Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Glucocorticoids and Metabolic Disorders

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 39822

Share This Special Issue

Special Issue Editor

Dr. Paola Marcolongo

E-Mail Website
Guest Editor

Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro, 53100 Siena, Italy
Interests: glycogen storage disease type 1b; endoplasmic reticulum enzymes; glucocorticoids; arterial tortuosity syndrome; autophagy; nutrients and hypertension

Special Issue Information

Dear colleagues,

Glucocorticoids, besides having well-known anti-inflammatory and immunosuppressive effects, also play a significant role in the control of metabolism and energy homeostasis.

Their production by the adrenal cortex under control of the hypothalamic–pituitary–adrenal axis occurs in parallel to the tissue-specific (e.g., liver and adipose tissue) mediated modulation of active glucocorticoid levels. The endoplasmic reticulum enzymes 11b-hydroxysteroid dehydrogenase types 1 and 2 regulate the active cortisol concentration at the pre-receptorial level, thus allowing fine-tuning of the glucocorticoid action in specific anatomic locations. These steroid hormones control the physiological equilibrium of metabolic functions, and an imbalance in the glucocorticoid–glucocorticoid receptor signaling can easily lead to severe alterations of proper metabolic control, affecting carbohydrate, protein and lipid metabolism. Metabolic disturbances involving glucocorticoids have been described in hyperglycemia, insulin resistance, diabetes, dyslipidemia, obesity and hypertension, all of which are risk factors for cardiovascular diseases; indeed, these clustered conditions define the metabolic syndrome.

This Special Issue “Glucocorticoids and Metabolic Disorders” calls for research papers and review articles focusing on different aspects of the connection between glucocorticoids and metabolism in order to provide a clear and up-to-date picture of the role of these steroid hormones in the pathogenesis of metabolic disturbances.

Dr. Paola Marcolongo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Glucocorticoids
Metabolic disorders
11β-hydroxysteroid dehydrogenase 1(11β-HSD1)
Endoplasmic reticulum
Obesity
Insulin resistance
Cardiovascular diseases
Metabolic syndrome

Published Papers (10 papers)

Download All Papers

Research

Jump to: Review

13 pages, 2486 KiB

Open AccessArticle

Role of Macrophages and Plasminogen Activator Inhibitor-1 in Delayed Bone Repair Induced by Glucocorticoids in Mice

by Kiyotaka Okada, Naoyuki Kawao, Daisho Nakai, Rei Wakabayashi, Yoshitaka Horiuchi, Katsumi Okumoto, Shinji Kurashimo, Yoshimasa Takafuji, Osamu Matsuo and Hiroshi Kaji

Int. J. Mol. Sci. 2022, 23(1), 478; https://doi.org/10.3390/ijms23010478 - 01 Jan 2022

Cited by 2 | Viewed by 2046

Abstract

Glucocorticoids delay fracture healing and induce osteoporosis. However, the mechanisms by which glucocorticoids delay bone repair have yet to be clarified. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of plasminogen activators and an adipocytokine that regulates metabolism. We herein investigated the roles of macrophages in glucocorticoid-induced delays in bone repair after femoral bone injury using PAI-1-deficient female mice intraperitoneally administered with dexamethasone (Dex). Dex significantly decreased the number of F4/80-positive macrophages at the damaged site two days after femoral bone injury. It also attenuated bone injury-induced decreases in the number of hematopoietic stem cells in bone marrow in wild-type and PAI-1-deficient mice. PAI-1 deficiency significantly weakened Dex-induced decreases in macrophage number and macrophage colony-stimulating factor (M-CSF) mRNA levels at the damaged site two days after bone injury. It also significantly ameliorated the Dex-induced inhibition of macrophage phagocytosis at the damaged site. In conclusion, we herein demonstrated that Dex decreased the number of macrophages at the damaged site during early bone repair after femoral bone injury partly through PAI-1 and M-CSF in mice. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

15 pages, 4661 KiB

Open AccessArticle

A Rat Model of Post-Traumatic Stress Syndrome Causes Phenotype-Associated Morphological Changes and Hypofunction of the Adrenal Gland

by Vadim Tseilikman, Maria Komelkova, Marina V. Kondashevskaya, Eugenia Manukhina, H. Fred Downey, Valerii Chereshnev, Margarita Chereshneva, Pavel Platkovskii, Anna Goryacheva, Anton Pashkov, Julia Fedotova, Olga Tseilikman, Natalya Maltseva, Olga Cherkasova, Charlotte Steenblock, Stefan R. Bornstein, Barbara Ettrich, George P. Chrousos and Enrico Ullmann

Int. J. Mol. Sci. 2021, 22(24), 13235; https://doi.org/10.3390/ijms222413235 - 08 Dec 2021

Cited by 10 | Viewed by 2639

Abstract

Background: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. Methods: Rats were exposed to PSS for ten days. Thirty days later, the rats’ anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. Results: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. Conclusion: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

15 pages, 3009 KiB

Open AccessArticle

Salt-Sensitive Hypertension in GR^+/− Rats Is Accompanied with Dysregulation in Adrenal Soluble Epoxide Hydrolase and Polyunsaturated Fatty Acid Pathways

by Paul-Emmanuel Vanderriele, Qing Wang, Anne-Marie Mérillat, Frédérique Ino, Gilles Aeschlimann, Xavier Ehret, David Ancin Del Olmo, Verónica Ponce de León, Ute I. Scholl, Denise V. Winter, Alex Odermatt, Edith Hummler and Sophia N. Verouti

Int. J. Mol. Sci. 2021, 22(24), 13218; https://doi.org/10.3390/ijms222413218 - 08 Dec 2021

Cited by 4 | Viewed by 2872

Abstract

Mutations within the glucocorticoid receptor (GR) gene locus lead to glucocorticoid resistance which is characterized by several clinical symptoms such as adrenal gland hyperplasia and salt-sensitive hypertension, although the underlying mechanisms are still unknown. We studied GR haploinsufficient (GR^+/−) Sprague Dawley rats which, on a standard diet, showed significantly increased plasma aldosterone and corticosterone levels and an adrenocortex hyperplasia accompanied by a normal systolic blood pressure. Following a high salt diet, these rats developed salt-sensitive hypertension and maintained elevated enzyme-soluble epoxide hydrolase (sEH) in adrenal glands, while sEH was significantly decreased in wild-type rats. Furthermore, GR^+/− rats showed dysregulation of the equilibrated linoleic and arachidonic acid pathways, with a significant increase of less active metabolites such as 8,9-DiHETrE. In Sprague Dawley rats, GR haploinsufficiency induced steroid disturbances, which provoked hypertension only in combination with high salt intake, which was accompanied by disturbances in sEH and fatty acid metabolism. Our results suggest that sEH inhibition could be a potential target to treat hypertension in patients with GR haploinsufficiency. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

17 pages, 2129 KiB

Open AccessArticle

Novel 2-(Adamantan-1-ylamino)Thiazol-4(5H)-One Derivatives and Their Inhibitory Activity towards 11β-HSD1—Synthesis, Molecular Docking and In Vitro Studies

by Renata Studzińska, Daria Kupczyk, Wojciech Płaziński, Szymon Baumgart, Rafał Bilski, Renata Paprocka and Renata Kołodziejska

Int. J. Mol. Sci. 2021, 22(16), 8609; https://doi.org/10.3390/ijms22168609 - 10 Aug 2021

Cited by 6 | Viewed by 1774

Abstract

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing’s syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11β-HSD1. Inhibition of 11β-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing’s syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5H)-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11β-HSD isoforms. For most of them, over 50% inhibition of 11β-HSD1 and less than 45% inhibition of 11β-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11β-HSD1 correctly reproduced the experimental IC₅₀ values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one (3i) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC₅₀ value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Graphical abstract

21 pages, 19460 KiB

Open AccessArticle

Decreased Glucocorticoid Signaling Potentiates Lipid-Induced Inflammation and Contributes to Insulin Resistance in the Skeletal Muscle of Fructose-Fed Male Rats Exposed to Stress

by Abdulbaset Zidane Shirif, Sanja Kovačević, Jelena Brkljačić, Ana Teofilović, Ivana Elaković, Ana Djordjevic and Gordana Matić

Int. J. Mol. Sci. 2021, 22(13), 7206; https://doi.org/10.3390/ijms22137206 - 04 Jul 2021

Cited by 4 | Viewed by 2718

Abstract

The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role in the maintenance of systemic energy homeostasis. We investigated whether 9-week fructose-enriched diet, with and without exposure to 4-week unpredictable stress, disturbs insulin signaling in the skeletal muscle of male rats and evaluated potential contributory roles of muscle lipid metabolism, glucocorticoid signaling and inflammation. The combination of fructose-enriched diet and stress increased peroxisome proliferator-activated receptors-α and -δ and stimulated lipid uptake, lipolysis and β-oxidation in the muscle of fructose-fed stressed rats. Combination of treatment also decreased systemic insulin sensitivity judged by lower R-QUICKI, and lowered muscle protein content and stimulatory phosphorylations of insulin receptor supstrate-1 and Akt, as well as the level of 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor. At the same time, increased levels of protein tyrosine phosphatase-1B, nuclear factor-κB, tumor necrosis factor-α, were observed in the muscle of fructose-fed stressed rats. Based on these results, we propose that decreased glucocorticoid signaling in the skeletal muscle can make a setting for lipid-induced inflammation and the development of insulin resistance in fructose-fed stressed rats. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

Review

Jump to: Research

22 pages, 845 KiB

Open AccessReview

Animal Model for Glucocorticoid Induced Osteoporosis: A Systematic Review from 2011 to 2021

by Andy Xavier, Hechmi Toumi and Eric Lespessailles

Int. J. Mol. Sci. 2022, 23(1), 377; https://doi.org/10.3390/ijms23010377 - 29 Dec 2021

Cited by 13 | Viewed by 3050

Abstract

Clinical and experimental data have shown that prolonged exposure to GCs leads to bone loss and increases fracture risk. Special attention has been given to existing emerging drugs that can prevent and treat glucocorticoid-induced osteoporosis GIOP. However, there is no consensus about the most relevant animal model treatments on GIOP. In this systematic review, we aimed to examine animal models of GIOP centering on study design, drug dose, timing and size of the experimental groups, allocation concealment, and outcome measures. The present review was written according to the PRISMA 2020 statement. Literature searches were performed in the PubMed electronic database via Mesh with the publication date set between April, 2011, and February 2021. A total of 284 full-text articles were screened and 53 were analyzed. The most common animal species used to model GIOP were rats (66%) and mice (32%). In mice studies, males (58%) were preferred and genetically modified animals accounted for 28%. Our work calls for a standardization of the establishment of the GIOP animal model with better precision for model selection. A described reporting design, conduction, and selection of outcome measures are recommended. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

22 pages, 1297 KiB

Open AccessReview

Management and Medical Therapy of Mild Hypercortisolism

by Vittoria Favero, Arianna Cremaschi, Alberto Falchetti, Agostino Gaudio, Luigi Gennari, Alfredo Scillitani, Fabio Vescini, Valentina Morelli, Carmen Aresta and Iacopo Chiodini

Int. J. Mol. Sci. 2021, 22(21), 11521; https://doi.org/10.3390/ijms222111521 - 26 Oct 2021

Cited by 14 | Viewed by 4465

Abstract

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing’s syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing’s syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the—nowadays—rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-βhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

20 pages, 3633 KiB

Open AccessReview

Glucocorticoid Receptor Signaling in Diabetes

by Ioanna Kokkinopoulou, Andriana Diakoumi and Paraskevi Moutsatsou

Int. J. Mol. Sci. 2021, 22(20), 11173; https://doi.org/10.3390/ijms222011173 - 16 Oct 2021

Cited by 24 | Viewed by 4253

Abstract

Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

19 pages, 1212 KiB

Open AccessReview

Genomic and Non-Genomic Actions of Glucocorticoids on Adipose Tissue Lipid Metabolism

by Negar Mir, Shannon A. Chin, Michael C. Riddell and Jacqueline L. Beaudry

Int. J. Mol. Sci. 2021, 22(16), 8503; https://doi.org/10.3390/ijms22168503 - 07 Aug 2021

Cited by 23 | Viewed by 8565

Abstract

Glucocorticoids (GCs) are hormones that aid the body under stress by regulating glucose and free fatty acids. GCs maintain energy homeostasis in multiple tissues, including those in the liver and skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). WAT stores energy as triglycerides, while BAT uses fatty acids for heat generation. The multiple genomic and non-genomic pathways in GC signaling vary with exposure duration, location (adipose tissue depot), and species. Genomic effects occur directly through the cytosolic GC receptor (GR), regulating the expression of proteins related to lipid metabolism, such as ATGL and HSL. Non-genomic effects act through mechanisms often independent of the cytosolic GR and happen shortly after GC exposure. Studying the effects of GCs on adipose tissue breakdown and generation (lipolysis and adipogenesis) leads to insights for treatment of adipose-related diseases, such as obesity, coronary disease, and cancer, but has led to controversy among researchers, largely due to the complexity of the process. This paper reviews the recent literature on the genomic and non-genomic effects of GCs on WAT and BAT lipolysis and proposes research to address the many gaps in knowledge related to GC activity and its effects on disease. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

19 pages, 1741 KiB

Open AccessReview

Glucocorticoids: Fuelling the Fire of Atherosclerosis or Therapeutic Extinguishers?

by Clare MacLeod, Patrick W. F. Hadoke and Mark Nixon

Int. J. Mol. Sci. 2021, 22(14), 7622; https://doi.org/10.3390/ijms22147622 - 16 Jul 2021

Cited by 30 | Viewed by 6065

Abstract

Glucocorticoids are steroid hormones with key roles in the regulation of many physiological systems including energy homeostasis and immunity. However, chronic glucocorticoid excess, highlighted in Cushing’s syndrome, is established as being associated with increased cardiovascular disease (CVD) risk. Atherosclerosis is the major cause of CVD, leading to complications including coronary artery disease, myocardial infarction and heart failure. While the associations between glucocorticoid excess and increased prevalence of these complications are well established, the mechanisms underlying the role of glucocorticoids in development of atheroma are unclear. This review aims to better understand the importance of glucocorticoids in atherosclerosis and to dissect their cell-specific effects on key processes (e.g., contractility, remodelling and lesion development). Clinical and pre-clinical studies have shown both athero-protective and pro-atherogenic responses to glucocorticoids, effects dependent upon their multifactorial actions. Evidence indicates regulation of glucocorticoid bioavailability at the vasculature is complex, with local delivery, pre-receptor metabolism, and receptor expression contributing to responses linked to vascular remodelling and inflammation. Further investigations are required to clarify the mechanisms through which endogenous, local glucocorticoid action and systemic glucocorticoid treatment promote/inhibit atherosclerosis. This will provide greater insights into the potential benefit of glucocorticoid targeted approaches in the treatment of cardiovascular disease. Full article

(This article belongs to the Special Issue Glucocorticoids and Metabolic Disorders)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Glucocorticoids and Metabolic Disorders

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI