Chronic glucocorticoid exposure causes brown adipose tissue whitening, alters whole‐body glucose metabolism and increases tissue uncoupling protein‐1

Abstract

Adipose tissue (AT) has been found to exist in two predominant forms, white and brown. White adipose tissue (WAT) is the body's conventional storage organ, and brown adipose tissue (BAT) is responsible for non-shivering thermogenesis which allows mammals to produce heat and regulate body temperature. Studies examining BAT and its role in whole-body metabolism have found that active BAT utilizes glucose and circulating fatty acids and is associated with improved metabolic outcomes. While the beiging of WAT is a growing area of interest, the possibility of the BAT depot to "whiten" and store more triglycerides also has metabolic and health implications. Currently, there are limited studies that examine the effects of chronic stress and its ability to induce a white-like phenotype in the BAT depot. This research examined how chronic exposure to the murine stress hormone, corticosterone, for 4 weeks can affect the whitening process of BAT in C57BL/6 male mice. Separate treatments with mirabegron, a known β3adrenergic receptor agonist, were used to directly compare the effects of corticosterone with a beiging phenotype. Corticosterone-treated mice had significantly higher body weight (p ≤ 0.05) and BAT mass (p ≤ 0.05), increased adipocyte area (p ≤ 0.05), were insulin resistant (p ≤ 0.05), and significantly elevated expressions of uncoupling protein 1 (UCP-1) in BAT (p ≤ 0.05) while mitochondrial content remained unchanged. This whitened phenotype has not been previously associated with increased uncoupling proteins under chronic stress and may represent a compensatory mechanism being initiated under these conditions. These findings have implications for the study of BAT in response to chronic glucocorticoid exposure potentially leading to BAT dysfunction and negative impacts on wholebody glucose metabolism.

Dexamethasone-Induced Adipose Tissue Redistribution and Metabolic Changes: Is Gene Expression the Main Factor? An Animal Model of Chronic Hypercortisolism

“…In the present experimental model, the BAT of GC-treated rats completely loses its well-known characteristics: there was an increase in mass, changes in morphology to an unilocular phenotype, reduced expression of genes related to thermogenesis/brown adipocytes markers, and most importantly, the decreased oxidative capacity ( Figure 7 a–g), which characterizes a whitening process [ 81 , 82 ]. Our results corroborate with some studies that have shown that GC excess leads to changes in the morphology and/or thermogenic function [ 83 , 84 , 85 , 86 , 87 ]. However, it is still unclear whether BAT dysfunctions are a cause or a consequence of the AT redistribution/obesity that occurs in Cushing’s syndrome, but the BAT whitening may also explain some metabolic changes in this model.…”

An insight into brown/beige adipose tissue whitening, a metabolic complication of obesity with the multifactorial origin

“…Of note, the whitened phenotype has not been previously associated with increased uncoupling proteins under chronic stress, however, Bel et al. ( 174 ) suggested that the increased UCP1 expression could be a compensatory mechanism under certain stress.…”

“…Consistently, UCP1 expression was downregulated, while the expression of WAT marker genes RB transcriptional corepressor 1 (Rb1), nuclear-receptor-interacting protein 1 (Nrip1), and Rbl1/p107 (RB transcriptional corepressor like 1) were upregulated ( 173 ). Other evidence showed that chronic exposure to corticosterone can induce the whitening of BAT in C57BL/6 mice, this was evident by increased adipocyte area and elevated expressions of UCP1 in BAT ( 174 ). Of note, the whitened phenotype has not been previously associated with increased uncoupling proteins under chronic stress, however, Bel et al.…”

Dexamethasone-associated metabolic effects in male mice are partially caused by depletion of endogenous corticosterone

“…This symptomatology is similar to that observed in Cushing’s patients with hypercortisolemia ( 7 ). In rodents, dexamethasone and corticosterone both cause insulin resistance and muscle atrophy ( 8 – 10 ). Corticosterone induces adiposity, but the effect of dexamethasone on body composition is not as clear, as both loss and gain of total fat mass have been reported ( 11 – 13 ).…”