacy. Br J Clin Pharmacol. 2013;75(3):588–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Oracz J, Nebesny E, Zyzelewicz D, Budryn G, Luzak B. Bioavailability and metabolism of selected cocoa bioactive compounds: a comprehensive review. Crit Rev Food Sci Nutr. 2020;60(12):1947–85.

    Article  PubMed  Google Scholar 

  197. Teng H, Chen L. Polyphenols and bioavailability: an update. Crit Rev Food Sci Nutr. 2019;59(13):2040–51.

    Article  CAS  PubMed  Google Scholar 

  198. Dima C, Assadpour E, Dima S, Jafari SM. Bioavailability and bioaccessibility of food bioactive compounds; overview and assessment by in vitro methods. Compr Rev Food Sci Food Saf. 2020;19(6):2862–84.

    Article  PubMed  Google Scholar 

  199. Jarosova V, Vesely O, Doskocil I, Tomisova K, Marsik P, Jaimes JD, Smejkal K, Kloucek P, Havlik J. Metabolism of cis- and trans-Resveratrol and Dihydroresveratrol in an Intestinal Epithelial Model. Nutrients. 2020;12(3).

  200. Luca SV, Macovei I, Bujor A, Miron A, Skalicka-Wozniak K, Aprotosoaie AC, et al. Bioactivity of dietary polyphenols: the role of metabolites. Crit Rev Food Sci Nutr. 2020;60(4):626–59.

    Article  CAS  PubMed  Google Scholar 

  201. Erlund I, Freese R, Marniemi J, Hakala P, Alfthan G. Bioavailability of quercetin from berries and the diet. Nutr Cancer. 2006;54(1):13–7.

    Article  CAS  PubMed  Google Scholar 

  202. Cai ZY, Li XM, Liang JP, Xiang LP, Wang KR, Shi YL, Yang R, Shi M, Ye JH, Lu JL, Zheng XQ, Liang YR. Bioavailability of Tea Catechins and Its Improvement. Molecules. 2018;23(9).

  203. Chen DJ, Hu HG, Xing SF, Liu HM, Piao XL. Metabolite profiling of gypenoside LVI in rat after oral and intravenous administration. Arch Pharm Res. 2015;38(6):1157–67.

    Article  CAS  PubMed  Google Scholar 

  204. Chen W, Miao YQ, Fan DJ, Yang SS, Lin X, Meng LK, et al. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats. AAPS PharmSciTech. 2011;12(2):705–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Liu YT, Hao HP, Xie HG, Lai L, Wang Q, Liu CX, et al. Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats. Drug Metab Dispos. 2010;38(10):1779–84.

    Article  CAS  PubMed  Google Scholar 

  206. Springer M, Moco S. Resveratrol and Its Human Metabolites-Effects on Metabolic Health and Obesity. Nutrients. 2019;11(1).

  207. Patel KR, Andreadi C, Britton RG, Horner-Glister E, Karmokar A, Sale S, Brown VA, Brenner DE, Singh R, Steward WP, Gescher AJ, Brown K. Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence. Sci Transl Med. 2013;5(205):205ra133.

  208. Gambini J, Ingles M, Olaso G, Lopez-Grueso R, Bonet-Costa V, Gimeno-Mallench L, et al. Properties of resveratrol: in vitro and in vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Med Cell Longev. 2015;2015:837042.

    Article  CAS  Google Scholar 

  209. Walle T. Bioavailability of resveratrol. Ann N Y Acad Sci. 2011;1215:9–15.

    Article  CAS  PubMed  Google Scholar 

  210. Hostetler GL, Ralston RA, Schwartz SJ. Flavones: food sources, bioavailability, metabolism, and bioactivity. Adv Nutr. 2017;8(3):423–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Gonzales GB, Smagghe G, Grootaert C, Zotti M, Raes K, Van Camp J. Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity. Drug Metab Rev. 2015;47(2):175–90.

    Article  CAS  PubMed  Google Scholar 

  212. Chimento A, De Amicis F, Sirianni R, Sinicropi MS, Puoci F, Casaburi I, Saturnino C, Pezzi V. Progress to Improve Oral Bioavailability and Beneficial Effects of Resveratrol. Int J Mol Sci. 2019;20(6).

  213. Thilakarathna SH, Rupasinghe HP. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients. 2013;5(9):3367–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  214. Aziz SA, Wakeling LA, Miwa S, Alberdi G, Hesketh JE, Ford D. Metabolic programming of a beige adipocyte phenotype by genistein. Mol Nutr Food Res. 2017;61(2).

  215. Song NJ, Choi S, Rajbhandari P, Chang SH, Kim S, Vergnes L, et al. Prdm4 induction by the small molecule butein promotes white adipose tissue browning. Nat Chem Biol. 2016;12(7):479–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Choi JH, Yun JW. Chrysin induces brown fat-like phenotype and enhances lipid metabolism in 3T3-L1 adipocytes. Nutrition. 2016;32(9):1002–10.

    Article  CAS  PubMed  Google Scholar 

  217. Matsukawa T, Villareal MO, Motojima H, Isoda H. Increasing cAMP levels of preadipocytes by cyanidin-3-glucoside treatment induces the formation of beige phenotypes in 3T3-L1 adipocytes. J Nutr Biochem. 2017;40:77–85.

    Article  CAS  PubMed  Google Scholar 

  218. Choi JH, Kim SW, Yu R, Yun JW. Monoterpene phenolic compound thymol promotes browning of 3T3-L1 adipocytes. Eur J Nutr. 2017;56(7):2329–41.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Liqing Yu.

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Choi, Y., Yu, L. Natural Bioactive Compounds as Potential Browning Agents in White Adipose Tissue. Pharm Res 38, 549–567 (2021). https://doi.org/10.1007/s11095-021-03027-7

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