EC Gastroenterology and Digestive System

Studies on the physiology of different types of fat deposition have increasingly recognized adipocytes as an essential endocrine organ with numerous metabolic activities. Human fat consists of white adipose tissue (WAT) and brown adipose tissue (BAT). WAT helps in energy storage, whereas BAT helps in energy consumption. Increased WAT levels may play a role in the progression of metabolic abnormalities and cardiovascular events. On the contrary, the thermogenic function of BAT allows for significant fatty acid intake due to the activation of uncoupling protein 1 (UCP1) in the internal mitochondrial membrane. In vertebrates, the sympathetic nervous system (SNS) stimulates the thermogenesis of BAT in response to cold, helping to maintain the body temperature. BAT may be a promising new therapeutic target for promoting weight reduction and improving metabolic health. Furthermore, activation of BAT is associated with improved glucose metabolism. This review encompasses the research on human BAT, including its functions and differentiation processes, its potential as a new therapeutic target for managing metabolic illnesses, such as obesity and diabetes, and its possible future applications.

Keywords: Diabetes; Fatty Acid Intake; Human Fat; Improved Glucose Metabolism; Insulin Resistance; Obesity; Thermogenesis

1. Trayhurn P. “Origins and early development of the concept that brown adipose tissue thermogenesis is linked to energy balance and obesity”. Biochimie 134 (2017): 62-70. https://pubmed.ncbi.nlm.nih.gov/27621146/
2. Lee P., et al. “Brown adipose tissue in adult humans: a metabolic renaissance”. Endocrine Reviews 3 (2013): 413-438. https://pubmed.ncbi.nlm.nih.gov/23550082/
3. Halpern B., et al. “Brown adipose tissue: what have we learned since its recent identification in human adults”. Arquivos Brasileiros De Endocrinologia E Metabologia 9 (2014): 889-899. https://pubmed.ncbi.nlm.nih.gov/25627043/
4. Wang W and Seale P. “Control of brown and beige fat development”. Nature Reviews Molecular Cell Biology11 (2016): 691-702. https://pubmed.ncbi.nlm.nih.gov/27552974/
5. Park A., et al. “Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells”. The World Journal of Stem Cells 1 (2014): 33-42. https://pubmed.ncbi.nlm.nih.gov/24567786/
6. Colaianni G., et al. “Anatomy and physiology of adipose tissue”. In: Multidisciplinary Approach to Obesity. Springer International Publishing (2015): 3-12.
7. Chen YCI., et al. “Measurement of human brown adipose tissue volume and activity using anatomic MR imaging and functional MR imaging”. The Journal of Nuclear Medicine 9 (2013): 1584-1587. https://pubmed.ncbi.nlm.nih.gov/23868958/
8. Cedikova M., et al. “Mitochondria in white, brown, and beige adipocytes”. Stem Cells International (2016): 6067349. https://pubmed.ncbi.nlm.nih.gov/27073398/
9. Parlee SD., et al. “Quantifying size and number of adipocytes in adipose tissue”. Methods in Enzymology 537 (2014): 93-122. https://pubmed.ncbi.nlm.nih.gov/24480343/
10. Alcalá M., et al. “Mechanisms of impaired brown adipose tissue recruitment in obesity”. Frontiers in Physiology 10 (2019): 94. https://pubmed.ncbi.nlm.nih.gov/30814954/
11. Luo L and Liu M. “Adipose tissue in control of metabolism”. Journal of Endocrinology 3 (2016): R77-R99. https://pubmed.ncbi.nlm.nih.gov/27935822/
12. Ojha S., et al. “Adipocytes in Normal Tissue Biology”. In: Pathobiology of Human Disease. Elsevier (2014): 2003-2013. https://www.researchgate.net/publication/300284439_Adipocytes_in_Normal_Tissue_Biology
13. Urisarri A., et al. “BMP8 and activated brown adipose tissue in human newborns”. Nature Communications 1 (2021): 5274. https://www.nature.com/articles/s41467-021-25456-z
14. Tam CS., et al. “Brown adipose tissue: mechanisms and potential therapeutic targets”. Circulation 22 (2012): 2782-2791. https://pubmed.ncbi.nlm.nih.gov/22665886/
15. Symonds ME. “Brown adipose tissue growth and development”. Scientifica (2013): 305763. https://pubmed.ncbi.nlm.nih.gov/24278771/
16. Zafrir B. “Brown adipose tissue: research milestones of a potential player in human energy balance and obesity”. Hormone and Metabolic Research 11 (2013): 774-785. https://pubmed.ncbi.nlm.nih.gov/23803970/
17. Chen HJ., et al. “The role of brown adipose tissue dysfunction in the development of cardiovascular disease”. Frontiers in Endocrinology 12 (2021): 652246. https://pubmed.ncbi.nlm.nih.gov/34113316/
18. Cypess AM., et al. “Identification and importance of brown adipose tissue in adult humans”. The New England Journal of Medicine 15 (2009): 1509-1517. https://pubmed.ncbi.nlm.nih.gov/19357406/
19. Carpentier AC., et al. “Brown adipose tissue energy metabolism in humans”. Frontiers in Endocrinology 9 (2018): 447. https://pubmed.ncbi.nlm.nih.gov/30131768/
20. Vijgen GHEJ., et al. “Increase in brown adipose tissue activity after weight loss in morbidly obese subjects”. The Journal of Clinical Endocrinology and Metabolism 7 (2012): E1229-1233. https://pubmed.ncbi.nlm.nih.gov/22535970/
21. Wu C., et al. “Activating brown adipose tissue for weight loss and lowering of blood glucose levels: a microPET study using obese and diabetic model mice”. PLoS One 12 (2014): e113742. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113742
22. Brown Fat Weight Loss Research: Brown Adipose Tissue (BAT) (2022).
23. Wolf G. “Brown adipose tissue: the molecular mechanism of its formation”. Nutrition Reviews 3 (2009): 167-171. https://www.sciencedirect.com/topics/medicine-and-dentistry/brown-adipose-tissue
24. Wang X., et al. “Gab2 deficiency suppresses high-fat diet-induced obesity by reducing adipose tissue inflammation and increasing brown adipose function in mice”. Cell Death and Disease 2 (2021): 212. https://www.nature.com/articles/s41419-021-03519-9
25. De-Lima-Júnior JC., et al. “Abnormal brown adipose tissue mitochondrial structure and function in IL10 deficiency”. Ebio Medicine 39 (2019): 436-447. https://pubmed.ncbi.nlm.nih.gov/30502051/
26. Abreu-Vieira G., et al. “Human brown adipose tissue estimated with magnetic resonance imaging undergoes changes in composition after cold exposure: An in vivo MRI study in healthy volunteers”. Frontiers in Endocrinology 10 (2019): 898. https://www.frontiersin.org/articles/10.3389/fendo.2019.00898/full
27. Schulz TJ and Tseng YH. “Brown adipose tissue: development, metabolism and beyond”. Biochemical Journal 2 (2013): 167-178. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887508/
28. Thuzar M and Ho KKY. “MECHANISMS IN ENDOCRINOLOGY: Brown adipose tissue in humans: regulation and metabolic significance”. European Journal of Endocrinology 1 (2016): R11-25. https://pubmed.ncbi.nlm.nih.gov/27220620/
29. Di Gregorio I., et al. “Environmental pollutants effect on brown adipose tissue”. Frontiers in Physiology 9 (2018): 1891. https://www.researchgate.net/publication/330249569_Environmental_Pollutants_Effect_on_Brown_Adipose_Tissue
30. La Merrill M., et al. “Perinatal exposure of mice to the pesticide DDT impairs energy expenditure and metabolism in adult female offspring”. PLoS One 7 (2014): e103337. https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0103337
31. Araujo JA., et al. “Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress”. Circulation Research 5 (2008): 589-596. https://pubmed.ncbi.nlm.nih.gov/18202315/
32. Xu X., et al. “Long-term exposure to ambient fine particulate pollution induces insulin resistance and mitochondrial alteration in adipose tissue”. Toxicological Sciences 1 (2011): 88-98. https://pubmed.ncbi.nlm.nih.gov/21873646/
33. Shabalina IG., et al. “The environmental pollutants perfluorooctane sulfonate and perfluorooctanoic acid upregulate uncoupling protein 1 (UCP1) in brown-fat mitochondria through a UCP1-dependent reduction in food intake”. Toxicological Sciences 2 (2015): 334-343. https://pubmed.ncbi.nlm.nih.gov/26001964/
34. Manna P and Jain SK. “Obesity, oxidative stress, adipose tissue dysfunction, and the associated health risks: Causes and therapeutic strategies”. Metabolic Syndrome and Related Disorders 10 (2015): 423-444. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808277/
35. Vgontzas AN., et al. “Sleep apnea and sleep disruption in obese patients”. Archives of Internal Medicine 15 (1994): 1705-1711. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/619157
36. Punjabi NM and Beamer BA. “C-reactive protein is associated with sleep-disordered breathing independent of adiposity”. Sleep 1 (2007): 29-34. https://pubmed.ncbi.nlm.nih.gov/17310862/
37. Lidell ME., et al. “Brown adipose tissue and its therapeutic potential”. Journal of Internal Medicine 4 (2014): 364-377. https://onlinelibrary.wiley.com/doi/pdf/10.1111/joim.12255
38. Ouellet V., et al. “Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans”. Journal of Clinical Investigation 2 (2012): 545-552. https://pubmed.ncbi.nlm.nih.gov/22269323/
39. Bartelt A., et al. “Brown adipose tissue activity controls triglyceride clearance”. Nature Medicine 2 (2011): 200-205. https://pubmed.ncbi.nlm.nih.gov/21258337/
40. Kajimura S., et al. “Brown and beige fat: Physiological roles beyond heat generation”. Cell Metabolism 4 (2015): 546-559. https://pubmed.ncbi.nlm.nih.gov/26445512/
41. Kajimura S and Saito M. “A new era in brown adipose tissue biology: molecular control of brown fat development and energyy homeostasis”. Annual Review of Physiology 1 (2014): 225-249. https://pubmed.ncbi.nlm.nih.gov/24188710/
42. Shan T., et al. “Lkb1 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3”. Nature Communications 1 (2016): 12205. https://www.nature.com/articles/ncomms12205
43. Montanari T., et al. “Factors involved in white-to-brown adipose tissue conversion and in thermogenesis: a review”. Obesity Reviews 5 (2017): 495-513. https://pubmed.ncbi.nlm.nih.gov/28187240/
44. Nedergaard J and Cannon B. “The browning of white adipose tissue: Some burning issues”. Cell Metabolism 3 (2014): 396-407. https://pubmed.ncbi.nlm.nih.gov/25127354/
45. Lu KY., et al. “Clinical application potential of small molecules that induce brown adipose tissue thermogenesis by improving fat metabolism”. Cell Transplantation 29 (2020): 963689720927394. https://pubmed.ncbi.nlm.nih.gov/32854518/
46. McNeill BT., et al. “MECHANISMS IN ENDOCRINOLOGY: Human brown adipose tissue as a therapeutic target: warming up or cooling down?” European Journal of Endocrinology6 (2021): R243-R259. https://pubmed.ncbi.nlm.nih.gov/33729178/
47. Brandão BB., et al. “Thermogenic fat: Development, physiological function, and therapeutic potential”. International Journal of Molecular Sciences 11 (2021): 5906. https://pubmed.ncbi.nlm.nih.gov/34072788/
48. Kim SH and Plutzky J. “Brown fat and browning for the treatment of obesity and related metabolic disorders”. Diabetes and Metabolism Journal 1 (2016): 12-21. https://pubmed.ncbi.nlm.nih.gov/26912151/
49. Marlatt KL and Ravussin E. “Brown adipose tissue: An update on recent findings”. Current Obesity Reports4 (2017): 389-396. https://pubmed.ncbi.nlm.nih.gov/29101739/
50. Chondronikola M., et al. “Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans”. Diabetes 12 (2014): 4089-4099. https://pubmed.ncbi.nlm.nih.gov/25056438/
51. Hanssen MJW., et al. “Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus”. Nature Medicine 8 (2015): 863-865. https://pubmed.ncbi.nlm.nih.gov/26147760/
52. Stanford KI., et al. “Brown adipose tissue regulates glucose homeostasis and insulin sensitivity”. Journal of Clinical Investigation 1 (2013): 215-223. https://pubmed.ncbi.nlm.nih.gov/23221344/
53. Cypess AM., et al. “Activation of human brown adipose tissue by a β3-adrenergic receptor agonist”. Cell Metabolism 1 (2015): 33-38. https://pubmed.ncbi.nlm.nih.gov/25565203/
54. Baskaran P., et al. “Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms: TRPV1 activates browning of WAT to counter obesity”. British Journal of Pharmacology 15 (2016): 2369-2389. https://pubmed.ncbi.nlm.nih.gov/27174467/
55. Saito M and Yoneshiro T. “Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans”. Current Opinion in Lipidology 1 (2013): 71-77. https://pubmed.ncbi.nlm.nih.gov/23298960/
56. Beiroa D., et al. “GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK”. Diabetes 10 (2014): 3346-3358. https://pubmed.ncbi.nlm.nih.gov/24917578/
57. Kim SN., et al. “Antiobesity effects of coumestrol through expansion and activation of brown adipose tissue metabolism”. Journal of Nutritional Biochemistry 108300 (2020): 108300. https://europepmc.org/article/med/31812908
58. Moon J., et al. “Brown adipose tissue ameliorates autoimmune arthritis via inhibition of Th17 cells”. Scientific Reports 1 (2020): 12374. https://www.nature.com/articles/s41598-020-68749-x
59. Grundy SM. “Adipose tissue and metabolic syndrome: too much, too little or neither”. European Journal of Clinical Investigation 11 (2015): 1209-1217. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049481/
60. Graja A and Schulz TJ. “Mechanisms of aging-related impairment of brown adipocyte development and function”. Gerontology 3 (2015): 211-217. https://www.karger.com/Article/Fulltext/366557
61. Raiko J., et al. “High brown fat activity correlates with cardiovascular risk factor levels cross-sectionally and subclinical atherosclerosis at 5-year follow-up”. Arteriosclerosis, Thrombosis, and Vascular Biology 5 (2020): 1289-1295. https://pubmed.ncbi.nlm.nih.gov/31941384/
62. Exploring brown fat: The long road ahead (2022).
63. Tamucci KA., et al. “The dark side of browning”. Protein Cell 2 (2018): 152-163. https://pubmed.ncbi.nlm.nih.gov/28677104/
64. Jung SM., et al. “Brown adipose tissue development and metabolism”. The Handbook of Experimental Pharmacology 251 (2019): 3-36. https://pubmed.ncbi.nlm.nih.gov/30203328/