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Current Obesity Reports

, Volume 4, Issue 2, pp 224–229 | Cite as

The Whitening of Brown Fat and Its Implications for Weight Management in Obesity

  • Ippei Shimizu
  • Kenneth Walsh
Obesity Treatment (CM Apovian, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Obesity Treatment

Abstract

Systemic inflammation resulting from dysfunction of white adipose tissue (WAT) accelerates the pathologies of diabetes and cardiovascular diseases. In contrast to WAT, brown adipose tissue (BAT) is abundant in mitochondria that produce heat by uncoupling respiratory chain process of ATP synthesis. Besides BAT’s role in thermogenesis, accumulating evidence has shown that it is involved in regulating systemic metabolism. Studies have analyzed the “browning” processes of WAT as a means to combat obesity, whereas few studies have focused on the impact and molecular mechanisms that contribute to obesity-linked BAT dysfunction—a process that is associated with the “whitening” of this tissue. Compared to WAT, a dense vascular network is required to support the high energy consumption of BAT. Recently, vascular rarefaction was shown to be a significant causal factor in the whitening of BAT in mouse models. Vascular insufficiency leads to mitochondrial dysfunction and loss in BAT and contributes to systemic insulin resistance. These data suggest that BAT “whitening,” resulting from vascular dysfunction, can impact obesity and obesity-linked diseases. Conversely, agents that promote BAT function could have utility in the treatment of these conditions.

Keywords

Obesity Whitening of BAT Insulin resistance VEGF-A 

Notes

Acknowledgments

This work was supported by Manpei Suzuki Diabetes Foundation, Kanae Foundation for the Promotion of Medical Science, and Novartis Research Foundation (to IS) and National Institutes of Health (NIH) grants HL081587, HL116591, HL120160, and 126141 (to KW).

Compliance with Ethics Guidelines

Conflict of Interest

Ippei Shimizu and Kenneth Walsh declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

  1. 1.
    Prospective Studies Collaboration, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, et al. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373(9669):1083–96.CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85–97.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Nedergaard J, Cannon B. The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metab. 2010;11(4):268–72.Google Scholar
  4. 4.
    Seale P, Lazar MA. Brown fat in humans: turning up the heat on obesity. Diabetes. 2009;58(7):1482–4.Google Scholar
  5. 5.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    TsengYH, Cypess AM, Kahn CR. Cellular bioenergetics as a target for obesity therapy. Nat Rev Drug Discov. 2010;9(6):465–82.Google Scholar
  7. 7.
    Stephens M, Ludgate M, Rees DA. Brown fat and obesity: the next big thing? Clin Endocrinol (Oxf). 2011;74(6):66170.Google Scholar
  8. 8.
    Ouellet V, Labbe SM, Blondin DP, Phoenix S, Guerin B, Haman F, et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012;122(2):545–52.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest. 2013;123(8):3395–403.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.•
    Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest. 2013;123(8):3404–8.Google Scholar
  11. 11.
    Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17(2):200–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Nicholls DG. The thermogenicmechanismof brown adipose tissue. Rev Biosci Rep. 1983;3(5):431–41.Google Scholar
  13. 13.
    Hamann A, Flier JS, Lowell BB. Decreased brown fat markedly enhances susceptibility to diet-induced obesity, diabetes, and hyperlipidemia. Endocrinology. 1996;137(1):21–9.Google Scholar
  14. 14.
    Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293(2):E444–52.Google Scholar
  15. 15.
    Enerback S. Human brown adipose tissue. Cell Metab. 2010;11(4):248–52.Google Scholar
  16. 16.
    Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-alphadependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463–8.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 2012;15(3):395–404.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown? Genes Dev. 2013;27(3):234–50.Google Scholar
  19. 19.
    Nedergaard J, Cannon B. UCP1 mRNA does not produce heat. Biochim Biophys Acta. 2013;1831(5):943–9.Google Scholar
  20. 20.
    Pfannenberg C, Werner MK, Ripkens S, Stef I, Deckert A, Schmadl M, et al. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes. 2010;59(7):1789–93.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, et al. Dichotomous effects of VEGF-A on adipose tissue dysfunction. Proc Natl Acad Sci U S A. 2012;109(15):5874–9.CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Sung HK, Doh KO, Son JE, Park JG, Bae Y, Choi S, et al. Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab. 2013;17(1):61–72.CrossRefPubMedGoogle Scholar
  23. 23.
    Kolonin MG, Saha PK, Chan L, Pasqualini R, Arap W. Reversal of obesity by targeted ablation of adipose tissue. Nat Med. 2004;10(6):625–32.CrossRefPubMedGoogle Scholar
  24. 24.
    Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, et al. Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A. 2002;99(16):10730–5.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Brakenhielm E, Cao R, Gao B, Angelin B, Cannon B, Parini P, et al. Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res. 2004;94(12):1579–88.CrossRefPubMedGoogle Scholar
  26. 26.
    Xue Y, Petrovic N, Cao R, Larsson O, Lim S, Chen S, et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab. 2009;9(1):99–109.CrossRefPubMedGoogle Scholar
  27. 27.•
    Shimizu I, Aprahamian T, Kikuchi R, Shimizu A, Papanicolaou KN, MacLauchlan S, et al. Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest. 2014;124(5):2099–112.Google Scholar
  28. 28.
    Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 2009;9(2):203–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Arch JR. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol. 2002;440(2–3):99–107.Google Scholar
  30. 30.
    Buemann B, Toubro S, Astrup A. Effects of the two beta3-agonists, ZD7114 and ZD2079 on 24 hour energy expenditure and respiratory quotient in obese subjects. Int J Obes Relat Metab Disord. 2000;24(12):1553–60.Google Scholar
  31. 31.
    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.CrossRefPubMedGoogle Scholar
  32. 32.
    Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10(3):167–77.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Lockie SH, Heppner KM, Chaudhary N, Chabenne JR, Morgan DA, Veyrat-Durebex C, et al. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon-like peptide-1 receptor signaling. Diabetes. 2012;61(11):2753–62.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 2010;11(3):206–12.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Wei W, Dutchak PA, Wang X, Ding X, Bookout AL, Goetz R, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci U S A. 2012;109(8):3143–8.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessi-Fulgheri P, Zhang C, et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J Clin Invest. 2012;122(3):1022–36.CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Nguyen KD, Qiu Y, Cui X, Goh YP, Mwangi J, David T, et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 2011;480(7375):104–8.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Villarroya F, Vidal-Puig A. Beyond the sympathetic tone: the new brown fat activators. Cell Metab. 2013;17(5):638–43.Google Scholar
  41. 41.
    Peirce V, Carobbio S, Vidal-Puig A. The different shades of fat. Nature. 2014;510(7503):76–83.Google Scholar
  42. 42.
    HarmsM, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19(10):1252–63.Google Scholar
  43. 43.
    Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1–2):20–44.Google Scholar
  44. 44.
    Vernochet C, Damilano F, Mourier A, Bezy O, Mori MA, Smyth G, et al. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. FASEB J. 2014;28(10):4408–19.CrossRefPubMedGoogle Scholar
  45. 45.
    Mori MA, Thomou T, Boucher J, Lee KY, Lallukka S, Kim JK, et al. Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest. 2014;124(8):3339–51.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Fredriksson JM, Lindquist JM, Bronnikov GE, Nedergaard J. Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a betaadrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2. J Biol Chem. 2000;275(18):13802–11.CrossRefPubMedGoogle Scholar
  47. 47.
    Elias I, Franckhauser S, Ferre T, Vila L, Tafuro S, Munoz S, et al. Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance. Diabetes. 2012;61(7):1801–13.CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.•
    Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, et al. Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. Proc Natl Acad Sci U S A. 2004;101(8):2476–81.Google Scholar
  49. 49.
    Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11(6):467–78.CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Singh R, Xiang Y, Wang Y, Baikati K, Cuervo AM, Luu YK, et al. Autophagy regulates adipose mass and differentiation in mice. J Clin Invest. 2009;119(11):3329–39.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Zhang Y, Goldman S, Baerga R, Zhao Y, Komatsu M, Jin S. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc Natl Acad Sci U S A. 2009;106(47):19860–5.CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Chatzigeorgiou A, Kandaraki E, Papavassiliou AG, Koutsilieris M. Peripheral targets in obesity treatment: a comprehensive update. Obes Rev. 2014;15(6):487–503.CrossRefPubMedGoogle Scholar
  53. 53.
    Guarente L, Picard F. Calorie restriction—the SIR2 connection. Cell. 2005;120(4):473–82.Google Scholar
  54. 54.
    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.CrossRefPubMedGoogle Scholar
  55. 55.
    Andrade JM, Frade AC, Guimaraes JB, Freitas KM, Lopes MT, Guimaraes AL, et al. Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. Eur J Nutr. 2014;53(7):1503–10.CrossRefPubMedGoogle Scholar
  56. 56.
    Maizel J, Xavier S, Chen J, Lin CH, Vasko R, Goligorsky MS. Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction. Am J Physiol Heart Circ Physiol. 2014;307(12):H1691–704.CrossRefPubMedGoogle Scholar
  57. 57.
    Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F, et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 2007;21(20):2644–58. doi: 10.1007/s13679-015-0157-8.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Cardiovascular Biology and Medicine, Division of Molecular Aging and Cell BiologyNiigata University Graduate School of Medical and Dental SciencesNiigataJapan
  2. 2.Molecular Cardiology and Whitaker Cardiovascular InstituteBoston University School of MedicineBostonUSA

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