Abstract
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.
Highlights
Obesity is associated with an increase in size and de novo formation of white adipocytes [1]
Brown adipocytes in control group showed typical morphology: polygonal shape, rounded nuclei that occupy a central position in cell and many tiny-sized lipid inclusions in cytoplasm (Fig. 1)
Development of obesity was accompanied by the change of brown adipocytes' morphology: round shape of the cells, flat nucleus in eccentric position and unilocular massive lipid droplet, which corresponds to a white adipose tissue appearance [30]
Summary
Obesity is associated with an increase in size (hypertrophy) and de novo formation of white adipocytes (hyperplasia) [1]. Obesity-related changes occur in white adipose tissue, and in brown adipose tissue (BAT). These changes are manifested in several processes, which are collectively named "whitening" of BAT [2]. Indirect, mechanism was proposed – pro-inflammatory cytokines recruit inflammation-driven macrophages to BAT, which affects norepinephrine sensitivity of brown adipocytes (the main activation mechanism of UCP 1 production) by inflammasome-mediated pathway. These changes may involve regulation of monoamine oxidase A (a catecholamine degrading enzyme) and norepinephrine transporter, that influence on norepinephrine bioavailability [11, 12]. The long-term consumption of high-fat diet results in attraction of lymphocytes and granulocytes to BAT (besides macrophages and monocytes), which promotes pro-inflammatory state in tissue [13, 14]
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Schedule a callMore From: Bulletin of Taras Shevchenko National University of Kyiv. Series: Biology
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