Review

International Journal of Obesity (2010) 34, S43–S46; doi:10.1038/ijo.2010.183

Brown adipose tissue in humans

S Enerbäck1

1Department of Medical and Clinical genetics, Göteborg University, Göteborg, Sweden

Correspondence: Dr S Enerbäck, Department of Medical and Clinical genetics, Göteborg University, Medicinareg. 9A Box 440, Göteborg SE 405 30, Sweden. E-mail: sven.enerback@medgen.gu.se

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Abstract

Obesity is endemic in many regions of the world and a forerunner of several serious and sometimes fatal diseases such as ischemic heart disease, stroke, kidney failure and neoplasia. Although we know its origin—it results when energy intake exceeds energy expenditure—at present, the only proven therapy is bariatric surgery. This is a major abdominal procedure that, for reasons that are largely unknown (it cannot be explained solely by a reduction in ventricular volume), significantly reduces energy intake, but because of cost and limited availability, it will most likely be reserved for only a small fraction of those who stand to gain from effective antiobesity treatment. Clearly, alternative ways to treat obesity are needed. Another way to combat excessive accumulation of white adipose tissue would be to increase energy expenditure. Rodents, hibernators and human infants all have a specialized tissue—brown adipose tissue (BAT)—with the unique capacity to regulate energy expenditure by a process called adaptive thermogenesis. This process depends on the expression of uncoupling protein-1 (UCP1), which is a unique marker for BAT. UCP1 is an inner mitochondrial membrane protein that short circuits the mitochondrial proton gradient, so that oxygen consumption is no longer coupled to adenosine triphosphate synthesis. As a consequence, heat is generated. Mice lacking ucp-1 are severely compromised in their ability to maintain normal body temperature when acutely exposed to cold and they are also prone to become obese. We have shown that, in mice, BAT protects against diet-induced obesity, insulin resistance and type 2 diabetes. This is based on prevention of excessive accumulation of triglyceride in non-adipose tissues such as muscle and liver. Ectopic triglyceride storage at these locations is associated with initiation of insulin resistance and, ultimately, development of type 2 diabetes.

Keywords:

brown adipose tissue; white adipose tissue; type 2 diabetes; uncoupling protein 1; insulin resistance

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Introduction

Brown adipose tissue (BAT) has been considered without physiological relevance in adult humans. Recently, this view was radically changed by identification of significant amounts of metabolically active BAT in healthy adults (hBAT). This was recently published in The New England Journal of Medicine,1, 2, 3 making BAT-mediated dissipation of excess energy in humans a real possibility. This new knowledge is part of an explosion of information regarding BAT function that has accumulated during the last few years, and catapulted brown fat from a position of relative obscurity—as an animal-only tissue—to the center stage of human physiology. Together, these advances are stimulating a reassessment of the role of BAT in human pathophysiology. Furthermore, these new data also afford exciting new opportunities for the development of entirely new classes of therapeutics for metabolic diseases such as obesity and type 2 diabetes. Any effective treatment for obesity must, over time, affect the total energy balance by either increasing expenditure or reducing intake. Complex hormonal, neuronal, genetic and behavioral networks govern food intake and satiety. Research in these areas is focusing on new ways to combat obesity by modulating energy intake. The development of strategies to increase the amount of and/or activity of hBAT provides an alternative and a conceptually attractive way to enhance energy expenditure, especially as this system has evolved with the sole purpose of safely dissipating large amounts of chemical energy. These issues are best addressed by using a multidisciplinary approach that will combine the skills and expertise from several different research milieus spanning from molecular regulation of metabolism to whole-body energy expenditure, which will involve imaging, internal medicine, surgery, genetics, molecular biology, biochemistry and systems biology.4, 5, 6, 7, 8, 9, 10, 11

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Origin of BAT

Until recently, many investigators assumed a common origin of brown and white adipocytes. This was based on several observations, such as that brown and white adipoblasts have very similar morphology, that they both store triglycerides in intracellular lipid droplets and that, with a few notable exceptions (for example, uncoupling protein-1 (UCP1)), they display very similar gene expression profiles. However, several recent studies weigh against a common origin of the white and brown adipocyte.12, 13 Atit et al.12 proposed a common lineage for muscle and brown fat, based on their finding that specific cells of the dermamyotome (derived from paraxial mesoderm) expressing the transcription factor engrailed-1 give rise to both muscle and brown fat cells, but not to white adipocytes. In support of this idea, expression profiling revealed that muscle and brown fat cells both express myogenic factors such as Myf5,14 and in vivo lineage tracing demonstrated a common origin for brown adipocytes and myocytes13 (Figure 1). Seal et al.13 also demonstrated that two types of brown adipocytes exist. Those induced by adrenergic stimuli (β3-agonist, CL316243) are negative for the marker, and are thus derived from a lineage of cells that have never expressed Myf5 (Figure 1). Such cells are interspersed in white adipose tissue and probably stem from activation of dormant precursor cells. In contrast, brown fat cells derived from Myf5+ cells are located at ‘classical’ brown fat locations, for example, around the kidney and between the shoulder blades. Myf5− cells originate from blood vessel-associated pericyte-like cells15 that are of lateral plate mesoderm origin.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

The different origins of white adipose tissue (WAT) and brown adipose tissue (BAT).

Full figure and legend (109K)

Thus, it is likely that brown adipocytes that differentiate in response to ‘environmental’ cues such as adrenergic stimulation have a different origin from those derived from the dermamyotome (which is derived from paraxial mesoderm). This finding of two—to some extent different—pools of BAT cells is supported by studies indicating that genetic variability affects the development of brown adipocytes in white fat but not in interscapular BAT.16

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Genes and signaling pathways in BAT

Mitochondrial activity is essential for many cellular functions such as adenosine triphosphate production, oxidative phosphorylation and biosynthesis of amino acids and lipids.17 The peroxisome proliferator-activated receptor-γ coactivator-1 family of coactivators is also an important component of the regulatory networks that govern expression of nuclear genes during BAT differentiation and mitochondrial biogenesis. Peroxisome proliferator-activated receptor-γ coactivator-1s are key regulators of mitochondrial biogenesis and are involved in the regulation of brown adipocyte-specific genes. One of the family members, peroxisome proliferator-activated receptor-γ coactivator-1α, lies upstream of the nuclear-encoded mitochondrial transcription factor A, which is indispensible for mitochondrial biogenesis and thus serves as a nutrient-sensing system that regulates mitochondrial biogenesis.18 Peroxisome proliferator-activated receptor-γ coactivator-1α-responsive genes linked to mitochondrial function are suppressed in humans with diabetes.19 Several investigations have indicated that the mitochondrial respiratory chain may have a direct role in metabolic disorders such as insulin resistance and type 2 diabetes.20, 21 The biogenesis of the respiratory chain is uniquely dependent on the coordinated expression of both nuclear- and mitochondrial-encoded subunits. However, only a minority of the respiratory chain subunits (13 of about 100) are encoded by mitochondrial DNA, but these subunits are nevertheless essential—as disruption of mitochondrial DNA expression leads to severely impaired respiratory chain function that is in turn linked to metabolic disorders.22 How nuclear factors communicate with the mitochondrial gene expression machinery is not well understood, but tightly regulated intracellular signaling pathways must exist. These pathways, which are coupled to a massive induction of mitochondrial biogenesis, need to be activated in brown adipocytes. Moreover, it was recently shown that cyclic AMP, which activates mitochondrial protein kinase A, does not originate from cytoplasmic sources but is generated within the mitochondrion by the carbon dioxide/bicarbonate-regulated soluble mitochondrial adenylyl cyclase in response to metabolically generated carbon dioxide.23 In the latter report, it was demonstrated for the first time that a complete protein kinase A signaling pathway resides within this organelle. This pathway is believed to function as a metabolic sensor, modulating adenosine triphosphate production in response to metabolic needs by mitochondrial protein kinase A-mediated regulation of respiratory chain activity.

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Future development

Activation, substrate preference and metabolic role of hBAT

Combined positron emission tomography and computed tomography was used for acquisition of biopsies that made it possible to identify hBAT, based on cold-induced 18F-FDG uptake in computed tomography-verified adipose tissue.1 Investigation of hBAT in vivo metabolism in greater detail would be interesting, for example, to study the metabolic profile of activated BAT using tracers for glucose (18F-FDG) and to trace fatty acids the palmitate analog 18F-fluorohaptadecanoid acid and 15O-H2O for the quantitation of glucose and fatty acid uptake and perfusion in hBAT, respectively. This would enable correlations to be made between total uptake of substrate, as well as substrate preference and metabolic rate. This is an important issue, as in rodents, only small amounts of glucose are taken up by activated BAT, whereas more than 90% of substrate uptake in BAT consists of fatty acids.24

Are there different kinds of hBAT?

Recent results in the mouse show the presence of Myf5+ BAT cells at ‘classical’ BAT locations such as around the kidneys, along large blood vessels, as well as interscapularly, whereas Myf5− BAT cells, recruited by treatment with a β3-receptor agonist, were mainly found interspersed in white adipose tissue.13 This opens up interesting and fundamental questions regarding the existence of two distinct types of BAT cell populations in humans. By analogy with the situation in the mouse, it would be interesting to exploit the possibility of distinct BAT cell populations in humans based on anatomical location and in response to catecholamines: are there ‘classical’ populations located at the supraclavicular depot and others induced bycatecholamines? Here, patients with pheochromocytoma—a rare tumor derived from chromaffin cells that secrete catecholamines—offers an interesting opportunity. This notion gains support from a recent publication reporting enhanced amounts of BAT in a pheochromocytoma patient, as measured by 18F-FDG positron emission tomography.25 Another way of inducing hBAT formation would be to study patients with elevated levels of circulating thyroid hormones triiodothyronine (T3) and thyroxine (T4). Thyroid hormones have an athermogenic effect on many tissues, mediating an increased metabolic rate and oxygen consumption. In hyperthyroidism, the thyroid gland secretes an excess of thyroid hormones and this results in stimulated energy expenditure. It is also known that activation of BAT requires thyroid hormones and that thyroid hormones directly regulate UCP1.26

To determine the role of human BAT in energy expenditure and its value as a potential target for intervention, more studies are clearly needed. Larger prospective studies would be of great interest; here, standardized protocols for measuring human BAT mass and activity, and its inducibility by various external cues such as cold exposure, would be of great value, as this would facilitate evaluation and comparison of studies.

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Conflict of interest

The author declares no conflict of interest.

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References

  1. 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: 1518–1525. | Article | PubMed | ChemPort |
  2. Cypress 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: 1509–1517. | Article | PubMed | ChemPort |
  3. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND et al. Cold-activated adipose tissue in healthy adult men. N Engl J Med 2009; 360: 1500–1508. | Article | PubMed | ChemPort |
  4. Adams TD, Gress RE, Smith SC, Halverson RC, Simper SC, Rosamond WD et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007; 357: 753–761. | Article | PubMed | ChemPort |
  5. Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007; 357: 741–752. | Article | PubMed
  6. Lowell BB, Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature 2000; 404: 652–660. | Article | PubMed | ISI | ChemPort |
  7. 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: 90–94. | Article | PubMed | ISI | ChemPort |
  8. 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: 203–209. | Article | PubMed | ChemPort |
  9. Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 2001; 106: 563–573. | Article | PubMed | ISI | ChemPort |
  10. Kim JK, Kim HJ, Park SY, Cederberg A, Westergren R, Nilsson D et al. Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance. Diabetes 2005; 54: 1657–1663. | Article | PubMed | ChemPort |
  11. Unger RH, Orci L. Lipotoxic diseases of nonadipose tissues in obesity. Int J Obes Relat Metab Disord 2000; 24 (Suppl 4): S28–S32. | Article | PubMed
  12. Atit R, Sgaier SK, Mohamed OA, Taketo MM, Dufort D, Joyner AL et al. Beta-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev Biol 2006; 296: 164–176. | Article | PubMed | ChemPort |
  13. 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: 961–967. | Article | PubMed | ChemPort |
  14. Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci USA 2007; 104: 4401–4406. | Article | PubMed | ChemPort |
  15. Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE et al. White fat progenitor cells reside in the adipose vasculature. Science 2008; 322: 583–586. | Article | PubMed | ChemPort |
  16. Xue B, Rim JS, Hogan JC, Coulter AA, Koza RA, Kozak LP. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J Lipid Res 2007; 48: 41–51. | Article | PubMed | ChemPort |
  17. Civitarese AE, Ravussin E. Mitochondrial energetics and insulin resistance. Endocrinology 2008; 149: 950–954. | Article | PubMed
  18. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005; 434: 113–118. | Article | PubMed | ISI | ChemPort |
  19. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267–273. | Article | PubMed | ISI | ChemPort |
  20. Bjorntorp P, Schersten T, Fagerberg SE. Respiration and phosphorylation of mitochondria isolated from the skeletal muscle of diabetic and normal subjects. Diabetologia 1967; 3: 346–352. | Article | PubMed | ChemPort |
  21. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7: 45–56. | Article | PubMed | ChemPort |
  22. Asin-Cayuela J, Gustafsson CM. Mitochondrial transcription and its regulation in mammalian cells. Trends Biochem Sci 2007; 32: 111–117. | Article | PubMed | ChemPort |
  23. Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G. Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 2009; 9: 265–276. | Article | PubMed | ChemPort |
  24. Ma SW, Foster DO. Uptake of glucose and release of fatty acids and glycerol by rat brown adipose tissue in vivo. Can J Physiol Pharmacol 1986; 64: 609–614. | PubMed | ChemPort |
  25. Iyer RB, Guo CC, Perrier N. Adrenal pheochromocytoma with surrounding brown fat stimulation. AJR Am J Roentgenol 2009; 192: 300–301. | Article | PubMed
  26. Ribeiro MO, Bianco SD, Kaneshige M, Schultz JJ, Cheng SY, Bianco AC et al. Expression of uncoupling protein 1 in mouse brown adipose tissue is thyroid hormone receptor-{beta} isoform specific and required for adaptive thermogenesis. Endocrinology 2010; 151: 432–440. | Article | PubMed
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Acknowledgements

I apologize to all colleagues who have been cited only cursorily, or have not been cited because of space constraints. This work was supported by generous grants from the Söderberg Foundation, the Swedish Research Council (Grant K2005-32BI-15324-01A), the Arne and IngaBritt Lundberg Foundation, the Knut and Alice Wallenberg Foundation and the Swedish Foundation for Strategic Research through the Center for Cardiovascular and Metabolic Research.

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