Correlation among body composition and metabolic regulation in a male mouse model of Cushing’s syndrome

Uehara, Masaaki; Yamazaki, Hiroki; Yoshikawa, Noritada; Kuribara-Souta, Akiko; Tanaka, Hirotoshi

doi:10.1507/endocrj.ej19-0205

Cited by 11 publications

(12 citation statements)

References 41 publications

(45 reference statements)

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“…Male mice were exposed to oral treatments (n = 10/treatment) at target doses consisting either of corticosterone (100 µg/ml at the beginning of the treatment and lowered to 50 µg/ml on day 20 of the study), mirabegron (0.0048 or 0.048 mg/ml), vehicle (<1% ethanol), or naïve control (autoclaved water). The dose of 100 µg/ml of oral corticosterone was selected as it was the dose that has been found to model Cushing's disease, metabolic syndrome, and stress‐related obesity (Fransson et al, 2013 ; Karatsoreos et al, 2010 ; Tamashiro et al, 2011 ; Uehara et al, 2020 ). Mirabegron, a β3AR agonist known to increase BAT activity, was used as a positive control in order to compare the effects of corticosterone against changes observed in BAT under chronic activation.…”

Section: Methodsmentioning

confidence: 99%

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

Bel

Tai

Khaper

et al. 2022

Physiological Reports

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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.

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Section: Methodsmentioning

confidence: 99%

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

Bel

Tai

Khaper

et al. 2022

Physiological Reports

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“…Dexamethasone, a potent synthetic glucocorticoid, is known to lead to changes in the metabolisms of carbohydrates, lipids, and proteins and to act in other tissues, in a time and dose-dependent manner [3]. Additionally, chronic glucocorticoid excess disrupts the internal milieu, resulting in central obesity, muscle atrophy, and fatty liver [21]. Given the severity of this disease, we sought to standardize a rat model of Cushing's syndrome induced by chronic glucocorticoid over levels and then to assess the potential effects of the administration of the branched-chain amino acid leucine on the pathophysiological process since there are few studies regarding the systemic effects of this amino acid.…”

Section: Discussionmentioning

confidence: 99%

“…Male adult Wistar rats (Rattus norvegicus) weighing between 250-300 g were obtained from the Biotherium of the Center of Agricultural Sciences of Federal University of Piauí. The animals were kept under controlled conditions of temperature (22 ± 2ºC), relative humidity of 55 ± 10% and a light-dark cycle (lights on from 6 a.m. to 6 p.m.), with free access to water and food (Presence®, Paulínea, SP, Brazil), following the guidelines for the ethical use of animals (21), which was previously approved by the Animal Ethics and Experimentation Committee of the Federal University of Piauí (protocol number 314/17).…”

Section: Animals and Proceduresmentioning

confidence: 99%

Leucine supplementation affects metabolic parameters and redox balance in a Cushing’s syndrome model in rats

Borges

Sá

Santos

et al. 2022

Preprint

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Cushing’s syndrome (CS) is a disease that promotes several metabolic disorders and redox imbalance. Thus, in this paper, we standardized an experimental model of CS in rats and evaluated the effects of supplementation with leucine (LEU). Rats were injected intraperitoneally with dexamethasone (0.4; 0.6; 0.8; and 1.0 mg/kg) 4x/wk. for four weeks. The effects of LEU supplementation (0.5, 1.0, and 1.5% v/v in water to drink) were also evaluated. In vitro and in vivo evaluation of metabolic and redox parameters by biochemical and molecular assays defined the severity of the disease. Dexamethasone 1.0 mg/kg promoted the most severe symptoms of CS: such as weight loss, adiposity increase, glucose intolerance, and insulin resistance, as well as an increase in oxidative status in the liver. Moreover, LEU promoted a pattern of mixed dyslipidemia, adiposity increase, and raised serum levels of aspartate aminotransferase (AST). Likewise, it increased myeloperoxidase (MPO) activities and decreased the CAT mRNA in the liver, while it reduced NADPH oxidase (NOX) mRNA. Supplementation with LEU worsens metabolic status and liver damage in rats with CS without an evident antioxidant potential, suggesting that the administration of LEU represents a risky strategy to patients suffering from CS.

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“…Protein breakdown and lipid metabolism in skeletal muscle are essential for maintaining normal bone cell function [41]. With changes in diet, bone cells can adversely affect the skeletal system by altering the activity of glucocorticoid levels causing muscle wasting, osteoporosis, and insulin resistance [42]. A large number of studies have shown that secondary osteoporosis, muscle atrophy, insulin resistance, and type 2 diabetes caused by excessive glucocorticoid in skeletal muscle are mainly caused by high-fat diets [43].…”

Section: Discussionmentioning

confidence: 99%

Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet

Fan

Wang

et al. 2021

Animals

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Type 2 diabetes and metabolic syndrome caused by a high fat diet (HFD) have become public health problems worldwide. These diseases are characterized by the oxidation of skeletal muscle mitochondria and disruption of insulin resistance, but the mechanisms are not well understood. Therefore, this study aims to reveal how high-fat diet causes skeletal muscle metabolic disorders. In total, 16 weaned rabbits were randomly divided into two groups, one group was fed a standard normal diet (SND) and the other group was fed a high fat diet (HFD) for 5 weeks. At the end of the five-week experiment, skeletal muscle tissue samples were taken from each rabbit. Untargeted metabolomic analysis was performed using ultra-performance liquid chromatography combined with mass spectrometry (UHPLC-MS/MS). The results showed that high fat diet significantly altered the expression levels of phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosterone in skeletal muscle. Principal component analysis (PCA) and least squares discriminant analysis (PLS-DA) showed that, compared with the SND group, skeletal muscle metabolism in HFD group was significantly up-regulated. Among 43 skeletal muscle metabolites in the HFD group, phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosteroids were identified as biomarkers of skeletal muscle metabolic diseases, and may become potential physiological targets of related diseases in the future. Untargeted metabonomics analysis showed that high-fat diet altered the metabolism of phospholipids, carnitine, amino acids and steroids in skeletal muscle of rabbits. Notably, phospholipids, LCACs, histidine, carnopeptide, and tetrahydrocorticosteroids block the oxidative capacity of mitochondria and disrupt the oxidative capacity of glucose and the fatty acid-glucose cycle in rabbit skeletal muscle.

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Correlation among body composition and metabolic regulation in a male mouse model of Cushing’s syndrome

Cited by 11 publications

References 41 publications

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

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

Leucine supplementation affects metabolic parameters and redox balance in a Cushing’s syndrome model in rats

Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet

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