Could “Brown Adipose Tissue Failure” be a Cause of Metabolic Syndrome ?

Main Article Content

Norihiko Kobayashi Masako Nakahara Masako Oka Kumiko Saeki


Human brown adipose tissue (BAT) is recognized as one of the most important target tissues in the drug discovery for the treatment of obesity- related metabolic disorders. It is suggested that the BAT improves glucose metabolism independently of its calorigenic capacity, probably via secreting factors. Although several molecules have been identified as BAT-derived glucose metabolism-improving hormones (i.e. BATkines), the crucial factor(s) remains undiscovered. The difficulty in discovering those crucial BATkines may be attributed to the fact that Rnase1 and a variety of chymotrypsin family peptidases are expressed at relatively high levels in murine BATs, which have been used as a material in BATkine hunting. In this review, we describe a new strategy for discovering novel BATkines by using brown adipocytes (BAs) derived from human pluripotent stem cells. We also discuss the possible mechanism how human BAs are involved in the regulation of glucose metabolism.

Article Details

How to Cite
KOBAYASHI, Norihiko et al. Could “Brown Adipose Tissue Failure” be a Cause of Metabolic Syndrome ?. Medical Research Archives, [S.l.], v. 4, n. 7, nov. 2016. ISSN 2375-1924. Available at: <>. Date accessed: 20 jan. 2018.
brown adipose tissue, human embryonic stem cells, human induced pluripotent stem cells, BATkine, glucose metabolism, metabolic syndrome,
Review Articles


Ahfeldt T, Schinzel RT, Lee YK, Hendrickson D, Kaplan A, Lum DH, Camahort R, Xia F, Shay J, Rhee EP, Clish CB, Deo RC, Shen T, Lau FH, Cowley A, Mowrer G, Al-Siddiqi H, Nahrendorf M, Musunuru K, Gerszten RE, Rinn JL, Cowan CA. Programming human pluripotent stem cells into white and brown adipocytes. Nat Cell Biol. 14:209-219, 2012.
Atit R, Sgaier SK, Mohamed OA, Taketo MM, Dufort D, Joyner AL, Niswander L, Conlon RA. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev Biol 296: 164-176, 2006.
Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, Giacobino JP, De Matteis R, Cinti S. The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab. 298: E1244-E1253, 2010.
Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, Kaul MG, Tromsdorf UI, Weller H, Waurisch C, Eychmüller A, Gordts PL, Rinninger F, Bruegelmann K, Freund B, Nielsen P, Merkel M, Heeren J. Brown adipose tissue activity controls triglyceride clearance. Nat Med 17:200-205, 2011.
Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 84:277-359, 2004.
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. 360, 1509–1517, 2009.
Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA, Huang TL, Roberts-Toler C, Weiner LS, Sze C, Chacko AT, Deschamps LN, Herder LM, Truchan N, Glasgow AL, Holman AR, Gavrila A, Hasselgren PO, Mori MA, Molla M, Tseng YH. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med 19:635-629, 2013.
Dekaban AS. Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 4:345-356, 1978.
Dib J, Lapsha VI, Gurin VN. Catecholamine concentration in adrenergic plexuses of the spleen and intestine during cold-induced and emotional stress. Neurophysiology 22: 261–266, 1990.
Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, Zhang C, Seki T, Hosaka K, Wahlberg E, Yang J, Zhang L, Länne T, Sun B, Li X, Liu Y, Zhang Y, Cao Y. Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metab. 18: 118-129, 2013.
Enerbäck S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, Kozak LP. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature. 387:90-94, 1997.
Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151:400-413, 2012. doi: 10.1016/j.cell.2012.09.010.
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 9:203-209, 2009. doi: 10.1016/j.cmet.2008.12.014.
Friend A, Craig L, Turner S. The prevalence of metabolic syndrome in children: a systematic review of the literature. Metab Syndr Relat Disord. 11:71-80, 2013. doi: 10.1089/met.2012.0122.
Gupta RK, Mepani RJ, Kleiner S, Lo JC, Khandekar MJ, Cohen P, Frontini A, Bhowmick DC, Ye L, Cinti S, Spiegelman BM. Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15:230-239, 2012. doi: 10.1016/j.cmet.2012.01.010.
Hamann A, Flier JS, Lowell BB. Decreased brown fat markedly enhances susceptibility to diet-induced obesity, diabetes, and hyperlipidemia. Endocrinology 137:21-29, 1996. DOI: 10.1210/endo.137.1.8536614.
Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, Kurokawa M, Won KJ, Seale P. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab 19: 593-604, 2014. doi: 10.1016/j.cmet.2014.03.007.
Heikens MJ, Gorbach AM, Eden HS, Savastano DM, Chen KY, Skarulis MC, Yanovski JA. Core body temperature in obesity. Am J Clin Nutr 93:963-967, 2011. doi: 10.3945/ajcn.110.006270.
Hildrum B, Mykletun A, Hole T, Midthjell K, Dahl AA. Age-specific prevalence of the metabolic syndrome defined by the International Diabetes Federation and the National Cholesterol Education Program: the Norwegian HUNT 2 study. BMC Public Health. 7: 220, 2007. DOI: 10.1186/1471-2458-7-220
Jasper M. A. de Jong, Larsson O., Cannon B., Nedergaard J. A stringent validation of mouse adipose tissue identity markers. Am. J. Physiol. Endocrinol Metab. 308, E1085–E1105, 2015. doi: 10.1152/ajpendo.00023.2015.
Kishida T, Ejima A, Yamamoto K, Tanaka S, Yamamoto T, Mazda O. Reprogrammed Functional Brown Adipocytes Ameliorate Insulin Resistance and Dyslipidemia in Diet-Induced Obesity and Type 2 Diabetes. Stem Cell Reports 5: 569-581, 2015. doi: 10.1016/j.stemcr.2015.08.007.
Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, Glass CK, Hume DA, Kellie S, Sweet MJ. Expression analysis of G Protein-Coupled Receptors in mouse macrophages. Immunome Res 4: 5, 2008. doi: 10.1186/1745-7580-4-5.
Lee P, Smith S, Linderman J, Courville AB, Brychta RJ, Dieckmann W, Werner CD1, Chen KY, Celi FS. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes. 63: 3686-3698, 2014. doi: 10.2337/db14-0513.
Lowell BB, S-Susulic V, Hamann A, Lawitts JA, Himms-Hagen J, Boyer BB, Kozak LP, Flier JS. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366: 740-742, 1993. DOI: 10.1038/366740a0
Mantzoros CS, Frederich RC, Qu D, Lowell BB, Maratos-Flier E, Flier JS. Severe leptin resistance in brown fat-deficient uncoupling protein promoter- driven diphtheria toxin A mice despite suppression of hypothalamic neuropeptide Y and circulating corticosterone concentrations. Diabetes 47:230-238, 1998. PMID: 9519718
Nakamura N, Saeki K, Mitsumoto M, Matsuyama S, Nishio M, Saeki K, Hasegawa M, Miyagawa Y, Ohkita H, Kiyokawa N, Toyoda M, Akutsu H, Umezawa A, Yuo A. Feeder-free and serum-free production of hepatocytes, cholangiocytes, and their proliferating progenitors from human pluripotent stem cells: application to liver-specific functional and cytotoxic assays. Cell Reprogram 14: 171-185, 2012. doi: 10.1089/cell.2011.0064.
Nishio M, Yoneshiro T, Nakahara M, Suzuki S, Saeki K, Hasegawa M, Kawai Y, Akutsu H, Umezawa A, Yasuda K, Tobe K, Yuo A, Kubota K, Saito M, Saeki K. Production of functional classical brown adipocytes from human pluripotent stem cells using specific hemopoietin cocktail without gene transfer. Cell Metab. 16: 394-406, 2012. doi: 10.1016/B978-0-12-411619-1.00010-0.
Nishio M, Saeki K. Differentiation of human pluripotent stem cells into highly functional classical brown adipocytes. Methods Enzymol 537: 177-197, 2014.
Nishio M, Nakahara M, Sato C, Saeki K, Akutsu H, Umezawa A, Tobe K, Yasuda K, Yuo A, Saeki K. New categorization of human vascular endothelial cells by pro- vs anti-proliferative phenotypes. World J Transl Med 4: 88-100, 2015a.
Nishio M, Nakahara M, Saeki K, Fujiu K, Iwata H, Manabe I, Yuo A, Saeki K. Pro- vs anti-stenotic capacities of type-I versus type-II human iPS-derived endothelial cells. World J Transl Med 4:113-122, 2015b.
Nishio M, Nakahara M, Yuo A, Saeki K. Human pluripotent stem cells: Towards therapeutic development for the treatment of lifestyle diseases. World J Stem Cells 8: 56-61, 2016. doi: 10.4252/wjsc.v8.i2.56.
Okamatsu-Ogura Y, Nio-Kobayashi J, Iwanaga T, Terao A, Kimura K, Saito M. Possible involvement of uncoupling protein 1 in appetite control by leptin. Exp Biol Med (Maywood) 236:1274-1281, 2011. doi: 10.1258/ebm.2011.011143.
Okamatsu-Ogura Y., Fukano K., Tsubota A., Uozumi A., Terao A., Kimura K., Saito M. Thermogenic ability of uncoupling protein 1 in beige adipocytes in mice. PLoS One. 8: e84229, 2013. doi: 10.1371/journal.pone.0084229.
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 285: 7153-7164, 2010. doi: 10.1074/jbc.M109.053942.
Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531, 2009. doi: 10.2337/db09-0530.
Saito M. Capsaicin and Related Food Ingredients Reducing Body Fat Through the Activation of TRP and Brown Fat Thermogenesis. Adv Food Nutr Res 76: 1-28, 2015. doi: 10.1016/bs.afnr.2015.07.002.
Sawabe M, Saito M, Naka M, Kasahara I, Saito Y, Arai T, Hamamatsu A, Shirasawa T. Standard organ weights among elderly Japanese who died in the hospital, including 50 centenarians. Pathology International 56: 315-323, 2006. DOI: 10.1111/j.1440-1827.2006.01966.x
Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scimè A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454: 961-967, 2008. doi: 10.1038/nature07182.
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 5: 1196-1203, 2013. doi: 10.1016/j.celrep.2013.10.044
Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 7: e49452, 2012. doi: 10.1371/journal.pone.0049452
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 123: 215-223, 2013. doi: 10.1172/JCI62308
Speakman JR, Keijer J. Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans. Mol Metab. 2: 5-9, 2012. doi: 10.1016/j.molmet.2012.10.002
Tran KV, Gealekman O, Frontini A, Zingaretti MC, Morroni M, Giordano A, Smorlesi A, Perugini J, De Matteis R, Sbarbati A, Corvera S, Cinti S. The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab 15:222-229, 2012. doi: 10.1016/j.cmet.2012.01.008
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. 360, 1500–1508, 2009. doi: 10.1056/NEJMoa0808718
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerba ̈ck S, Nuutila P. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525, 2009. doi: 10.1056/NEJMoa0808949
Waldén TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, "brite," and white adipose tissues. Am J Physiol Endocrinol Metab 302: E19-E31, 2012. doi: 10.1152/ajpendo.00249.2011
Wang GX, Zhao XY, Lin JD. The brown fat secretome: metabolic functions beyond thermogenesis. Trends Endocrinol Metab. 26: 231-237, 2015. doi: 10.1016/j.tem.2015.03.002
Wikstrom JD, Mahdaviani K, Liesa M, Sereda SB, Si Y, Las G, Twig G, Petrovic N, Zingaretti C, Graham A, Cinti S, Corkey BE, Cannon B, Nedergaard J, Shirihai OS. Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J 33: 418-436, 2014. doi: 10.1002/embj.201385014
Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, Hodge CL, Haase J, Janes J, Huss JW 3rd, Su AI. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 10: R130, 2009. doi: 10.1186/gb-2009-10-11-r130
Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman BM. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150: 366-376, 2012. doi: 10.1016/j.cell.2012.05.016.
Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T, Kawai Y, Miyagawa M, Tsujisaki M, Saito M. Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity 19: 1755-1760, 2011. PMID: 24897476
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. 123: 3404-3408, 2013. doi: 10.1172/JCI67803

Most read articles by the same author(s)

Obs.: This plugin requires at least one statistics/report plugin to be enabled. If your statistics plugins provide more than one metric then please also select a main metric on the admin's site settings page and/or on the journal manager's settings pages.