REVIEW ARTICLE Brown adipose tissue and novel therapeutic approaches to treat metabolic disorders Q16 SABINIANO ROMAN, AHMAD AGIL, MACARENA PERAN, EDUARDO ALVARO-GALUE, F. J. RUIZ-OJEDA, and JUAN A. MARCHAL Q1 GRANADA AND JA  EN, SPAIN; SHEFFIELD, UK; AND WINSTON SALEM, NC In humans, 2 functionally different types of adipose tissue coexist: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is involved in energy storage, whereas BAT is involved in energy expenditure. Increased amounts of WAT may contribute to the development of metabolic disorders, such as obesity-associated type 2 diabetes mellitus and cardiovascular diseases. In contrast, the thermogenic function of BAT allows high consumption of fatty acids because of the activity of un- coupling protein 1 in the internal mitochondrial membrane. Interestingly, obesity reduction and insulin sensitization have been achieved by BAT activation/regener- ation Q2 in animal models. This review describes the origin, function, and differentiation mechanisms of BAT to identify new therapeutic strategies for the treatment of metabolic disorders related to obesity. On the basis of the animal studies, novel ap- proaches for BAT regeneration combining stem cells from the adipose tissue with active components, such as melatonin, may have potential for the treatment of metabolic disorders in humans. (Translational Research 2014;-:1–16) Abbreviations: --- ¼ --- Q3 INTRODUCTION A dipose tissue is one of the largest organs in the body and plays an important role in central energy balance and lipid homeostasis. 1 Two types of adipose tissue are found in mammals, white ad- ipose tissue (WAT) and brown adipose tissue (BAT). WAT functions to store energy, whereas BAT special- izes in energy expenditure. 2 In WAT cells, energy is stored via synthesis of triglyc- erides (TGs) that accumulate in lipid vesicles. WAT is composed of visceral and subcutaneous fat and repre- sents 10% of healthy body weight. 3,4 Excess WAT is related to several metabolic disorders. Although visceral fat is less sensitive to insulin than subcutaneous fat, both fat tissues play a role in the development of type 2 diabetes mellitus (T2DM) and cardiovascular complications. 5-8 In addition, an increase in fatty acids (FAs), derived from excessive WATenergy storage, leads to an increased liver glucose From the Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, Granada, Spain; Tissue Engineering Group, Kroto Research Institute, University of Sheffield, Sheffield, UK; Department of Pharmacology and Neurosciences Institute, Faculty of Medicine, University of Granada, Granada, Spain; Department of Health Sciences, University of Ja en, Ja en, Spain; Wake Forest Institute for Regenerative Medicine Wake Forest School of Medicine, Winston Salem, NC; Institute of Nutrition and Food Technology, Centre for Biomedical Research, University of Granada, Granada, Spain; Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Granada, Spain. Submitted for publication June 11, 2014; revision submitted October 16, 2014; accepted for publication November 4, 2014. Reprint requests: Juan A. Marchal, Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, Aveni- dade Madrid 11, E-18012 Granada, Spain; e-mail: jmarchal@ugr.es. 1931-5244/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trsl.2014.11.002 1 REV 5.2.0 DTD  TRSL850_proof  26 November 2014  3:10 pm  ce 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127