REFERENCES

1. Curtin SC, Garnett MF, Ahmad FB. Provisional estimates of suicide by demographic characteristics: United States, 2022. Available from: https://stacks.cdc.gov/view/cdc/135466 [Last accessed on 24 Apr 2024].

2. Elizabeth A, Kochanek KD, Xu J, Tejada-Vera B. Provisional life expectancy estimates for 2022. Available from: https://stacks.cdc.gov/view/cdc/135467 [Last accessed on 24 Apr 2024].

3. Spencer MR, Miniño MA, Warner M. Drug overdose deaths in the United States, 2001-2021. Available from: https://stacks.cdc.gov/view/cdc/122556 [Last accessed on 24 Apr 2024].

4. Statista. Life expectancy (from birth) in the United States, from 1860 to 2020*. Available from: https://www.statista.com/statistics/1040079/life-expectancy-united-states-all-time/ [Last accessed on 24 Apr 2024].

5. Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell 2014;156:20-44.

6. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004;84:277-359.

7. Himms-Hagen J. Brown adipose tissue thermogenesis and obesity. Prog Lipid Res 1989;28:67-115.

8. Gohlke S, Zagoriy V, Cuadros Inostroza A, et al. Identification of functional lipid metabolism biomarkers of brown adipose tissue aging. Mol Metab 2019;24:1-17.

9. Ikeda K, Yamada T. UCP1 dependent and independent thermogenesis in brown and beige adipocytes. Front Endocrinol 2020;11:498.

10. Kazak L, Chouchani ET, Jedrychowski MP, et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 2015;163:643-55.

11. Kazak L, Chouchani ET, Lu GZ, et al. Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity. Cell Metab 2017;26:693.

12. Yamashita H, Ohira Y, Wakatsuki T, et al. Increased growth of brown adipose tissue but its reduced thermogenic activity in creatine-depleted rats fed beta-guanidinopropionic acid. Biochim Biophys Acta 1995;1230:69-73.

13. Pant M, Bal NC, Periasamy M. Sarcolipin: a key thermogenic and metabolic regulator in skeletal muscle. Trends Endocrinol Metab 2016;27:881-92.

14. Sahoo SK, Shaikh SA, Sopariwala DH, Bal NC, Periasamy M. Sarcolipin protein interaction with sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) is distinct from phospholamban protein, and only sarcolipin can promote uncoupling of the SERCA pump. J Biol Chem 2013;288:6881-9.

15. Smith WS, Broadbridge R, East JM, Lee AG. Sarcolipin uncouples hydrolysis of ATP from accumulation of Ca2+ by the Ca2+-ATPase of skeletal-muscle sarcoplasmic reticulum. Biochem J 2002;361:277-86.

16. de Meis L. Brown adipose tissue Ca2+-ATPase: uncoupled ATP hydrolysis and thermogenic activity. J Biol Chem 2003;278:41856-61.

17. Ikeda K, Kang Q, Yoneshiro T, et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med 2017;23:1454-65.

18. Manteiga S, Choi K, Jayaraman A, Lee K. Systems biology of adipose tissue metabolism: regulation of growth, signaling and inflammation. Wiley Interdiscip Rev Syst Biol Med 2013;5:425-47.

19. Li X, Frazier JA, Spahiu E, McPherson M, Miller RA. Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice. Aging 2020;12:8766-89.

20. Lizcano F. The beige adipocyte as a therapy for metabolic diseases. Int J Mol Sci 2019;20:5058.

21. Zoico E, Rubele S, De Caro A, et al. Brown and beige adipose tissue and aging. Front Endocrinol 2019;10:368.

22. Ou MY, Zhang H, Tan PC, Zhou SB, Li QF. Adipose tissue aging: mechanisms and therapeutic implications. Cell Death Dis 2022;13:300.

23. Vatner DE, Zhang J, Oydanich M, et al. Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14. Aging Cell 2018;17:e12751.

24. Cinti S. Anatomy and physiology of the nutritional system. Mol Aspects Med 2019;68:101-7.

25. Cypess AM, Lehman S, Williams G, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509-17.

26. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500-8.

27. Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518-25.

28. Cinti S. The adipose organ at a glance. Dis Model Mech 2012;5:588-94.

29. Barbatelli G, Murano I, Madsen L, et al. 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 2010;298:E1244-53.

30. Machado SA, Pasquarelli-do-Nascimento G, da Silva DS, et al. Browning of the white adipose tissue regulation: new insights into nutritional and metabolic relevance in health and diseases. Nutr Metab 2022;19:61.

31. Stanford KI, Middelbeek RJ, Townsend KL, et al. A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis. Diabetes 2015;64:2002-14.

32. Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M. Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J Biol Chem 2001;276:1486-93.

33. Villarroya F, Peyrou M, Giralt M. Transcriptional regulation of the uncoupling protein-1 gene. Biochimie 2017;134:86-92.

34. Bargut TCL, Souza-Mello V, Aguila MB, Mandarim-de-Lacerda CA. Browning of white adipose tissue: lessons from experimental models. Horm Mol Biol Clin Investig 2017;31.

35. Grujic D, Susulic VS, Harper ME, et al. Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem 1997;272:17686-93.

36. Lim S, Park J, Um JY. Ginsenoside Rb1 induces beta 3 adrenergic receptor-dependent lipolysis and thermogenesis in 3T3-L1 adipocytes and db/db mice. Front Pharmacol 2019;10:1154.

37. Evans BA, Merlin J, Bengtsson T, Hutchinson DS. Adrenoceptors in white, brown, and brite adipocytes. Br J Pharmacol 2019;176:2416-32.

38. Chernogubova E, Hutchinson DS, Nedergaard J, Bengtsson T. Alpha1- and beta1-adrenoceptor signaling fully compensates for beta3-adrenoceptor deficiency in brown adipocyte norepinephrine-stimulated glucose uptake. Endocrinology 2005;146:2271-84.

39. Bengtsson T, Cannon B, Nedergaard J. Differential adrenergic regulation of the gene expression of the β-adrenoceptor subtypes β1, β2 and β3 in brown adipocytes. Biochem J 2000;347:643-51.

40. Straat ME, Hoekx CA, van Velden FHP, et al. Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue. Cell Rep Med 2023;4:100942.

41. Li Y, Wang D, Ping X, et al. Local hyperthermia therapy induces browning of white fat and treats obesity. Cell 2022;185:949-66.e19.

42. Patsouris D, Qi P, Abdullahi A, et al. Burn induces browning of the subcutaneous white adipose tissue in mice and humans. Cell Rep 2015;13:1538-44.

43. Vinaik R, Barayan D, Abdullahi A, Jeschke MG. NLRP3 inflammasome mediates white adipose tissue browning after burn. Am J Physiol Endocrinol Metab 2019;317:E751-9.

44. Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481:463-8.

45. Roberts LD, Boström P, O’Sullivan JF, et al. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 2014;19:96-108.

46. Fabbiano S, Suárez-Zamorano N, Rigo D, et al. Caloric restriction leads to browning of white adipose tissue through type 2 immune signaling. Cell Metab 2016;24:434-46.

47. Li G, Xie C, Lu S, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab 2017;26:672-85.e4.

48. Liu B, Page AJ, Hutchison AT, Wittert GA, Heilbronn LK. Intermittent fasting increases energy expenditure and promotes adipose tissue browning in mice. Nutrition 2019;66:38-43.

49. Suárez-Zamorano N, Fabbiano S, Chevalier C, et al. Microbiota depletion promotes browning of white adipose tissue and reduces obesity. Nat Med 2015;21:1497-501.

50. Cohen P, Levy JD, Zhang Y, et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 2014;156:304-16.

51. Min SY, Kady J, Nam M, et al. Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med 2016;22:312-8.

52. Stanford KI, Middelbeek RJ, Townsend KL, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 2013;123:215-23.

53. Ahmadian M, Abbott MJ, Tang T, et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab 2011;13:739-48.

54. Gutierrez AD, Gao Z, Hamidi V, et al. Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes. Cell Rep Med 2022;3:100813.

55. Villarroya F, Cereijo R, Villarroya J, Giralt M. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol 2017;13:26-35.

56. Yang FT, Stanford KI. Batokines: mediators of inter-tissue communication (a mini-review). Curr Obes Rep 2022;11:1-9.

57. Hondares E, Iglesias R, Giralt A, et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011;286:12983-90.

58. Emanuelli B, Vienberg SG, Smyth G, et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest 2014;124:515-27.

59. He JL, Zhao M, Xia JJ, et al. FGF21 ameliorates the neurocontrol of blood pressure in the high fructose-drinking rats. Sci Rep 2016;6:29582.

60. Ruan CC, Kong LR, Chen XH, et al. A(2A) receptor activation attenuates hypertensive cardiac remodeling via promoting brown adipose tissue-derived FGF21. Cell Metab 2020;32:689.

61. Qing H, Desrouleaux R, Israni-Winger K, et al. Origin and function of stress-induced IL-6 in murine models. Cell 2020;182:372-87.e14.

62. Liu Y, Chen M. Neuregulin 4 as a novel adipokine in energy metabolism. Front Physiol 2022;13:1106380.

63. Gunawardana SC, Piston DW. Reversal of type 1 diabetes in mice by brown adipose tissue transplant. Diabetes 2012;61:674-82.

64. Villarroya J, Cereijo R, Villarroya F. An endocrine role for brown adipose tissue? Am J Physiol Endocrinol Metab 2013;305:E567-72.

65. Cereijo R, Gavaldà-Navarro A, Cairó M, et al. CXCL14, a brown adipokine that mediates brown-fat-to-macrophage communication in thermogenic adaptation. Cell Metab 2018;28:750-63.e6.

66. Pinckard KM, Shettigar VK, Wright KR, et al. A novel endocrine role for the BAT-released lipokine 12,13-diHOME to mediate cardiac function. Circulation 2021;143:145-59.

67. Lynes MD, Leiria LO, Lundh M, et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 2017;23:631-7.

68. Stanford KI, Lynes MD, Takahashi H, et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab 2018;27:1111-20.e3.

69. Kong X, Yao T, Zhou P, et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab 2018;28:631-43.e3.

70. Campderrós L, Moure R, Cairó M, et al. Brown adipocytes secrete GDF15 in response to thermogenic activation. Obesity 2019;27:1606-16.

71. Thomou T, Mori MA, Dreyfuss JM, et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 2017;542:450-5.

72. Vatner DE, Oydanich M, Zhang J, Campbell SC, Vatner SF. Exercise enhancement by RGS14 disruption is mediated by brown adipose tissue. Aging Cell 2023;22:e13791.

73. Aherne W, Hull D. Brown adipose tissue and heat production in the newborn infant. J Pathol Bacteriol 1966;91:223-34.

74. Yoneshiro T, Aita S, Matsushita M, et al. Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity 2011;19:13-6.

75. Leitner BP, Huang S, Brychta RJ, et al. Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci USA 2017;114:8649-54.

76. Saito M, Okamatsu-Ogura Y, Matsushita M, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009;58:1526-31.

77. 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 2014;38:812-7.

78. Graja A, Schulz TJ. Mechanisms of aging-related impairment of brown adipocyte development and function. Gerontology 2015;61:211-7.

79. Berry DC, Jiang Y, Arpke RW, et al. Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab 2017;25:166-81.

80. Lee P, Swarbrick MM, Ho KK. Brown adipose tissue in adult humans: a metabolic renaissance. Endocr Rev 2013;34:413-38.

81. Félix-Soriano E, Sáinz N, Gil-Iturbe E, et al. Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice. FASEB J 2021;35:e21592.

82. Gonçalves LF, Machado TQ, Castro-Pinheiro C, de Souza NG, Oliveira KJ, Fernandes-Santos C. Ageing is associated with brown adipose tissue remodelling and loss of white fat browning in female C57BL/6 mice. Int J Exp Pathol 2017;98:100-8.

83. Sellayah D, Sikder D. Orexin restores aging-related brown adipose tissue dysfunction in male mice. Endocrinology 2014;155:485-501.

84. Darcy J, McFadden S, Fang Y, et al. Brown adipose tissue function is enhanced in long-lived, male ames dwarf mice. Endocrinology 2016;157:4744-53.

85. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature 1996;384:33.

86. Li Y, Knapp JR, Kopchick JJ. Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice. Exp Biol Med 2003;228:207-15.

87. Ortega-Molina A, Efeyan A, Lopez-Guadamillas E, et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell Metab 2012;15:382-94.

88. Ma X, Xu L, Gavrilova O, Mueller E. Role of forkhead box protein A3 in age-associated metabolic decline. Proc Natl Acad Sci USA 2014;111:14289-94.

89. Saito M, Okamatsu-Ogura Y. Thermogenic brown fat in humans: implications in energy homeostasis, obesity and metabolic disorders. World J Mens Health 2023;41:489-507.

90. Yuko OO, Saito M. Brown fat as a regulator of systemic metabolism beyond thermogenesis. Diabetes Metab J 2021;45:840-52.

91. Becher T, Palanisamy S, Kramer DJ, et al. Brown adipose tissue is associated with cardiometabolic health. Nat Med 2021;27:58-65.

92. Pereira RO, McFarlane SI. The role of brown adipose tissue in cardiovascular disease protection: current evidence and future directions. Int J Clin Res Trials 2019;4:136.

93. Chen HJ, Meng T, Gao PJ, Ruan CC. The role of brown adipose tissue dysfunction in the development of cardiovascular disease. Front Endocrinol 2021;12:652246.

94. Tsoli M, Moore M, Burg D, et al. Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. Cancer Res 2012;72:4372-82.

95. Cao Q, Hersl J, La H, et al. A pilot study of FDG PET/CT detects a link between brown adipose tissue and breast cancer. BMC Cancer 2014;14:126.

96. Huang YC, Chen TB, Hsu CC, et al. The relationship between brown adipose tissue activity and neoplastic status: an 18F-FDG PET/CT study in the tropics. Lipids Health Dis 2011;10:238.

97. Rousseau C, Bourbouloux E, Campion L, et al. Brown fat in breast cancer patients: analysis of serial 18F-FDG PET/CT scans. Eur J Nucl Med Mol Imaging 2006;33:785-91.

98. Singh R, Parveen M, Basgen JM, et al. Increased expression of beige/brown adipose markers from host and breast cancer cells influence xenograft formation in mice. Mol Cancer Res 2016;14:78-92.

99. Tayanloo-Beik A, Nikkhah A, Alaei S, et al. Brown adipose tissue and Alzheimer’S disease. Metab Brain Dis 2023;38:91-107.

100. O’Shaughnessy CT, Rothwell NJ, Shrewsbury-Gee J. Sympathetically mediated hypermetabolic response to cerebral ischemia in the rat. Can J Physiol Pharmacol 1990;68:1334-7.

101. Chao CM, Chen CL, Niu KC, et al. Hypobaric hypoxia preconditioning protects against hypothalamic neuron apoptosis in heat-exposed rats by reversing hypothalamic overexpression of matrix metalloproteinase-9 and ischemia. Int J Med Sci 2020;17:2622-34.

102. Gong B, Tang J, Jiang X, et al. In situ fluorescence-photoacoustic measurement of the changes of brown adipose tissue in mice under hindlimb unloading. J Appl Physiol 2023;135:251-9.

103. Tsuji T, Bussberg V, MacDonald AM, Narain NR, Kiebish MA, Tseng YH. Transplantation of brown adipose tissue with the ability of converting omega-6 to omega-3 polyunsaturated fatty acids counteracts high-fat-induced metabolic abnormalities in mice. Int J Mol Sci 2022;23:5321.

104. Dominici FP, Hauck S, Argentino DP, Bartke A, Turyn D. Increased insulin sensitivity and upregulation of insulin receptor, insulin receptor substrate (IRS)-1 and IRS-2 in liver of Ames dwarf mice. J Endocrinol 2002;173:81-94.

105. Bokov AF, Lindsey ML, Khodr C, Sabia MR, Richardson A. Long-lived ames dwarf mice are resistant to chemical stressors. J Gerontol A Biol Sci Med Sci 2009;64:819-27.

106. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A. Delayed occurrence of fatal neoplastic diseases in ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci 2003;58:291-6.

107. Schrag M, Sharma S, Brown-Borg H, Ghribi O. Hippocampus of ames dwarf mice is resistant to beta-amyloid-induced tau hyperphosphorylation and changes in apoptosis-regulatory protein levels. Hippocampus 2008;18:239-44.

108. Puig KL, Kulas JA, Franklin W, et al. The ames dwarf mutation attenuates Alzheimer’s disease phenotype of APP/PS1 mice. Neurobiol Aging 2016;40:22-40.

109. Arum O, Rickman DJ, Kopchick JJ, Bartke A. The slow-aging growth hormone receptor/binding protein gene-disrupted (GHR-KO) mouse is protected from aging-resultant neuromusculoskeletal frailty. Age 2014;36:117-27.

110. Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 2000;141:2608-13.

111. Ikeno Y, Hubbard GB, Lee S, et al. Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 2009;64:522-9.

112. Lu S, Strand KA, Mutryn MF, et al. PTEN (Phosphatase and Tensin Homolog) Protects Against Ang II (Angiotensin II)-induced pathological vascular fibrosis and remodeling-brief report. Arterioscler Thromb Vasc Biol 2020;40:394-403.

113. Garcia-Cao I, Song MS, Hobbs RM, et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 2012;149:49-62.

114. Knafo S, Sánchez-Puelles C, Palomer E, et al. PTEN recruitment controls synaptic and cognitive function in Alzheimer’s models. Nat Neurosci 2016;19:443-53.

115. Crackower MA, Oudit GY, Kozieradzki I, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 2002;110:737-49.

116. Liang T, Gao F, Jiang J, et al. Loss of phosphatase and tensin homolog promotes cardiomyocyte proliferation and cardiac repair after myocardial infarction. Circulation 2020;142:2196-9.

117. Oydanich M, Zhang J, Vatner DE, Vatner SF. Two mechanisms mediating enhanced glucose tolerance with regulator of GS protein 14 disruption; increased exercise capacity and increased brown adipose tissue. Diabetes 2018;67:757-P.

118. Zhang J, Vatner DE, Vatner SF. Abstract 18750: increased brown adipose tissue as a novel mechanism mediating cardioprotection. Circulation 2016;134:A18750. Available from: https://www.ahajournals.org/doi/10.1161/circ.134.suppl_1.18750 [Last accessed on 24 Apr 2024].

119. Zhang J, Guers JJ, Oydanich M, Vatner DE, Vatner SF. Abstract P427: inhibition of the regulator of G protein signaling 14, a novel anti-hypertensive mechanism. Hypertension 2017;70:AP427.

120. Chen B, Yu J, Lu L, et al. Upregulated forkhead-box A3 elevates the expression of forkhead-box A1 and forkhead-box A2 to promote metastasis in esophageal cancer. Oncol Lett 2019;17:4351-60.

121. Darcy J, Tseng YH. ComBATing aging-does increased brown adipose tissue activity confer longevity? Geroscience 2019;41:285-96.

122. Peres Valgas da Silva C, Shettigar VK, Baer LA, et al. Brown adipose tissue prevents glucose intolerance and cardiac remodeling in high-fat-fed mice after a mild myocardial infarction. Int J Obes 2022;46:350-8.

123. Gomez-Hernandez A, Lopez-Pastor AR, Rubio-Longas C, et al. Specific knockout of p85alpha in brown adipose tissue induces resistance to high-fat diet-induced obesity and its metabolic complications in male mice. Mol Metab 2020;31:1-13.

124. Chen Z, Wang GX, Ma SL, et al. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol Metab 2017;6:863-72.

125. Shi L, Li Y, Xu X, et al. Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice. Nat Metab 2022;4:1573-90.

126. Wang GX, Zhao XY, Meng ZX, et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med 2014;20:1436-43.

127. Wang H, Wang L, Hu F, et al. Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway. Cardiovasc Diabetol 2022;21:205.

128. Zhang P, Chen Z, Kuang H, et al. Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment. Cell Metab 2022;34:1359-76.e7.

129. Mattson MP. Perspective: does brown fat protect against diseases of aging? Ageing Res Rev 2010;9:69-76.

130. Afshin A, Forouzanfar MH, Reitsma MB, et al. GBD 2015 Obesity Collaborators. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med 2017;377:13-27.

131. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444-52.

132. 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;9:203-9.

133. Smith RE, Roberts JC. Thermogenesis of brown adipose tissue in cold-acclimated rats. Am J Physiol 1964;206:143-8.

134. Seale P, Kajimura S, Yang W, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007;6:38-54.

135. Liu X, Wang S, You Y, et al. Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology 2015;156:2461-9.

136. White JD, Dewal RS, Stanford KI. The beneficial effects of brown adipose tissue transplantation. Mol Aspects Med 2019;68:74-81.

137. Liu X, Zheng Z, Zhu X, et al. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res 2013;23:851-4.

138. Zhu Z, Spicer EG, Gavini CK, Goudjo-Ako AJ, Novak CM, Shi H. Enhanced sympathetic activity in mice with brown adipose tissue transplantation (transBATation). Physiol Behav 2014;125:21-9.

139. Gunawardana SC, Piston DW. Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown adipose tissue transplant. Am J Physiol Endocrinol Metab 2015;308:E1043-55.

140. Darcy J, McFadden S, Fang Y, et al. Increased environmental temperature normalizes energy metabolism outputs between normal and ames dwarf mice. Aging 2018;10:2709-22.

141. Shankar K, Kumar D, Gupta S, et al. Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice. Eur J Pharmacol 2019;854:354-64.

142. Yamada Y, Wang XD, Yokoyama S, Fukuda N, Takakura N. Cardiac progenitor cells in brown adipose tissue repaired damaged myocardium. Biochem Biophys Res Commun 2006;342:662-70.

143. Wang H, Shi J, Wang Y, et al. Promotion of cardiac differentiation of brown adipose derived stem cells by chitosan hydrogel for repair after myocardial infarction. Biomaterials 2014;35:3986-98.

144. Martí-Pàmies Í, Thoonen R, Morley M, et al. Brown adipose tissue and BMP3b decrease injury in cardiac ischemia-reperfusion. Circ Res 2023;133:353-65.

145. Takx RA, Ishai A, Truong QA, MacNabb MH, Scherrer-Crosbie M, Tawakol A. Supraclavicular brown adipose tissue 18F-FDG uptake and cardiovascular disease. J Nucl Med 2016;57:1221-5.

146. Valero-Muñoz M, Li S, Wilson RM, et al. Heart failure with preserved ejection fraction induces beiging in adipose tissue. Circ Heart Fail 2016;9:e002724.

147. Tahara A, Tahara N, Maeda-Ogata S, et al. Brown adipose tissue activation in severe heart failure. Eur Heart J 2020;41:2415.

148. Yoshida Y, Shimizu I, Shimada A, et al. Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism. Sci Rep 2022;12:14883.

149. Thoonen R, Ernande L, Cheng J, et al. Functional brown adipose tissue limits cardiomyocyte injury and adverse remodeling in catecholamine-induced cardiomyopathy. J Mol Cell Cardiol 2015;84:202-11.

150. Lowell BB, S-Susulic V, Hamann A, et al. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993;366:740-2.

151. Cittadini A, Mantzoros CS, Hampton TG, et al. Cardiovascular abnormalities in transgenic mice with reduced brown fat: an animal model of human obesity. Circulation 1999;100:2177-83.

152. Than A, Xu S, Li R, Leow MK, Sun L, Chen P. Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis. Signal Transduct Target Ther 2017;2:17022.

153. Ledent C, Vaugeois JM, Schiffmann SN, et al. Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 1997;388:674-8.

154. Huang Cao ZF, Stoffel E, Cohen P. Role of perivascular adipose tissue in vascular physiology and pathology. Hypertension 2017;69:770-7.

155. Kim HW, Belin de Chantemèle EJ, Weintraub NL. Perivascular adipocytes in vascular disease. Arterioscler Thromb Vasc Biol 2019;39:2220-7.

156. Lu C, Su LY, Lee RM, Gao YJ. Alterations in perivascular adipose tissue structure and function in hypertension. Eur J Pharmacol 2011;656:68-73.

157. Kong LR, Zhou YP, Chen DR, Ruan CC, Gao PJ. Decrease of perivascular adipose tissue browning is associated with vascular dysfunction in spontaneous hypertensive rats during aging. Front Physiol 2018;9:400.

158. Persson P, Marchetti M, Friederich-Persson M. Browning of perivascular adipose tissue prevents vascular dysfunction and reduces hypertension in angiotensin II-infused mice. Am J Physiol Regul Integr Comp Physiol 2023;325:R290-8.

159. Das E, Moon JH, Lee JH, Thakkar N, Pausova Z, Sung HK. Adipose tissue and modulation of hypertension. Curr Hypertens Rep 2018;20:96.

160. Yang SJ, Hong HC, Choi HY, et al. Effects of a three-month combined exercise programme on fibroblast growth factor 21 and fetuin-A levels and arterial stiffness in obese women. Clin Endocrinol 2011;75:464-9.

161. Semba RD, Crasto C, Strait J, Sun K, Schaumberg DA, Ferrucci L. Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults. J Hum Hypertens 2013;27:397-9.

162. Walsh MF, Barazi M, Pete G, Muniyappa R, Dunbar JC, Sowers JR. Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide. Endocrinology 1996;137:1798-803.

163. Marczin N, Papapetropoulos A, Catravas JD. Tyrosine kinase inhibitors suppress endotoxin- and IL-1 beta-induced NO synthesis in aortic smooth muscle cells. Am J Physiol 1993;265:H1014-8.

164. Friederich-Persson M, Nguyen Dinh Cat A, Persson P, Montezano AC, Touyz RM. Brown adipose tissue regulates small artery function through NADPH oxidase 4-derived hydrogen peroxide and redox-sensitive protein kinase G-1α. Arterioscler Thromb Vasc Biol 2017;37:455-65.

165. Xue Y, Petrovic N, Cao R, et al. Hypoxia-independent angiogenesis in adipose tissues during cold acclimation. Cell Metab 2009;9:99-109.

166. Xue Y, Xu X, Zhang XQ, Farokhzad OC, Langer R. Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles. Proc Natl Acad Sci USA 2016;113:5552-7.

167. Sun K, Kusminski CM, Luby-Phelps K, et al. Brown adipose tissue derived VEGF-a modulates cold tolerance and energy expenditure. Mol Metab 2014;3:474-83.

168. Bagchi M, Kim LA, Boucher J, Walshe TE, Kahn CR, D’Amore PA. Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. FASEB J 2013;27:3257-71.

169. Zhang Q, Liang Z, Zhang Y, et al. Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma. FASEB J 2023;37:e23315.

170. Chen L, Wang L, Li Y, et al. Transplantation of Normal adipose tissue improves blood flow and reduces inflammation in high fat fed mice with hindlimb ischemia. Front Physiol 2018;9:197.

171. Seki T, Hosaka K, Fischer C, et al. Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning. J Exp Med 2018;215:611-26.

172. Tupone D, Madden CJ, Morrison SF. Autonomic regulation of brown adipose tissue thermogenesis in health and disease: potential clinical applications for altering BAT thermogenesis. Front Neurosci 2014;8:14.

173. Kopelman PG. Obesity as a medical problem. Nature 2000;404:635-43.

174. Han JC, Lawlor DA, Kimm SY. Childhood obesity. Lancet 2010;375:1737-48.

175. Martin AR, Chung S, Koehler K. Is exercise a match for cold exposure? Common molecular framework for adipose tissue browning. Int J Sports Med 2020;41:427-42.

176. Roubenoff R. Sarcopenia and its implications for the elderly. Eur J Clin Nutr 2000;54 Suppl 3:S40-7.

177. Gonzalez-Freire M, de Cabo R, Bernier M, et al. Reconsidering the role of mitochondria in aging. J Gerontol A Biol Sci Med Sci 2015;70:1334-42.

178. Joseph AM, Adhihetty PJ, Buford TW, et al. The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals. Aging Cell 2012;11:801-9.

179. Short KR, Bigelow ML, Kahl J, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA 2005;102:5618-23.

180. Coen PM, Jubrias SA, Distefano G, et al. Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J Gerontol A Biol Sci Med Sci 2013;68:447-55.

181. Conley KE, Jubrias SA, Cress ME, Esselman P. Exercise efficiency is reduced by mitochondrial uncoupling in the elderly. Exp Physiol 2013;98:768-77.

182. Garatachea N, Pareja-Galeano H, Sanchis-Gomar F, et al. Exercise attenuates the major hallmarks of aging. Rejuvenation Res 2015;18:57-89.

183. Liu CJ, Latham NK. Progressive resistance strength training for improving physical function in older adults. Cochrane Database Syst Rev 2009;2009:CD002759.

184. Serra-Rexach JA, Bustamante-Ara N, Hierro Villarán M, et al. Short-term, light- to moderate-intensity exercise training improves leg muscle strength in the oldest old: a randomized controlled trial. J Am Geriatr Soc 2011;59:594-602.

185. Sullivan DH, Roberson PK, Smith ES, Price JA, Bopp MM. Effects of muscle strength training and megestrol acetate on strength, muscle mass, and function in frail older people. J Am Geriatr Soc 2007;55:20-8.

186. Ellis T, Motl RW. Physical activity behavior change in persons with neurologic disorders: overview and examples from Parkinson disease and multiple sclerosis. J Neurol Phys Ther 2013;37:85-90.

187. Meeusen R. Exercise, nutrition and the brain. Sports Med 2014;44 Suppl 1:S47-56.

188. Kajimura S, Spiegelman BM, Seale P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab 2015;22:546-59.

189. Oh-ishi S, Kizaki T, Toshinai K, et al. Swimming training improves brown-adipose-tissue activity in young and old mice. Mech Ageing Dev 1996;89:67-78.

190. Yoshioka K, Yoshida T, Wakabayashi Y, Nishioka H, Kondo M. Effects of exercise training on brown adipose tissue thermogenesis in ovariectomized obese rats. Endocrinol Jpn 1989;36:403-8.

191. Slusher AL, Whitehurst M, Zoeller RF, Mock JT, Maharaj M, Huang CJ. Attenuated fibroblast growth factor 21 response to acute aerobic exercise in obese individuals. Nutr Metab Cardiovasc Dis 2015;25:839-45.

192. Wu MV, Bikopoulos G, Hung S, Ceddia RB. Thermogenic capacity is antagonistically regulated in classical brown and white subcutaneous fat depots by high fat diet and endurance training in rats: impact on whole-body energy expenditure. J Biol Chem 2014;289:34129-40.

193. De Matteis R, Lucertini F, Guescini M, et al. Exercise as a new physiological stimulus for brown adipose tissue activity. Nutr Metab Cardiovasc Dis 2013;23:582-90.

194. Tanaka R, Fuse S, Kuroiwa M, et al. Vigorous-intensity physical activities are associated with high brown adipose tissue density in humans. Int J Environ Res Public Health 2020;17:2796.

195. Motiani P, Virtanen KA, Motiani KK, et al. Decreased insulin-stimulated brown adipose tissue glucose uptake after short-term exercise training in healthy middle-aged men. Diabetes Obes Metab 2017;19:1379-88.

196. Singhal V, Maffazioli GD, Ackerman KE, et al. Effect of chronic athletic activity on brown fat in young women. PLoS One 2016;11:e0156353.

197. Vosselman MJ, Hoeks J, Brans B, et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int J Obes 2015;39:1696-702.

198. Sebaa R, Johnson J, Pileggi C, et al. SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1. Mol Metab 2019;25:35-49.

199. Cheng A, Yang Y, Zhou Y, et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab 2016;23:128-42.

200. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab 2010;12:662-7.

201. Cho SY, Chung YS, Yoon HK, Roh HT. Impact of exercise intensity on systemic oxidative stress, inflammatory responses, and sirtuin levels in healthy male volunteers. Int J Environ Res Public Health 2022;19:11292.

202. Zhou L, Pinho R, Gu Y, Radak Z. The role of SIRT3 in exercise and aging. Cells 2022;11:2596.

203. Gao P, Jiang Y, Wu H, et al. Inhibition of mitochondrial calcium overload by SIRT3 prevents obesity- or age-related whitening of brown adipose tissue. Diabetes 2020;69:165-80.

204. Vellano CP, Brown NE, Blumer JB, Hepler JR. Assembly and function of the regulator of G protein signaling 14 (RGS14)·H-Ras signaling complex in live cells are regulated by Gαi1 and Gαi-linked G protein-coupled receptors. J Biol Chem 2013;288:3620-31.

205. Deng Y, Larrivée B, Zhuang ZW, et al. Endothelial RAF1/ERK activation regulates arterial morphogenesis. Blood 2013;121:3988-96.

206. Chim SM, Kuek V, Chow ST, et al. EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades. J Cell Physiol 2015;230:82-94.

207. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.

208. Petruzzelli M, Schweiger M, Schreiber R, et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 2014;20:433-47.

209. Alnabulsi A, Cash B, Hu Y, Silina L, Alnabulsi A, Murray GI. The expression of brown fat-associated proteins in colorectal cancer and the relationship of uncoupling protein 1 with prognosis. Int J Cancer 2019;145:1138-47.

210. Seki T, Yang Y, Sun X, et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature 2022;608:421-8.

211. Liu D, Li Y, Shang Y, Wang W, Chen SZ. Effect of brown adipose tissue/cells on the growth of mouse hepatocellular carcinoma in vitro and in vivo. Oncol Lett 2019;17:3203-10.

212. Lee P, Greenfield JR, Ho KK, Fulham MJ. A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2010;299:E601-6.

213. Lim S, Hosaka K, Nakamura M, Cao Y. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis. Oncotarget 2016;7:38282-91.

214. Shellock FG, Riedinger MS, Fishbein MC. Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. J Cancer Res Clin Oncol 1986;111:82-5.

215. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH. Cancer-associated cachexia. Nat Rev Dis Primers 2018;4:17105.

216. Dolly A, Dumas JF, Servais S. Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know? J Cachexia Sarcopenia Muscle 2020;11:1413-28.

217. Kir S, Spiegelman BM. Cachexia & brown fat: a burning issue in cancer. Trends Cancer 2016;2:461-3.

218. Dong M, Lin J, Lim W, Jin W, Lee HJ. Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia. Front Med 2018;12:130-8.

219. Becker AS, Zellweger C, Bacanovic S, et al. Brown fat does not cause cachexia in cancer patients: a large retrospective longitudinal FDG-PET/CT cohort study. PLoS One 2020;15:e0239990.

220. Eljalby M, Huang X, Becher T, et al. Brown adipose tissue is not associated with cachexia or increased mortality in a retrospective study of patients with cancer. Am J Physiol Endocrinol Metab 2023;324:E144-53.

221. Coleman RA, Liang C, Patel R, Ali S, Mukherjee J. Brain and brown adipose tissue metabolism in transgenic Tg2576 mice models of alzheimer disease assessed using 18F-FDG PET imaging. Mol Imaging 2017;16:1536012117704557.

222. Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 2010;19:R12-20.

223. Iqbal K, Grundke-Iqbal I. Neurofibrillary pathology leads to synaptic loss and not the other way around in Alzheimer disease. J Alzheimers Dis 2002;4:235-8.

224. Mandelkow EM, Mandelkow E. Tau in Alzheimer’s disease. Trends Cell Biol 1998;8:425-7.

225. Almeida MC, Carrettiero DC. Chapter 44 - hypothermia as a risk factor for Alzheimer disease. Handb Clin Neurol 2018;157:727-35.

226. Pražienková V, Schirmer C, Holubová M, et al. Lipidized prolactin-releasing peptide agonist attenuates hypothermia-induced tau hyperphosphorylation in neurons. J Alzheimers Dis 2019;67:1187-200.

227. Sa-Nguanmoo P, Tanajak P, Kerdphoo S, et al. FGF21 improves cognition by restored synaptic plasticity, dendritic spine density, brain mitochondrial function and cell apoptosis in obese-insulin resistant male rats. Horm Behav 2016;85:86-95.

228. Choi HM, Doss HM, Kim KS. Multifaceted physiological roles of adiponectin in inflammation and diseases. Int J Mol Sci 2020;21:1219.

229. Forny-Germano L, De Felice FG, Vieira MNDN. The role of leptin and adiponectin in obesity-associated cognitive decline and Alzheimer’s disease. Front Neurosci 2018;12:1027.

230. Kshirsagar V, Thingore C, Juvekar A. Insulin resistance: a connecting link between Alzheimer’s disease and metabolic disorder. Metab Brain Dis 2021;36:67-83.

231. Sędzikowska A, Szablewski L. Insulin and insulin resistance in Alzheimer’s disease. Int J Mol Sci 2021;22:9987.

The Journal of Cardiovascular Aging

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/

Portico

All published articles are preserved here permanently:

https://www.portico.org/publishers/oae/