Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

Circulation Research

Volumn 118, Issue 1, 2016, Pages 173-182

  Hoeke, Geerte ^a   Kooijman, Sander ^a   Boon, Mariëtte R ^a   Rensen, Patrick C N ^a   Berbeé, Jimmy F P ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

adipose tissue, brown; atherosclerosis; cholesterol; energy metabolism; fatty acids; lipoproteinlipase

Indexed keywords

APOLIPOPROTEIN E; CHOLESTEROL; FATTY ACID; GLUCOSE; LIPOPROTEIN; LIPOPROTEIN LIPASE; LOW DENSITY LIPOPROTEIN RECEPTOR; TRIACYLGLYCEROL; LIPOPROTEIN TRIGLYCERIDE; LOW DENSITY LIPOPROTEIN;

ADIPOCYTE; ATHEROSCLEROSIS; BEIGE ADIPOCYTE; BROWN ADIPOCYTE; BROWN ADIPOSE TISSUE; CARDIOVASCULAR MORTALITY; CHOLESTEROL BLOOD LEVEL; COMPUTER ASSISTED EMISSION TOMOGRAPHY; FATTY ACID TRANSPORT; GLUCOSE TRANSPORT; GOLD STANDARD; HUMAN; HYDROLYSIS; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; HYPERTRIGLYCERIDEMIA; LIPID STORAGE; LIPOPROTEIN METABOLISM; MORBIDITY; NONHUMAN; PRIORITY JOURNAL; REVIEW; RISK FACTOR; TRIACYLGLYCEROL BLOOD LEVEL; ANIMAL; LIPID METABOLISM; METABOLISM; PHYSIOLOGY;

ADIPOSE TISSUE, BROWN; ANIMALS; ATHEROSCLEROSIS; HUMANS; HYPERCHOLESTEROLEMIA; LIPID METABOLISM; LIPOPROTEIN LIPASE; LIPOPROTEINS; LIPOPROTEINS, LDL; TRIGLYCERIDES;

EID: 84954564100     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.115.306647     Document Type: Review

References (108)

1. Jukema JW, Cannon CP, de Craen AJ, Westendorp RG, Trompet S. The controversies of statin therapy: weighing the evidence. J Am Coll Cardiol. 2012;60:875-881. doi: 10.1016/j.jacc.2012.07.007.
2. Geerling JJ, Boon MR, Kooijman S, Parlevliet ET, Havekes LM, Romijn JA, Meurs IM, Rensen PC. Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies. J Lipid Res. 2014;55:180-189. doi: 10.1194/jlr.R045013.
3. Chan DC, Barrett PH, Watts GF. The metabolic and pharmacologic bases for treating atherogenic dyslipidaemia. Best Pract Res Clin Endocrinol Metab. 2014;28:369-385. doi: 10.1016/j.beem.2013.10.001.
4. Hegele RA, Ginsberg HN, Chapman MJ, et al; European Atherosclerosis Society Consensus Panel. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655-666. doi: 10.1016/S2213-8587(13)70191-8.
5. Langsted A, Freiberg JJ, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Nordestgaard BG. Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up. J Intern Med. 2011;270:65-75. doi: 10.1111/j.1365-2796.2010.02333.x.
6. Choi HD, Shin WG, Lee JY, Kang BC. Safety and efficacy of fibrate-statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta-analysis. Vascul Pharmacol. 2015;65-66:23-30. doi: 10.1016/j.vph.2014.11.002.
7. Andersson C, Lyass A, Vasan RS, Massaro JM, D'Agostino RB Sr, Robins SJ. Long-term risk of cardiovascular events across a spectrum of adverse major plasma lipid combinations in the Framingham Heart Study. Am Heart J. 2014;168:878-83.e1. doi: 10.1016/j.ahj.2014.08.007.
8. Bartelt A, Bruns OT, Reimer R, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200-205. doi: 10.1038/nm.2297.
9. Berbeé JF, Boon MR, Khedoe PP, et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun. 2015;6:6356. doi: 10.1038/ncomms7356.
10. De Lorenzo F, Mukherjee M, Kadziola Z, Sherwood R, Kakkar VV. Central cooling effects in patients with hypercholesterolaemia. Clin Sci (Lond). 1998;95:213-217.
11. Geerling JJ, Boon MR, van der Zon GC, van den Berg SA, van den Hoek AM, Lombès M, Princen HM, Havekes LM, Rensen PC, Guigas B. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes. 2014;63:880-891. doi: 10.2337/db13-0194.
12. Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Invest. 2015;125:478-486. doi: 10.1172/JCI78362.
13. Heaton JM. The distribution of brown adipose tissue in the human. J Anat. 1972;112:35-39.
14. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 2009;23:3113-3120. doi: 10.1096/fj.09-133546.
15. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509-1517. doi: 10.1056/NEJMoa0810780.
16. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360:1500-1508. doi: 10.1056/NEJMoa0808718.
17. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360:1518-1525. doi: 10.1056/NEJMoa0808949.
18. Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging. 2002;29:1393-1398. doi: 10.1007/s00259-002-0902-6.
19. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293:E444-E452. doi: 10.1152/ajpendo.00691.2006.
20. Blondin DP, Labbé SM, Noll C, Kunach M, Phoenix S, Guérin B, Turcotte ÉE, Haman F, Richard D, Carpentier AC. Selective impairment of glucose but not fatty acid or oxidative metabolism in brown adipose tissue of subjects with type 2 diabetes. Diabetes. 2015;64:2388-2397. doi: 10.2337/db14-1651.
21. Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F, Turcotte EE, Richard D, Carpentier AC. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012;122:545-552. doi: 10.1172/JCI60433.
22. Vijgen GH, Bouvy ND, Teule GJ, Brans B, Schrauwen P, van Marken Lichtenbelt WD. Brown adipose tissue in morbidly obese subjects. PLoS One. 2011;6:e17247. doi: 10.1371/journal.pone.0017247.
23. Wang Q, Zhang M, Xu M, Gu W, Xi Y, Qi L, Li B, Wang W. Brown adipose tissue activation is inversely related to central obesity and metabolic parameters in adult human. PLoS One. 2015;10:e0123795. doi: 10.1371/journal.pone.0123795.
24. van der Lans AA, Hoeks J, Brans B, Vijgen GH, Visser MG, Vosselman MJ, Hansen J, Jörgensen JA, Wu J, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest. 2013;123:3395-3403. doi: 10.1172/JCI68993.
25. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, Iwanaga T, Saito M. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest. 2013;123:3404-3408. doi: 10.1172/JCI67803.
26. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B. The principle of temperature-dependent gating in cold-and heat-sensitive TRP channels. Nature. 2004;430:748-754. doi: 10.1038/nature02732.
27. Bamshad M, Song CK, Bartness TJ. CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am J Physiol. 1999;276:R1569-R1578.
28. Kooijman S, van den Berg R, Ramkisoensing A, Boon MR, Kuipers EN, Loef M, Zonneveld TC, Lucassen EA, Sips HC, Chatzispyrou IA, Houtkooper RH, Meijer JH, Coomans CP, Biermasz NR, Rensen PC. Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity. Proc Natl Acad Sci USA. 2015;112:6748-6753. doi: 10.1073/pnas.1504239112.
29. Townsend KL, Tseng YH. Brown fat fuel utilization and thermogenesis. Trends Endocrinol Metab. 2014;25:168-177. doi: 10.1016/j. tem.2013.12.004.
30. Labbé SM, Caron A, Bakan I, Laplante M, Carpentier AC, Lecomte R, Richard D. In vivo measurement of energy substrate contribution to coldinduced brown adipose tissue thermogenesis. FASEB J. 2015;29:2046-2058. doi: 10.1096/fj.14-266247.
31. Blondin DP, Labbé SM, Tingelstad HC, Noll C, Kunach M, Phoenix S, Guérin B, Turcotte EE, Carpentier AC, Richard D, Haman F. Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J Clin Endocrinol Metab. 2014;99:E438-E446. doi: 10.1210/jc.2013-3901.
32. Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell. 2012;151:400-413. doi: 10.1016/j.cell.2012.09.010.
33. Mirbolooki MR, Upadhyay SK, Constantinescu CC, Pan ML, Mukherjee J. Adrenergic pathway activation enhances brown adipose tissue metabolism: a [F]FDG PET/CT study in mice. Nucl Med Biol. 2014;41:10-16. doi: 10.1016/j.nucmedbio.2013.08.009.
34. Park JW, Jung KH, Lee JH, Quach CH, Moon SH, Cho YS, Lee KH. 18F-FDG PET/CT monitoring of 3 agonist-stimulated brown adipocyte recruitment in white adipose tissue. J Nucl Med. 2015;56:153-158. doi: 10.2967/jnumed.114.147603.
35. Festuccia WT, Blanchard PG, Deshaies Y. Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPAR. Front Endocrinol (Lausanne). 2011;2:84. doi: 10.3389/fendo.2011.00084.
36. Hao Q, Yadav R, Basse AL, Petersen S, Sonne SB, Rasmussen S, Zhu Q, Lu Z, Wang J, Audouze K, Gupta R, Madsen L, Kristiansen K, Hansen JB. Transcriptome profiling of brown adipose tissue during cold exposure reveals extensive regulation of glucose metabolism. Am J Physiol Endocrinol Metab. 2015;308:E380-E392. doi: 10.1152/ajpendo.00277.2014.
37. Liu X, Wang S, You Y, et al. Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology. 2015;156:2461-2469. doi: 10.1210/en.2014-1598.
38. Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, Markan KR, Nakano K, Hirshman MF, Tseng YH, Goodyear LJ. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2013;123:215-223. doi: 10.1172/JCI62308.
39. Chondronikola M, Volpi E, Børsheim E, et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014;63:4089-4099. doi: 10.2337/db14-0746.
40. Raiko J, Holstila M, Virtanen KA, Orava J, Saunavaara V, Niemi T, Laine J, Taittonen M, Borra RJ, Nuutila P, Parkkola R. Brown adipose tissue triglyceride content is associated with decreased insulin sensitivity, independently of age and obesity. Diabetes Obes Metab. 2015;17:516-519. doi: 10.1111/dom.12433.
41. Amutha A, Ali MK, Unnikrishnan R, Anjana RM, Ranjani H, Gokulakrishnan K, Mohan V, Narayan KM. Insulin sensitivity and secretion in youth onset type 2 diabetes with and without visceral adiposity. Diabetes Res Clin Pract. 2015;109:32-39. doi: 10.1016/j. diabres.2015.05.018.
42. Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerbäck S, Virtanen KA. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011;14:272-279. doi: 10.1016/j.cmet.2011.06.012.
43. Hanssen MJ, Wierts R, Hoeks J, Gemmink A, Brans B, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Glucose uptake in human brown adipose tissue is impaired upon fasting-induced insulin resistance. Diabetologia. 2015;58:586-595. doi: 10.1007/s00125-014-3465-8.
44. Qu S, Zhang T, Dong HH. Effect of hepatic insulin expression on lipid metabolism in diabetic mice [published online ahead of print April 7, 2015]. J Diabetes. doi: 10.1111/1753-0407.12293.
45. Ramasamy I. Recent advances in physiological lipoprotein metabolism. Clin Chem Lab Med. 2013;1-33.
46. Augustus AS, Kako Y, Yagyu H, Goldberg IJ. Routes of FA delivery to cardiac muscle: modulation of lipoprotein lipolysis alters uptake of TGderived FA. Am J Physiol Endocrinol Metab. 2003;284:E331-E339. doi: 10.1152/ajpendo.00298.2002.
47. Laplante M, Festuccia WT, Soucy G, Blanchard PG, Renaud A, Berger JP, Olivecrona G, Deshaies Y. Tissue-specific postprandial clearance is the major determinant of PPARgamma-induced triglyceride lowering in the rat. Am J Physiol Regul Integr Comp Physiol. 2009;296:R57-R66. doi: 10.1152/ajpregu.90552.2008.
48. Coburn CT, Knapp FF Jr, Febbraio M, Beets AL, Silverstein RL, Abumrad NA. Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem. 2000;275:32523-32529. doi: 10.1074/jbc.M003826200.
49. Yacoub LK, Vanni TM, Goldberg IJ. Lipoprotein lipase mRNA in neonatal and adult mouse tissues: comparison of normal and combined lipase deficiency (cld) mice assessed by in situ hybridization. J Lipid Res. 1990;31:1845-1852.
50. Goudriaan JR, den Boer MA, Rensen PC, Febbraio M, Kuipers F, Romijn JA, Havekes LM, Voshol PJ. CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance. J Lipid Res. 2005;46:2175-2181. doi: 10.1194/jlr.M500112-JLR200.
51. Putri M, Syamsunarno MR, Iso T, Yamaguchi A, Hanaoka H, Sunaga H, Koitabashi N, Matsui H, Yamazaki C, Kameo S, Tsushima Y, Yokoyama T, Koyama H, Abumrad NA, Kurabayashi M. CD36 is indispensable for thermogenesis under conditions of fasting and cold stress. Biochem Biophys Res Commun. 2015;457:520-525. doi: 10.1016/j.bbrc.2014.12.124.
52. Khedoe PP, Hoeke G, Kooijman S, Dijk W, Buijs JT, Kersten S, Havekes LM, Hiemstra PS, Berbeé JF, Boon MR, Rensen PC. Brown adipose tissue takes up plasma triglycerides mostly after lipolysis. J Lipid Res. 2015;56:51-59. doi: 10.1194/jlr.M052746.
53. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004;306:1383-1386. doi: 10.1126/science.1100747.
54. Wu J, Boström P, Sparks LM, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366-376. doi: 10.1016/j.cell.2012.05.016.
55. Rosell M, Kaforou M, Frontini A, et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am J Physiol Endocrinol Metab. 2014;306:E945-E964. doi: 10.1152/ajpendo.00473.2013.
56. Contreras GA, Lee YH, Mottillo EP, Granneman JG. Inducible brown adipocytes in subcutaneous inguinal white fat: the role of continuous sympathetic stimulation. Am J Physiol Endocrinol Metab. 2014;307:E793-E799. doi: 10.1152/ajpendo.00033.2014.
57. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem. 2010;285:7153-7164. doi: 10.1074/jbc.M109.053942.
58. Rachid TL, Penna-de-Carvalho A, Bringhenti I, Aguila MB, Mandarimde-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. doi: 10.1016/j.mce.2014.12.027.
59. Boon MR, van den Berg SA, Wang Y, et al. BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS One. 2013;8:e74083. doi: 10.1371/journal.pone.0074083.
60. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121:96-105. doi: 10.1172/JCI44271.
61. Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, Cinti S. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol. 2000;279:C670-C681.
62. Vitali A, Murano I, Zingaretti MC, Frontini A, Ricquier D, Cinti S. The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J Lipid Res. 2012;53:619-629. doi: 10.1194/jlr.M018846.
63. Rosenwald M, Perdikari A, Rülicke T, Wolfrum C. Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol. 2013;15:659-667. doi: 10.1038/ncb2740.
64. Schulz TJ, Huang TL, Tran TT, Zhang H, Townsend KL, Shadrach JL, Cerletti M, McDougall LE, Giorgadze N, Tchkonia T, Schrier D, Falb D, Kirkland JL, Wagers AJ, Tseng YH. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci USA. 2011;108:143-148. doi: 10.1073/pnas.1010929108.
65. Vegiopoulos A, Müller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Berriel Diaz M, Rozman J, Hrabe de Angelis M, Nüsing RM, Meyer CW, Wahli W, Klingenspor M, Herzig S. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science. 2010;328:1158-1161. doi: 10.1126/science.1186034.
66. Lee YH, Petkova AP, Mottillo EP, Granneman JG. In vivo identification of bipotential adipocyte progenitors recruited by 3-adrenoceptor activation and high-fat feeding. Cell Metab. 2012;15:480-491. doi: 10.1016/j. cmet.2012.03.009.
67. Cypess AM, White AP, Vernochet C, et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med. 2013;19:635-639. doi: 10.1038/nm.3112.
68. Shinoda K, Luijten IH, Hasegawa Y, Hong H, Sonne SB, Kim M, Xue R, Chondronikola M, Cypess AM, Tseng YH, Nedergaard J, Sidossis LS, Kajimura S. Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat Med. 2015;21:389-394. doi: 10.1038/nm.3819.
69. van Dam AD, Nahon KJ, Kooijman S, van den Berg SM, Kanhai AA, Kikuchi T, Heemskerk MM, van Harmelen V, Lombès M, van den Hoek AM, de Winther MP, Lutgens E, Guigas B, Rensen PC, Boon MR. Salsalate activates brown adipose tissue in mice. Diabetes. 2015;64:1544-1554. doi: 10.2337/db14-1125.
70. Boon MR, Kooijman S, van Dam AD, et al. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity. FASEB J. 2014;28:5361-5375. doi: 10.1096/fj.13-247643.
71. Sun K, Kusminski CM, Luby-Phelps K, Spurgin SB, An YA, Wang QA, Holland WL, Scherer PE. Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Mol Metab. 2014;3:474-483. doi: 10.1016/j.molmet.2014.03.010.
72. Jbilo O, Ravinet-Trillou C, Arnone M, Buisson I, Bribes E, Péleraux A, Pénarier G, Soubrié P, Le Fur G, Galiègue S, Casellas P. The CB1 receptor antagonist rimonabant reverses the diet-induced obesity phenotype through the regulation of lipolysis and energy balance. FASEB J. 2005;19:1567-1569. doi: 10.1096/fj.04-3177fje.
73. Tam J, Godlewski G, Earley BJ, Zhou L, Jourdan T, Szanda G, Cinar R, Kunos G. Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity. Am J Physiol Endocrinol Metab. 2014;306:E457-E468. doi: 10.1152/ajpendo.00489.2013.
74. Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, Cypess AM, Mishina Y, Gussoni E, Tseng YH. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature. 2013;495:379-383. doi: 10.1038/nature11943.
75. Boström P, Wu J, Jedrychowski MP, et al. A PGC1-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463-468. doi: 10.1038/nature10777.
76. Chechi K, Blanchard PG, Mathieu P, Deshaies Y, Richard D. Brown fat like gene expression in the epicardial fat depot correlates with circulating HDL-cholesterol and triglycerides in patients with coronary artery disease. Int J Cardiol. 2013;167:2264-2270. doi: 10.1016/j.ijcard.2012.06.008.
77. Bakker LE, Boon MR, van der Linden RA, Arias-Bouda LP, van Klinken JB, Smit F, Verberne HJ, Jukema JW, Tamsma JT, Havekes LM, van Marken Lichtenbelt WD, Jazet IM, Rensen PC. Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study. Lancet Diabetes Endocrinol. 2014;2:210-217. doi: 10.1016/S2213-8587(13)70156-6.
78. Mantha L, Deshaies Y. beta-Adrenergic modulation of triglyceridemia under increased energy expenditure. Am J Physiol. 1998;274:R1769-R1776.
79. Bartesaghi S, Hallen S, Huang L, Svensson PA, Momo RA, Wallin S, Carlsson EK, Forslöw A, Seale P, Peng XR. Thermogenic activity of UCP1 in human white fat-derived beige adipocytes. Mol Endocrinol. 2015;29:130-139. doi: 10.1210/me.2014-1295.
80. Okla M, Ha JH, Temel RE, Chung S. BMP7 drives human adipogenic stem cells into metabolically active beige adipocytes. Lipids. 2015;50:111-120. doi: 10.1007/s11745-014-3981-9.
81. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366:665-675. doi: 10.1016/S0140-6736(05)67139-5.
82. Kuji I, Imabayashi E, Minagawa A, Matsuda H, Miyauchi T. Brown adipose tissue demonstrating intense FDG uptake in a patient with mediastinal pheochromocytoma. Ann Nucl Med. 2008;22:231-235. doi: 10.1007/s12149-007-0096-x.
83. Yamaga LY, Thom AF, Wagner J, Baroni RH, Hidal JT, Funari MG. The effect of catecholamines on the glucose uptake in brown adipose tissue demonstrated by (18)F-FDG PET/CT in a patient with adrenal pheochromocytoma. Eur J Nucl Med Mol Imaging. 2008;35:446-447. doi: 10.1007/s00259-007-0538-7.
84. Frontini A, Vitali A, Perugini J, Murano I, Romiti C, Ricquier D, Guerrieri M, Cinti S. White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma. Biochim Biophys Acta. 2013;1831:950-959. doi: 10.1016/j.bbalip.2013.02.005.
85. Heeren J, Beisiegel U, Grewal T. Apolipoprotein E recycling: implications for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:442-448. doi: 10.1161/01.ATV.0000201282.64751.47.
86. Ishibashi S, Herz J, Maeda N, Goldstein JL, Brown MS. The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA. 1994;91:4431-4435.
87. Talmud PJ, Shah S, Whittall R, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013;381:1293-1301. doi: 10.1016/S0140-6736(12)62127-8.
88. Vermeer BJ, Frants RR, Havekes LM. Familial dysbetalipoproteinemia: a genetically heterogenous disease caused by mutations of the ligand apolipoprotein E. J Invest Dermatol. 1992;98:57S-60S.
89. Dong M, Yang X, Lim S, et al. Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metab. 2013;18:118-129. doi: 10.1016/j.cmet.2013.06.003.
90. Gelissen IC, McLachlan AJ. The pharmacogenomics of statins. Pharmacol Res. 2014;88:99-106. doi: 10.1016/j.phrs.2013.12.002.
91. Norata GD, Tibolla G, Catapano AL. PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges. Vascul Pharmacol. 2014;62:103-111. doi: 10.1016/j.vph.2014.05.011.
92. Matsushita M, Yoneshiro T, Aita S, Kameya T, Sugie H, Saito M. Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans. Int J Obes (Lond). 2014;38:812-817. doi: 10.1038/ijo.2013.206.
93. Ursino MG, Vasina V, Raschi E, Crema F, De Ponti F. The beta3-adrenoceptor as a therapeutic target: current perspectives. Pharmacol Res. 2009;59:221-234. doi: 10.1016/j.phrs.2009.01.002.
94. Cypess AM, Weiner LS, Roberts-Toler C, Franquet Eliá E, Kessler SH, Kahn PA, English J, Chatman K, Trauger SA, Doria A, Kolodny GM. Activation of human brown adipose tissue by a 3-adrenergic receptor agonist. Cell Metab. 2015;21:33-38. doi: 10.1016/j.cmet.2014.12.009.
95. Mattsson CL, Csikasz RI, Chernogubova E, Yamamoto DL, Hogberg HT, Amri EZ, Hutchinson DS, Bengtsson T.-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated-adrenergic receptor-knockout mice via nonshivering thermogenesis. Am J Physiol Endocrinol Metab. 2011;301:E1108-E1118. doi: 10.1152/ajpendo.00085.2011.
96. Redman LM, de Jonge L, Fang X, Gamlin B, Recker D, Greenway FL, Smith SR, Ravussin E. Lack of an effect of a novel beta3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals: a doubleblind, placebo-controlled randomized study. J Clin Endocrinol Metab. 2007;92:527-531. doi: 10.1210/jc.2006-1740.
97. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A. Effect of a 28-d treatment with L-796568, a novel beta(3)-adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr. 2002;76:780-788.
98. Weyer C, Tataranni PA, Snitker S, Danforth E Jr, Ravussin E. Increase in insulin action and fat oxidation after treatment with CL 316,243, a highly selective beta3-adrenoceptor agonist in humans. Diabetes. 1998;47:1555-1561.
99. Emanuelli B, Vienberg SG, Smyth G, Cheng C, Stanford KI, Arumugam M, Michael MD, Adams AC, Kharitonenkov A, Kahn CR. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest. 2014;124:515-527. doi: 10.1172/JCI67353.
100. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014;19:302-309. doi: 10.1016/j.cmet.2013.12.017.
101. Lee P, Werner CD, Kebebew E, Celi FS. Functional thermogenic beige adipogenesis is inducible in human neck fat. Int J Obes (Lond). 2014;38:170-176. doi: 10.1038/ijo.2013.82.
102. Hanssen MJ, Broeders E, Samms RJ, Vosselman MJ, van der Lans AA, Cheng CC, Adams AC, van Marken Lichtenbelt WD, Schrauwen P. Serum FGF21 levels are associated with brown adipose tissue activity in humans. Sci Rep. 2015;5:10275. doi: 10.1038/srep10275.
103. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013;18:333-340. doi: 10.1016/j.cmet.2013.08.005.
104. Salpeter SR, Buckley NS, Kahn JA, Salpeter EE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med. 2008;121:149-157.e2. doi: 10.1016/j.amjmed.2007.09.016.
105. Wulffelé MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256:1-14. doi: 10.1111/j.1365-2796.2004.01328.x.
106. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
107. Abbasi F, Chu JW, McLaughlin T, Lamendola C, Leary ET, Reaven GM. Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus. Metabolism. 2004;53:159-164.
108. Ohira M, Yamaguchi T, Saiki A, Ban N, Kawana H, Nagayama D, Nagumo A, Murano T, Shirai K, Tatsuno I. Metformin reduces circulating malondialdehyde-modified low-density lipoprotein in type 2 diabetes mellitus. Clin Invest Med. 2014;37:E243-E251.