Inflammation features of brown adipose tissue of rats with diet-induced obesity development after different regimes of melatonin administration

O. Kalmukova, Y. Leonova, O. Savchuk, N. Skrypnyk, M. Dzerzhynsky
Taras Shevchenko National University of Kyiv, Kyiv; Taras Shevchenko National University of Kyiv, Kyiv; Taras Shevchenko National University of Kyiv, Kyiv; Taras Shevchenko National University of Kyiv, Kyiv; Taras Shevchenko National University of Kyiv, Kyiv


One of the prominent obesity-related changes is the development of systemic low-grade proinflammatory state. Brown adipose tissue (BAT) may serve as a potential target for activation by melatonin to facilitate heat  production and simultaneously stimulate lipolysis during obesity development. At the same time, melatonin is known to have immunomodulatory properties, which are performed via endocrine and paracrine signal pathways in variety cell types (including brown adipocytes)and change significantly during the day. Therefore, it can be used in a wide range of doses and at different times of the day (chronotherapeutic approach). Thus, the main goal of our research was to analyze the inflammation state of brown adipose tissue of rats during high-calorie diet induced-obesity development after different daily melatonin application in different regimes. Melatonin was administered by gavage for 7 weeks in dose 30 mg/kg 1 h before lights-off (HCD ZT11, M ZT11, evening),
or 1 h after lights-on (HCD ZT01, M ZT01, morning). Tissue collagen content and leukocyte infiltration levels in BAT, detected by Van Gieson trichrome staining, were used as markers for the assessment of BAT inflammation state BAT. Propagation of obesity resulted in the increase of BATfibrosis level (the relative area occupied by collagen fibers) and tissue leukocyte infiltration in comparison to control rats. BAT fibrosis level after melatonin administrations to obese rats of HCD ZT01 and HCD ZT11 groups decreased to control values. Similar effects were observedinBAT tissue leukocyte infiltration after both regimes (HCD ZT01 and HCD ZT11 groups) of melatonin intake: this parameter decreased significantly, comparing to obese rats, but was still elevated, comparing to controls. At the same time, melatonin treatmentin morning or evening regimes did not have any impact on BAT fibrosis propagation and leukocyte infiltration in animals that consumed standard diet (M ZT01 and M ZT11 groups). To sum up, we suggest corrective properties of melatonin in context of chronic low-grade inflammation in obese rats BAT and suppose its wide potential for the therapeutic use combined with virtually absent side effects on BAT histophysiology of non-obese rats.


chronobiology, histochemistry, brown adipocytes, fibrosis, leukocyte infiltration, high-calorie diet-induced obesity

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ShinSK, Cho HW, Song SE, Im SS, Bae JH, Song DK. Oxidative stress resulting from the removal of endogenous catalase induces obesity by promoting hyperplasia and hypertrophy of white adipocytes. Redox

biology. 2020;37:101749.doi: 10.1016/j.redox.2020.101749.

Shimizu I, Walsh K. The whitening of brown fat and its implications for weight management in obesity. Current obesity reports. 2015;4(2): 224-229. doi: 10.1007/s13679-015-0157-8.

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 [S]. Journal of lipid research. 2018;59(5): 784-794. doi: 10.1194/jlr.M079665.

Muir LA, Neeley CK, Meyer KA, Baker NA, Brosius AM, Washabaugh AR, et al. Adipose tissue fibrosis, hypertrophy, and hyperplasia: Correlations with diabetes in human obesity. Obesity. 2016;24(3): 597-605.doi: 10.1002/oby.21377.

Sakamoto T, Nitta T, Maruno K, Yeh YS, Kuwata H, Tomita K, et al. Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice. American Journal of Physiology Endocrinology and Metabolism. 2016;310(8):E676-E687.doi: 10.1152/ajpendo.00028.2015.

Roberts‐Toler C, O'Neill BT, Cypess AM. Diet‐induced obesity causes insulin resistance in mouse brown adipose tissue. Obesity. 2015;23(9):1765-1770.doi: 10.1002/oby.21134.

Bae J, Ricciardi CJ, Esposito D, Komarnytsky S, Hu P, Curry BJ, et al. Activation of pattern recognition receptors in brown adipocytes induces inflammation and suppresses uncoupling protein 1 expression and mitochondrial respiration. American Journal of Physiology-Cell Physiology. 2014;306(10):C918-C930.doi: 10.1152/ajpcell.00249.2013.

Orava J, Nuutila P, Noponen T, Parkkola R, Viljanen T, Enerbäck S, et al. Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans. Obesity. 2013;21(11): 2279-2287. doi: 10.1002/oby.20456.

Nøhr MK, Bobba N, Richelsen B, Lund S, Pedersen SB. Inflammation downregulates UCP1 expression in brown adipocytes potentially via SIRT1 and DBC1 interaction. International journal of molecular sciences. 2017;18(5): 1006.doi: 10.3390/ijms18051006.

Porras A, Valladares A, Álvarez AM, Roncero C, Benito M. Differential role of PPARγ in the regulation of UCP-1 and adipogenesis by

TNF-α in brown adipocytes. Febs Letters. 2002;520(1-3): 58-62.doi: 10.1016/s0014-5793(02)02762-x.

Villarroya F, Cereijo R, Villarroya J, Gavaldà-Navarro A, Giralt M. Toward an understanding of how immune cells control brown and beige adipobiology. Cell metabolism. 2018;27(5): 954-961.doi: 10.1016/j.cmet.2018.04.006.

Camell CD, Sander J, Spadaro O, Lee A, Nguyen KY, Wing A, et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature. 2017;550(7674): 119-123. doi: 10.1038/nature24022.

Villarroya F, Cereijo R, Gavaldà‐Navarro A, Villarroya J, Giralt M. Inflammation of brown/beige adipose tissues in obesity and metabolic disease. Journal of Internal Medicine. 2018;284(5): 492-504.doi: 10.1111/joim.12803.

Song Z, Revelo X, Shao W, Tian L, Zeng K, Lei H, et al. Dietary curcumin intervention targets mouse white adipose tissue inflammation and brown adipose tissue UCP1 expression. Obesity. 2018;26(3): 547-558. doi:10.1002/oby.22110.

Buechler C, Krautbauer S, Eisinger K. Adipose tissue fibrosis. World journal of diabetes. 2015;6(4): 548. doi: 10.4239/wjd.v6.i4.548.

Divoux A, Clement K. Architecture and the extracellular matrix: the still unappreciated components of the adipose tissue. obesity

reviews. 2011;12(5): e494-e503.doi: 10.1111/j.1467-789X.2010.00811.x.

Sun K, Halberg N, Khan M, Magalang UJ, Scherer PE. Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue

dysfunction. Molecular and cellular biology. 2013;33(5): 904-917. doi: 10.1128/MCB.00951-12.

Li S, Gao H, Hasegawa Y, Lu X. Mini-Review: Fight against fibrosis in adipose tissue remodeling. American Journal of PhysiologyEndocrinology and Metabolism. 2021;321(1); E169-E175. doi: 10.1152/ajpendo.00558.2020.

Maestroni GJ, Conti A. Melatonin in relation to the immune system. In Melatonin: CRC Press. 2020. p. 289-309.

Prado NJ, Ferder L, Manucha W, Diez ER. Anti-inflammatory effects of melatonin in obesity and hypertension. Current hypertension reports. 2018;20(5): 1-12. doi: 10.1007/s11906-018-0842-6.

Olesçuck IF, Camargo LS, Carvalho PVV, Souza CAP, Gallo CC, do Amaral FG. Melatonin and brown adipose tissue: novel insights to a complex interplay. Melatonin Research. 2019:2(4):

Radogna F, Diederich M, Ghibelli L. Melatonin: a pleiotropic molecule regulating inflammation. Biochemical pharmacology. 2010;80(12): 1844-1852.doi: 10.1016/j.bcp.2010.07.041.

Agil A, Navarro-Alarcon M, Ali FAZ, Albrakati A, Salagre D, Campoy C, Elmahallawy EK. Melatonin Enhances the Mitochondrial Functionality of Brown Adipose Tissue in Obese–Diabetic Rats. Antioxidants. 2021;10(9): 1482.doi: 10.3390/antiox10091482.

Halenova T, Raksha N, Vovk T, Savchuk O, Ostapchenko L, Prylutskyy Y, et al. Effect of C60 fullerene nanoparticles on the diet-induced obesity in rats. International Journal of Obesity. 2018; 42:1987–1998. doi: 10.1038/s41366-018-0016-2.

Szewczyk-Golec K, Woźniak A, Reiter RJ. Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity. J Pineal Res. 2015;59(3):277-91. doi: 10.1111/jpi.12257.

Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Complement Ther Med. 2019;42:65-81. doi: 10.1016/j.ctim.2018.11.003.

Mishra NS, Wanjari SP, Parwani RN, Wanjari PV, Kaothalker SP. Assessment of collagen and elastic fibres in various stages of oral

submucous fibrosis using Masson's trichrome, Verhoeffvangieson and picrosirius staining under light and polarizing microscopy. J Dent Special. 2015;3(2):170-175. DOI: 10.5958/2393-9834.2015.00009.1

Spencer M, Unal R, Zhu B, Rasouli N, McGeheeJrRE, Peterson CA, Kern PA. Adipose tissue extracellular matrix and vascular abnormalities in obesity and insulin resistance. The Journal of Clinical Endocrinology & Metabolism, 2011;96(12):E1990-E1998. doi: 10.1210/jc.2011-1567.

Teixeira LG, Leonel AJ, Aguilar EC, Batista NV, Alves AC, Coimbra CC, et al. The combination of high-fat diet-induced obesity and chronic ulcerative colitis reciprocally exacerbates adipose tissue and colon inflammation. Lipids in health and disease. 2011;10(1): 1-15.doi: 10.1186/1476-511X-10-204.

Kalmukova O, Dzerzhynsky M. The effects of melatonin administration in different times of day on the brown adipose tissue in rats

with high-calorie diet-induced obesity. Bulletin of Taras Shevchenko National University of Kyiv-Biology. 2019;77(1): 55-61.DOI:

Kalmukova OO, Dzerzhinsky ME. The effects of different time of melatonin administration on differentiation and functional status of the brown adipocytes in vivo. Cell and organ transplantology. 2018;6(1): 80-85. DOI: 10.22494/cot.v6i1.83.

Fernández Vázquez G, Reiter RJ, Agil A. Melatonin increases brown adipose tissue mass and function in Zücker diabetic fatty rats:

implications for obesity control. Journal of pineal research. 2018;64(4):e12472.doi: 10.1111/jpi.12472.

Fitzgibbons TP, Kogan S, Aouadi M, Hendricks GM, Straubhaar J, Czech MP. Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation. American Journal of Physiology-Heart and Circulatory Physiology. 2011;301(4): H1425-H1437. doi: 10.1152/ajpheart.00376.2011.

Zhang Z, Silveyra E, Jin N, Ribelayga CP. A congenic line of the C57 BL/6J mouse strain that is proficient in melatonin synthesis. Journal of pineal research. 2018;65(3): e12509.doi: 10.1111/jpi.12509.

McGregor RA, Kwon EY, Shin SK, Jung UJ, Kim E, Park JHY, et al. Time-course microarrays reveal modulation of developmental, lipid metabolism and immune gene networks in intrascapular brown adipose tissue during the development of diet-induced obesity. International journal of obesity. 2013;37(12): 1524-1531.doi: 10.1038/ijo.2013.52.

Fu P, Zhu R, Jia J, Hu Y, Wu C, Cieszczyk P, et al. Aerobic exercise promotes the functions of brown adipose tissue in obese mice via a mechanism involving COX2 in the VEGF signaling pathway. Nutrition & Metabolism. 2021;18(1): 1-14.doi: 10.1186/s12986-021-00581-0.

Fernández MR, Vilca CC, Batista LO, Figueiredo LS, Ribeiro RA, do Carmo MDGT, et al. Fasting and refeeding cycles alter subcutaneous white depot growth dynamics and the morphology of brown adipose tissue in female rats. British Journal of Nutrition. 2021;126(3): 460-469.doi: 10.1017/S0007114520004055.

Received: 06.09.2021

Revised: 06.10.2021

Signed for publishing: 08.10.2021



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