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Thermogenesis and cellular senescence of diabetic adipocytes in response to β-agonists and 18-carbon fatty acids

  • Seonjeong Park (Department of Food and Nutrition, Seoul Women's University) ;
  • Seung A Ock (Department of Food and Nutrition, Seoul Women's University) ;
  • Yun Jeong Park (Department of Food and Nutrition, Seoul Women's University) ;
  • Sung Nim Han (Department of Food and Nutrition, Seoul National University) ;
  • Sunhye Shin (Department of Food and Nutrition, Seoul Women's University)
  • 투고 : 2024.06.07
  • 심사 : 2024.08.06
  • 발행 : 2024.08.31

초록

Purpose: Adipocyte dysfunction has been reported in diabetes, and stimulating thermogenesis and suppressing senescence in adipocytes potentially alleviates metabolic dysregulation. This study aimed to investigate thermogenesis and cellular senescence in diabetic adipocytes under basal conditions and in response to stimuli. Methods: White and brown primary adipocytes derived from control (CON) and db/db (DB) mice were treated with β-agonists, such as norepinephrine (NE) and CL316,243, and 18-carbon fatty acids, including stearic acid, oleic acid (OLA), linoleic acid (LNA), and α-linolenic acid, and the expression of the genes related to thermogenesis and cellular senescence was measured. Results: Although no difference in the thermogenic and cellular senescence gene expression in white adipose tissue (WAT) was noted between the CON and DB mice, brown adipose tissue (BAT) from the DB mice exhibited lower uncoupling protein 1 (Ucp1) expression and higher cyclin-dependent kinase inhibitor (Cdkn)1a and Cdkn2a expression levels compared to that from the CON mice. Stromal vascular cells isolated from the BAT of the DB mice displayed higher peroxisome proliferator-activated receptor gamma (Pparg), CCAAT/enhancer-binding protein alpha (Cebpa), Cdkn1a, and Cdkn2a expression levels. White adipocytes from the DB mice exhibited lower Ucp1, peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (Pgc1a), and PR domain containing 16 (Prdm16) expression levels regardless of β-agonist treatment. NE upregulated Pgc1a in both white and brown adipocytes from the CON mice, but not in those from the DB mice. Although none of the fatty acids were observed to downregulate the cellular senescence genes in fully differentiated adipocytes, the OLA-treated brown adipocytes derived from DB mice exhibited lower Cdkn1a and Cdkn2b expression levels than the LNA-treated cells. Conclusion: These results indicate that the lower thermogenic capacity of diabetic adipocytes may be related to their cellular senescence, and different fatty acids potentially exert divergent effects on the expression of cellular senescence genes.

키워드

과제정보

The authors would like to thank Ungue Shin, YeKyoung Son, Na Young Kim, and Ga Young Lee for mouse husbandry.

참고문헌

  1. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15(7): 539-553.
  2. Kaisanlahti A, Glumoff T. Browning of white fat: agents and implications for beige adipose tissue to type 2 diabetes. J Physiol Biochem 2019; 75(1): 1-10.
  3. Kurylowicz A, Puzianowska-Kuznicka M. Induction of adipose tissue browning as a strategy to combat obesity. Int J Mol Sci 2020; 21(17): 6241.
  4. Palmer AK, Gustafson B, Kirkland JL, Smith U. Cellular senescence: at the nexus between ageing and diabetes. Diabetologia 2019; 62(10): 1835-1841.
  5. Murakami T, Inagaki N, Kondoh H. Cellular senescence in diabetes mellitus: distinct senotherapeutic strategies for adipose tissue and pancreatic β cells. Front Endocrinol (Lausanne) 2022; 13: 869414.
  6. Nagano T, Nakano M, Nakashima A, Onishi K, Yamao S, Enari M, et al. Identification of cellular senescence-specific genes by comparative transcriptomics. Sci Rep 2016; 6(1): 31758.
  7. Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 2008; 29(24): 2959-2971.
  8. Berry DC, Jiang Y, Arpke RW, Close EL, Uchida A, Reading D, et al. Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab 2017; 25(1): 166-181.
  9. Park J, Shin S, Liu L, Jahan I, Ong SG, Xu P, et al. Progenitor-like characteristics in a subgroup of UCP1+ cells within white adipose tissue. Dev Cell 2021; 56(7): 985-999.e4.
  10. Rabhi N, Hannou SA, Gromada X, Salas E, Yao X, Oger F, et al. Cdkn2a deficiency promotes adipose tissue browning. Mol Metab 2018; 8: 65-76.
  11. Wu R, Park J, Qian Y, Shi Z, Hu R, Yuan Y, et al. Genetically prolonged beige fat in male mice confers long-lasting metabolic health. Nat Commun 2023; 14(1): 2731.
  12. Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 2019; 18(3): e12950.
  13. Smith U, Li Q, Ryden M, Spalding KL. Cellular senescence and its role in white adipose tissue. Int J Obes 2021; 45(5): 934-943.
  14. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19(10): 1252-1263.
  15. Madsen L, Petersen RK, Kristiansen K. Regulation of adipocyte differentiation and function by polyunsaturated fatty acids. Biochim Biophys Acta 2005; 1740(2): 266-286.
  16. Shin S. Regulation of adipose tissue biology by long-chain fatty acids: metabolic effects and molecular mechanisms. J Obes Metab Syndr 2022; 31(2): 147-160.
  17. Shin S, Ajuwon KM. Divergent response of murine and porcine adipocytes to stimulation of browning genes by 18-carbon polyunsaturated fatty acids and beta-receptor agonists. Lipids 2018; 53(1): 65-75.
  18. Shin S, Ajuwon KM. Effects of diets differing in composition of 18-c fatty acids on adipose tissue thermogenic gene expression in mice fed high-fat diets. Nutrients 2018; 10(2): 256.
  19. Shin S, Ajuwon KM. Lipopolysaccharide alters thermogenic and inflammatory genes in white adipose tissue in mice fed diets with distinct 18-carbon fatty-acid composition. Lipids 2018; 53(9): 885-896.
  20. Park S, Ock SA, Park YJ, Lee YH, Park CY, Shin S. High-fat diet alters the thermogenic gene expression to β-agonists or 18-carbon fatty acids in adipocytes derived from the white and brown adipose tissue of mice. J Nutr Health 2024; 57(2): 171-184.
  21. Burke SJ, Batdorf HM, Burk DH, Noland RC, Eder AE, Boulos MS, et al. db/db mice exhibit features of human type 2 diabetes that are not present in weight-matched C57BL/6J mice fed a Western diet. J Diabetes Res 2017; 2017: 8503754.
  22. Shin S, El-Sabbagh AS, Lukas BE, Tanneberger SJ, Jiang Y. Adipose stem cells in obesity: challenges and opportunities. Biosci Rep 2020; 40(6): BSR20194076.
  23. Kotzbeck P, Giordano A, Mondini E, Murano I, Severi I, Venema W, et al. Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation. J Lipid Res 2018; 59(5): 784-794.
  24. Lapa C, Arias-Loza P, Hayakawa N, Wakabayashi H, Werner RA, Chen X, et al. Whitening and impaired glucose utilization of brown adipose tissue in a rat model of type 2 diabetes mellitus. Sci Rep 2017; 7(1): 16795.
  25. Feng X, Wang L, Zhou R, Zhou R, Chen L, Peng H, et al. Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging. Nat Commun 2023; 14(1): 3208.
  26. Pereira MJ, Vranic M, Kamble PG, Jernow H, Kristofi R, Holbikova E, et al. CDKN2C expression in adipose tissue is reduced in type II diabetes and central obesity: impact on adipocyte differentiation and lipid storage? Transl Res 2022; 242: 105-121.
  27. Rubio A, Raasmaja A, Silva JE. Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue. Endocrinology 1995; 136(8): 3277-3284.
  28. Bengtsson T, Redegren K, Strosberg AD, Nedergaard J, Cannon B. Down-regulation of beta3 adrenoreceptor gene expression in brown fat cells is transient and recovery is dependent upon a shortlived protein factor. J Biol Chem 1996; 271(52): 33366-33375.
  29. Jonsson C, Castor Batista AP, Kjolhede P, Stralfors P. Insulin and β-adrenergic receptors mediate lipolytic and anti-lipolytic signalling that is not altered by type 2 diabetes in human adipocytes. Biochem J 2019; 476(19): 2883-2908.
  30. Shimizu I, Yoshida Y, Katsuno T, Tateno K, Okada S, Moriya J, et al. p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure. Cell Metab 2012; 15(1): 51-64.
  31. Davalli P, Mitic T, Caporali A, Lauriola A, D'Arca D. ROS, cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid Med Cell Longev 2016; 2016(1): 3565127.
  32. Hatanaka E, Dermargos A, Hirata AE, Vinolo MA, Carpinelli AR, Newsholme P, et al. Oleic, linoleic and linolenic acids increase ros production by fibroblasts via NADPH oxidase activation. PLoS One 2013; 8(4): e58626.