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Besli N, Ercin N, Carmena-Bargueño M, Sarikamis B, Kalkan Cakmak R, Yenmis G, Pérez-Sánchez H, Beker M, Kilic U. Research into how carvacrol and metformin affect several human proteins in a hyperglycemic condition: A comparative study in silico and in vitro. Arch Biochem Biophys 2024; 758:110062. [PMID: 38880320 DOI: 10.1016/j.abb.2024.110062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/30/2024] [Accepted: 06/13/2024] [Indexed: 06/18/2024]
Abstract
Carvacrol (CV) is an organic compound found in the essential oils of many aromatic herbs. It is nearly unfeasible to analyze all the current human proteins for a query ligand using in vitro and in vivo methods. This study aimed to clarify whether CV possesses an anti-diabetic feature via Docking-based inverse docking and molecular dynamic (MD) simulation and in vitro characterization against a set of novel human protein targets. Herein, the best poses of CV docking simulations according to binding energy ranged from -7.9 to -3.5 (kcal/mol). After pathway analysis of the protein list through GeneMANIA and WebGestalt, eight interacting proteins (DPP4, FBP1, GCK, HSD11β1, INSR, PYGL, PPARA, and PPARG) with CV were determined, and these proteins exhibited stable structures during the MD process with CV. In vitro application, statistically significant results were achieved only in combined doses with CV or metformin. Considering all these findings, PPARG and INSR, among these target proteins of CV, are FDA-approved targets for treating diabetes. Therefore, CV may be on its way to becoming a promising therapeutic compound for treating Diabetes Mellitus (DM). Our outcomes expose formerly unexplored potential target human proteins, whose association with diabetic disorders might guide new potential treatments for DM.
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Affiliation(s)
- Nail Besli
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey.
| | - Nilufer Ercin
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey.
| | - Miguel Carmena-Bargueño
- Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, UCAM Universidad Católica de Murcia, Guadalupe, Spain.
| | - Bahar Sarikamis
- Department of Medical Biology, Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey.
| | - Rabia Kalkan Cakmak
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey; Department of Medical Biology, Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey.
| | - Guven Yenmis
- Department of Medical Biology, Faculty of Medicine, Biruni University, Istanbul, Turkey.
| | - Horacio Pérez-Sánchez
- Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, UCAM Universidad Católica de Murcia, Guadalupe, Spain.
| | - Merve Beker
- Department of Medical Biology, International School of Medicine, University of Health Sciences, Istanbul, Turkey.
| | - Ulkan Kilic
- Department of Medical Biology, Hamidiye School of Medicine, University of Health Sciences, Istanbul, Turkey; Department of Medical Biology, Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey.
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Hodel K, Fonseca A, Barbosa I, Medina C, Alves B, Maciel C, Nascimento D, Oliveira-Junior G, Pedreira L, de Souza M, Godoy AL. Obesity and its Relationship with Covid-19: A Review of the Main Pharmaceutical Aspects. Curr Pharm Biotechnol 2024; 25:1651-1663. [PMID: 38258769 DOI: 10.2174/0113892010264503231108070917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/28/2023] [Accepted: 10/04/2023] [Indexed: 01/24/2024]
Abstract
Important physiological changes are observed in patients with obesity, such as intestinal permeability, gastric emptying, cardiac output, and hepatic and renal function. These differences can determine variations in the pharmacokinetics of different drugs and can generate different concentrations at the site of action, which can lead to sub therapeutic or toxic concentrations. Understanding the physiological and immunological processes that lead to the clinical manifestations of COVID-19 is essential to correlate obesity as a risk factor for increasing the prevalence, severity, and lethality of the disease. Several drugs have been suggested to control COVID- 19 like Lopinavir, Ritonavir, Ribavirin, Sofosbuvir, Remdesivir, Oseltamivir, Oseltamivir phosphate, Oseltamivir carboxylate, Hydroxychloroquine, Chloroquine, Azithromycin, Teicoplanin, Tocilizumab, Anakinra, Methylprednisolone, Prednisolone, Ciclesonide and Ivermectin. Similarly, these differences between healthy people and obese people can be correlated to mechanical factors, such as insufficient doses of the vaccine for high body mass, impairing the absorption and distribution of the vaccine that will be lower than desired or can be linked to the inflammatory state in obese patients, which can influence the humoral immune response. Additionally, different aspects make the obese population more prone to persistent symptoms of the disease (long COVID), which makes understanding these mechanisms fundamental to addressing the implications of the disease. Thus, this review provides an overview of the relationship between COVID-19 and obesity, considering aspects related to pharmacokinetics, immunosuppression, immunization, and possible implications of long COVID in these individuals.
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Affiliation(s)
- Katharine Hodel
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Ananda Fonseca
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Islania Barbosa
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Caio Medina
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Brenda Alves
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Carine Maciel
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Daniel Nascimento
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Gessualdo Oliveira-Junior
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Lorena Pedreira
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Monielly de Souza
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
| | - Ana Leonor Godoy
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Bahia, Salvador, Brazil
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Kupczyk D, Studzińska R, Kołodziejska R, Baumgart S, Modrzejewska M, Woźniak A. 11β-Hydroxysteroid Dehydrogenase Type 1 as a Potential Treatment Target in Cardiovascular Diseases. J Clin Med 2022; 11:jcm11206190. [PMID: 36294507 PMCID: PMC9605099 DOI: 10.3390/jcm11206190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/27/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022] Open
Abstract
Glucocorticoids (GCs) belong to the group of steroid hormones. Their representative in humans is cortisol. GCs are involved in most physiological processes of the body and play a significant role in important biological processes, including reproduction, growth, immune responses, metabolism, maintenance of water and electrolyte balance, functioning of the central nervous system and the cardiovascular system. The availability of cortisol to the glucocorticoid receptor is locally controlled by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Evidence of changes in intracellular GC metabolism in the pathogenesis of obesity, metabolic syndrome (MetS) and cardiovascular complications highlights the role of selective 11β-HSD1 inhibition in the pharmacotherapy of these diseases. This paper discusses the role of 11β-HSD1 in MetS and its cardiovascular complications and the importance of selective inhibition of 11β-HSD1.
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Affiliation(s)
- Daria Kupczyk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland
- Correspondence: (D.K.); (R.S.)
| | - Renata Studzińska
- Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jurasza 2, 85-089 Bydgoszcz, Poland
- Correspondence: (D.K.); (R.S.)
| | - Renata Kołodziejska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland
| | - Szymon Baumgart
- Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jurasza 2, 85-089 Bydgoszcz, Poland
| | - Martyna Modrzejewska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland
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Kupczyk D, Bilski R, Kozakiewicz M, Studzińska R, Kędziora-Kornatowska K, Kosmalski T, Pedrycz-Wieczorska A, Głowacka M. 11β-HSD as a New Target in Pharmacotherapy of Metabolic Diseases. Int J Mol Sci 2022; 23:ijms23168984. [PMID: 36012251 PMCID: PMC9409048 DOI: 10.3390/ijms23168984] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/08/2022] [Accepted: 08/10/2022] [Indexed: 11/16/2022] Open
Abstract
Glucocorticoids (GCs), which are secreted by the adrenal cortex, are important regulators in the metabolism of carbohydrates, lipids, and proteins. For the proper functioning of the body, strict control of their release is necessary, as increased GCs levels may contribute to the development of obesity, type 2 diabetes mellitus, hypertension, cardiovascular diseases, and other pathological conditions contributing to the development of metabolic syndrome. 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) locally controls the availability of the active glucocorticoid, namely cortisol and corticosterone, for the glucocorticoid receptor. Therefore, the participation of 11β-HSD1 in the development of metabolic diseases makes both this enzyme and its inhibitors attractive targets in the pharmacotherapy of the above-mentioned diseases.
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Affiliation(s)
- Daria Kupczyk
- Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland
- Correspondence: (D.K.); (R.S.)
| | - Rafał Bilski
- Department of Medical Biology and Biochemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland
| | - Mariusz Kozakiewicz
- Department of Geriatrics, Nicolaus Copernicus University in Toruń, L. Rydygier Collegium Medicum in Bydgoszcz, Dębowa 3, 85-626 Bydgoszcz, Poland
| | - Renata Studzińska
- Department of Organic Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jurasza 2, 85-089 Bydgoszcz, Poland
- Correspondence: (D.K.); (R.S.)
| | - Kornelia Kędziora-Kornatowska
- Department of Geriatrics, Nicolaus Copernicus University in Toruń, L. Rydygier Collegium Medicum in Bydgoszcz, Dębowa 3, 85-626 Bydgoszcz, Poland
| | - Tomasz Kosmalski
- Department of Organic Chemistry, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Jurasza 2, 85-089 Bydgoszcz, Poland
| | | | - Mariola Głowacka
- Faculty of Health Sciences, Mazovian State University in Płock, Plac Dąbrowskiego 2, 09-402 Płock, Poland
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Bini J, Bhatt S, Hillmer AT, Gallezot JD, Nabulsi N, Pracitto R, Labaree D, Kapinos M, Ropchan J, Matuskey D, Sherwin RS, Jastreboff AM, Carson RE, Cosgrove K, Huang Y. Body Mass Index and Age Effects on Brain 11β-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study. Mol Imaging Biol 2021; 22:1124-1131. [PMID: 32133575 DOI: 10.1007/s11307-020-01490-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
CONTEXT Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11β-HSD1 in the brain has not been quantified directly in vivo. OBJECTIVE We analyzed positron emission tomography (PET) scans with an 11β-HSD1 inhibitor radioligand in twenty-eight individuals (23 M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of 11C-AS2471907 (n = 17) or 18F-AS2471907 (n = 11). Injected activity and mass doses were 246 ± 130 MBq and 0.036 ± 0.039 μg, respectively, for 11C-AS2471907, and 92 ± 15 MBq and 0.001 ± 0.001 μg for 18F-AS2471907. Correlations of mean whole brain and regional distribution volume (VT) with body mass index (BMI) and age were performed with a linear regression model. RESULTS Significant correlations of whole brain mean VT with BMI and age (VT = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain VT values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean VT values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower VT value in obese vs. lean individuals. A significant age-associated increase of 2.7 mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values. CONCLUSIONS In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11β-HSD1 in the brain and correlation of increased 11β-HSD1 levels in the brain with advancing age.
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Affiliation(s)
- Jason Bini
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA. .,Yale University PET Center, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
| | - Shivani Bhatt
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Ansel T Hillmer
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.,Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Jean-Dominique Gallezot
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Nabeel Nabulsi
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Richard Pracitto
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - David Labaree
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Michael Kapinos
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Jim Ropchan
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - David Matuskey
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.,Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
| | - Robert S Sherwin
- Department of Internal Medicine, Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Ania M Jastreboff
- Department of Internal Medicine, Endocrinology, Yale University School of Medicine, New Haven, CT, USA.,Department of Pediatrics, Pediatric Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Richard E Carson
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Kelly Cosgrove
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.,Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Yiyun Huang
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
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Targeting Energy Expenditure-Drugs for Obesity Treatment. Pharmaceuticals (Basel) 2021; 14:ph14050435. [PMID: 34066399 PMCID: PMC8148206 DOI: 10.3390/ph14050435] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/18/2021] [Accepted: 04/29/2021] [Indexed: 12/15/2022] Open
Abstract
Obesity and overweight are associated with lethal diseases. In this context, obese and overweight individuals infected by COVID-19 are at greater risk of dying. Obesity is treated by three main pharmaceutical approaches, namely suppressing appetite, reducing energy intake by impairing absorption, and increasing energy expenditure. Most compounds used for the latter were first envisaged for other medical uses. However, several candidates are now being developed explicitly for targeting obesity by increasing energy expenditure. This review analyzes the compounds that show anti-obesity activity exerted through the energy expenditure pathway. They are classified on the basis of their development status: FDA-approved, Withdrawn, Clinical Trials, and Under Development. The chemical nature, target, mechanisms of action, and description of the current stage of development are described for each one.
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Sumińska M, Podgórski R, Fichna P, Fichna M. Steroid Metabolism in Children and Adolescents With Obesity and Insulin Resistance: Altered SRD5A and 20α/20βHSD Activity. Front Endocrinol (Lausanne) 2021; 12:759971. [PMID: 34764940 PMCID: PMC8577858 DOI: 10.3389/fendo.2021.759971] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/11/2021] [Indexed: 01/22/2023] Open
Abstract
Alterations in glucocorticoid metabolism may contribute to the development of obesity and insulin resistance (IR). Obesity in turn affects the androgen balance. The peripheral metabolism of steroids is equally an important determinant of their bioavailability and activity. The aim of this study was to evaluate steroid metabolism in obese children and to define which enzyme alterations are associated with IR. Clinical characteristics and anthropometric measurements were determined in 122 obese children and adolescents (72 girls, 50 boys) aged 8 - 18 years. 26 of them (21.3%) were diagnosed with IR (13 boys, 13 girls). Routine laboratory tests were performed and 24h urinary steroid excretion profiles were analyzed by gas chromatography/mass spectrometry. Positive relationship between 5α-reductase (SRD5A) activity and IR was found. According to the androsterone to etiocholanolone (An/Et) ratio the activity of SRD5A was significantly increased in obese children with IR, but the difference remained insignificant once the 5α-dihydrotestosterone to testosterone (5αDHT/T) ratio was considered. Furthermore, this relationship persisted in boys but was not observed in girls. The activity of 20α-hydroxysteroid dehydrogenase (20αHSD) and 20β-hydroxysteroid dehydrogenase (20βHSD) was reduced only in obese girls with IR. Conclude, in the context of obese children and adolescents with IR, we surmise that increased SRD5A represents a compensatory mechanism to reduce local glucocorticoid availability. This phenomenon is probably different in the liver (restriction) and in the adipose tissue (expected increase in activity). We show significant changes in 20αHSD and 20βHSD activity in obese girls with IR, but it is difficult to clearly determine whether the activity of these enzymes is an indicator of the function in their ovaries or adrenal glands.
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Affiliation(s)
- Marta Sumińska
- Department of Pediatric Diabetes and Obesity, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
- *Correspondence: Marta Sumińska,
| | - Rafał Podgórski
- Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszow, Rzeszow, Poland
- Department of Biochemistry, Institute of Medical Sciences, Collegium of Medical Sciences, University of Rzeszow, Rzeszow, Poland
| | - Piotr Fichna
- Department of Pediatric Diabetes and Obesity, Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland
| | - Marta Fichna
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland
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Juszczak A, Gilligan LC, Hughes BA, Hassan-Smith ZK, McCarthy MI, Arlt W, Tomlinson JW, Owen KR. Altered cortisol metabolism in individuals with HNF1A-MODY. Clin Endocrinol (Oxf) 2020; 93:269-279. [PMID: 32395877 DOI: 10.1111/cen.14218] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 03/13/2020] [Accepted: 04/20/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE AND CONTEXT Maturity onset diabetes of the young due to variants in HNF1A (HNF1A-MODY) is the most common form of monogenic diabetes. Individuals with HNF1A-MODY usually have a lean phenotype which contrasts with type 2 diabetes (T2DM). Data from hepatocytes derived from Hnf1a knock-out mice demonstrated dysregulation of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regulates glucocorticoid availability and action in target tissues, together with 11β-HSD2 and steroid A-ring reductases, 5α- and 5β-reductase. We proposed that altered glucocorticoid metabolism might underpin some of the phenotypic differences between patients with HNF1A-MODY and those with T2DM. DESIGN A retrospective matched cohort study. PATIENTS AND MEASUREMENTS 24-hours urine steroid metabolome profiling was carried out by gas chromatography-mass spectrometry in 35 subjects with HNF1A-MODY, 35 individuals with T2DM and 35 healthy controls matched for age, sex and BMI. The steroid metabolites were expressed as μg/L in all groups and measured in mid-morning urine in diabetic subjects and 24-hour urine collection in healthy controls. Hence, only ratios were compared not the individual steroids. Established ratios of glucocorticoid metabolites were used to estimate 11β-HSD1/2 and 5α- and 5β-reductase activities. RESULTS While 11β-HSD1 activity was similar in all groups, 11β-HSD2 activity was significantly lower in subjects with HNF1A-MODY and T2DM than in healthy controls. The ratio of 5β- to 5α-metabolites of cortisol was higher in subjects with HNF1A-MODY than in T2DM and healthy controls, probably due to increased activity of the 5β-reductase (AKR1D1) in HNF1A-MODY. CONCLUSIONS This is the first report of steroid metabolites in HNF1A-MODY. We have identified distinct differences in steroid metabolism pathways in subjects with HNF1A-MODY that have the potential to alter steroid hormone availability. Further studies are required to explore whether these changes link to phenotype.
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Affiliation(s)
- Agata Juszczak
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK
| | - Lorna C Gilligan
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Beverly A Hughes
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Zaki K Hassan-Smith
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Mark I McCarthy
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK
- Wellcome Trust Centre for Human Genetics, Oxford, UK
| | - Wiebke Arlt
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Jeremy W Tomlinson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK
| | - Katharine R Owen
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK
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Gregory S, Hill D, Grey B, Ketelbey W, Miller T, Muniz-Terrera G, Ritchie CW. 11β-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis. Metabolism 2020; 108:154246. [PMID: 32333937 DOI: 10.1016/j.metabol.2020.154246] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/01/2020] [Accepted: 04/20/2020] [Indexed: 11/20/2022]
Abstract
INTRODUCTION 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular enzyme that catalyses conversion of cortisone into cortisol; correspondingly, 11β-HSD1 inhibitors inhibit this conversion. This systematic review focuses on the use of 11β-HSD1 inhibitors in diseases known to be associated with abnormalities in hypothalamic pituitary adrenal (HPA) axis function. METHODS The databases screened for suitable papers were: MedLine, EMBASE, Web of Science, ClinicalTrials.gov, and Cochrane Central. RESULTS 1925 papers were identified, of which 29 were included in the final narrative synthesis. 11β-HSD1 and its inhibitors have been studied in diabetes, obesity, metabolic syndrome (MetS), and Alzheimer's disease (AD). Higher expression of 11β-HSD1 is seen in obesity and MetS, but has not yet been described in obesity or AD. Genetic studies identify 11β-HSD1 SNPs of interest in populations with diabetes, MetS, and AD. One phase II trial successfully reduced HbA1c in a diabetic population, however trials in MetS, obesity, and AD have not met primary endpoints. CONCLUSIONS Translation of this research from preclinical studies has proved challenging so far, however this is a growing area of research and more studies should focus on understanding the complex relationships between 11β-HSD1 and disease pathology, especially given the therapeutic potential of 11β-HSD1 inhibitors in development.
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Affiliation(s)
- Sarah Gregory
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
| | - David Hill
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Ben Grey
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | | | | | - Graciela Muniz-Terrera
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Craig W Ritchie
- Centre for Dementia Prevention, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
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Ling T, Miller DJ, Lang WH, Griffith E, Rodriguez-Cortes A, El Ayachi I, Palacios G, Min J, Miranda-Carboni G, Lee RE, Rivas F. Mechanistic Insight on the Mode of Action of Colletoic Acid. J Med Chem 2019; 62:6925-6940. [PMID: 31294974 DOI: 10.1021/acs.jmedchem.9b00187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The natural product colletoic acid (CA) is a selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which primarily converts cortisone to the active glucocorticoid (GC) cortisol. Here, CA's mode of action and its potential as a chemical tool to study intracellular GC signaling in adipogenesis are disclosed. 11β-HSD1 biochemical studies of CA indicated that its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11β-HSD1 bound to CA at 2.6 Å resolution revealed the nature of those interactions, namely, a close-fitting and favorable interactions between the constrained CA spirocycle and the catalytic triad of 11β-HSD1. Structure-activity relationship studies culminated in the development of a superior CA analogue with improved target engagement. Furthermore, we demonstrate that CA selectively inhibits preadipocyte differentiation through 11β-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e., PPARγ, PGC-1α), presumably by negatively modulating the glucocorticoid signaling pathway. The combined findings provide an in-depth evaluation of the mode of action of CA and its potential as a tool compound to study adipose tissue and its implications in metabolic syndrome.
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Affiliation(s)
| | | | | | | | | | - Ikbale El Ayachi
- Department of Medicine , The University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States
| | | | | | - Gustavo Miranda-Carboni
- Department of Medicine , The University of Tennessee Health Science Center , Memphis , Tennessee 38163 , United States
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Davison B, Singh GR, McFarlane J. Hair cortisol and cortisone as markers of stress in Indigenous and non-Indigenous young adults. Stress 2019; 22:210-220. [PMID: 30663480 DOI: 10.1080/10253890.2018.1543395] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 10/27/2018] [Indexed: 12/17/2022] Open
Abstract
Chronic, ongoing stress can impact negatively on health and wellbeing. Indigenous Australians are at an increased risk of experiencing multiple stressors. Hair glucocorticoids have been used as a marker for chronic stress. This study aimed to assess the associations of hair cortisol and cortisone with sociodemographic (age, gender, Indigenous Identification), substance use, emotional wellbeing, and emotional stress, in a cohort at increased risk of stressful events and psychological distress. Cross-sectional data (age 21-28 years) are presented from two Australian longitudinal studies; the Aboriginal Birth Cohort (n = 253) and non-Indigenous Top End Cohort (n = 72). A third of the cohort reported psychological distress, with Indigenous participants reporting higher rates of stressful events compared to non-Indigenous (6 vs. 1; p < .001). Significantly higher levels of cortisone were seen in Indigenous women compared to non-Indigenous women (β 0.21; p = .003). A positive association with age was present in hair cortisol and cortisone in Indigenous young adults (β 0.29 and β 0.41; p < .001, respectively). No association with substance use, emotional wellbeing or emotional stress was seen. Sub-analysis in women suggested a possible curvilinear relationship between hair cortisone and the number of stressful events. In this culturally diverse cohort, hair sampling provides a noninvasive, easily conducted and generally well tolerated mechanism to measure stress markers. The association with age, even in this narrow age range, likely represents the manifold changes in circumstances (financial independence, becoming parents, increased risk of substance use and mental illness) that occur during this transitional period of life, particularly for young Indigenous women. LAY ABSTRACT Chronic stress can impact negatively on health and emotional wellbeing. A hair sample is an easy way to measure chronic stress in Indigenous and non-Indigenous young people. The markers of chronic stress, cortisol and cortisone, were different between Indigenous and non-Indigenous, men and women and increased with age in Indigenous young adults.
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Affiliation(s)
- Belinda Davison
- a Menzies School of Health Research , Charles Darwin University , Darwin , NT , Australia
| | - Gurmeet R Singh
- a Menzies School of Health Research , Charles Darwin University , Darwin , NT , Australia
- b Northern Territory Medical Program , Flinders University , Darwin , NT , Australia
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Impact of Bariatric surgery on antimularian hormone in reproductive age women. MIDDLE EAST FERTILITY SOCIETY JOURNAL 2018. [DOI: 10.1016/j.mefs.2018.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Papargyri P, Zapanti E, Salakos N, Papargyris L, Bargiota A, Mastorakos G. Links between HPA axis and adipokines: clinical implications in paradigms of stress-related disorders. Expert Rev Endocrinol Metab 2018; 13:317-332. [PMID: 30422016 DOI: 10.1080/17446651.2018.1543585] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION In the human organism, a constant interplay exists between the stress system [which includes the activity of the hypothalamic-pituitary-adrenal (HPA) axis] and the adipose tissue. This interplay is mediated by hormones of the HPA axis such as corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and glucocorticoids (GCs) and adipokines secreted by the adipose tissue. AREAS COVERED In this critical review, the bi-directional interactions between HPA axis and the most studied adipokines such as leptin and adiponectin, as well as the pro-inflammatory adipocytokines tumor necrosis factor (TNF) and interleukin (IL) 6 are presented. Furthermore, these interactions are described in normalcy as well as in specific clinical paradigms of stress-related disorders such as eating disorders, hypothalamic amenorrhea, and stress-related endogenous hypercortisolism states. Wherever new therapeutic strategies emerge, they are presented accordingly. EXPERT COMMENTARY Additional research is needed to clarify the mechanisms involved in the interplay between the HPA axis and the adipose tissue. Research should be focused, in particular, on the development of new therapeutic means targeting dysfunctional adipose tissue in stress-related situations.
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Affiliation(s)
- Panagiota Papargyri
- a Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion Hospital, School of Medicine , National and Kapodistrian University of Athens , Athens , Greece
| | - Evangelia Zapanti
- b Department of Endocrinology , Alexandra Hospital , Athens , Greece
| | - Nicolaos Salakos
- c Second Department of Obstetrics and Gynecology, Aretaieion Hospital, School of Medicine , National and Kapodistrian University of Athens , Athens , Greece
| | - Loukas Papargyris
- d CRCINA, INSERM, Université de Nantes, Université d'Angers , Angers , France
- e LabEx IGO "Immunotherapy, Graft, Oncology," , Angers , France
| | - Alexandra Bargiota
- f Department of Endocrinology and Metabolic Diseases, Larissa University Hospital, School of Medicine , University of Thessaly , Larissa , Greece
| | - George Mastorakos
- a Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion Hospital, School of Medicine , National and Kapodistrian University of Athens , Athens , Greece
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Kosicka K, Siemiątkowska A, Szpera-Goździewicz A, Krzyścin M, Bręborowicz GH, Główka FK. Increased cortisol metabolism in women with pregnancy-related hypertension. Endocrine 2018; 61:125-133. [PMID: 29611097 PMCID: PMC5997110 DOI: 10.1007/s12020-018-1586-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 03/17/2018] [Indexed: 02/03/2023]
Abstract
PURPOSE The diminished function of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) was found in placentae from preeclamptic pregnancies. Here, we examine the overall maternal glucocorticoid balance in pregnancy-related hypertension. We aim to answer the question if the functions of primary enzymes involved in cortisol metabolism: 11β-HSD1 and 11β-HSD2 and 5-reductases (both 5α- and 5β) are altered in the course of hypertensive pregnancy. METHODS We determined plasma and urinary cortisol and cortisone as well as their urinary tetrahydro- and allo-tetrahydrometabolites, both in free and conjugated forms in samples obtained from 181 Polish women in the third trimester of pregnancy. We compared steroid profiles in women with preeclampsia (PE), gestational hypertension (GH), chronic hypertension (CH) and in normotensives (controls). RESULTS We found significant differences in glucocorticoid balance in pregnancy-related hypertension. Plasma cortisol to cortisone was significantly lower in PE than in controls (3.00 vs. 4.79; p < 0.001). Increased function of renal 11β-HSD2 in PE and GH was manifested by significantly lower urinary free cortisol to cortisone ratio (0.169 and 0.206 vs. 0.277 in controls; p < 0.005). Markedly enhanced metabolism of cortisol was observed in pregnancy-related hypertension, with no significant alterations in CH, and the changes were more clearly expressed in PE than in GH. CONCLUSIONS The glucocorticoid balance in PE and GH is shifted towards decreasing cortisol concentration either due to intensified conversion to cortisone or enhanced production of tetrahydro and allo-tetrahydrometabolites.
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Affiliation(s)
- Katarzyna Kosicka
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, Poznań, 60-781, Poland.
| | - Anna Siemiątkowska
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, Poznań, 60-781, Poland
| | - Agata Szpera-Goździewicz
- Department of Perinatology and Gynecology, Poznan University of Medical Sciences, 33 Polna Street, Poznań, 60-535, Poland
| | - Mariola Krzyścin
- Department of Perinatology and Gynecology, Poznan University of Medical Sciences, 33 Polna Street, Poznań, 60-535, Poland
| | - Grzegorz H Bręborowicz
- Department of Perinatology and Gynecology, Poznan University of Medical Sciences, 33 Polna Street, Poznań, 60-535, Poland
| | - Franciszek K Główka
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, Poznań, 60-781, Poland
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Gant CM, Minovic I, Binnenmars H, de Vries L, Kema I, van Beek A, Navis G, Bakker S, Laverman GD. Lower Renal Function Is Associated With Derangement of 11- β Hydroxysteroid Dehydrogenase in Type 2 Diabetes. J Endocr Soc 2018; 2:609-620. [PMID: 29942925 PMCID: PMC6007243 DOI: 10.1210/js.2018-00088] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Accepted: 05/17/2018] [Indexed: 02/08/2023] Open
Abstract
Context Derangement of 11-β hydroxysteroid dehydrogenase type 1 and type 2 (11β-HSD1 and 11β-HSD2), which regulate intracellular cortisol production, has been suggested in both type 2 diabetes (T2D) and chronic kidney disease (CKD). However, activity of 11β-HSD enzymes in patients with T2D and CKD has never been assessed. Objectives To compare 11β-HSD activities between patients with T2D and healthy controls, and assess whether in T2D, renal function is associated with 11β-HSD activities. Design Cross-sectional analysis in the Diabetes and Lifestyle Cohort Twente (DIALECT-1). Setting Referral center for T2D. Patients Patient with T2D [n = 373, age 64 ± 9 years, 58% men, 26% of patients estimated glomerular filtration rate (eGFR) <60 mL/min·1.73 m2] and healthy controls (n = 275, age 53 ± 11 years, 48% men). Mean Outcome Measure We measured cortisol, cortisone, and metabolites [tetrahydrocortisol (THF), allo-THF (aTHF), and tetrahydrocortisone (THE)] in 24-hour urine samples. Whole body 11β-HSD and 11β-HSD2 activities were calculated as the urinary (THF + aTHF)/THE and cortisol/cortisone ratios, respectively. Results Patients with T2D had a higher (THF + aTHF)/THE ratio [1.02 (0.84 to 1.27) vs 0.94 (0.79 to 1.0), P < 0.001] and cortisol/cortisone ratio [0.70 (0.58 to 0.83) vs 0.63 (0.54 to 0.74), P < 0.001] than healthy controls. In T2D, lower eGFR was associated with a higher (THF + aTHF)/THE ratio (β = −0.35, P < 0.001), and a higher cortisol/cortisone ratio (β = −0.16, P = 0.001). Conclusions In this real-life secondary care setting of patients with T2D, 11β-HSD enzymes activities were shifted to higher intracellular cortisol production in T2D, which was further aggravated in patients with CKD. Prospective analyses are warranted to investigate causality of these associations.
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Affiliation(s)
- Christina Maria Gant
- Department of Internal Medicine/Nephrology, Ziekenhuisgroep Twente Hospital, PP Almelo and Hengelo, Netherlands.,Department of Nephrology, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - Isidor Minovic
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - Heleen Binnenmars
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - Laura de Vries
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - Ido Kema
- Department of Laboratory Medicine, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - André van Beek
- Department of Endocrinology, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - Gerjan Navis
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - Stephan Bakker
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, EZ Groningen, Netherlands
| | - Gozewijn Dirk Laverman
- Department of Internal Medicine/Nephrology, Ziekenhuisgroep Twente Hospital, PP Almelo and Hengelo, Netherlands
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Loerz C, Maser E. The cortisol-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 in skeletal muscle in the pathogenesis of the metabolic syndrome. J Steroid Biochem Mol Biol 2017; 174:65-71. [PMID: 28765040 DOI: 10.1016/j.jsbmb.2017.07.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 07/24/2017] [Accepted: 07/25/2017] [Indexed: 12/25/2022]
Abstract
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) contributes to intracellular glucocorticoid action by converting inactive cortisone to its receptor-active form cortisol (11-dehydrocorticosterone and corticosterone in mice and rats). The potential role of 11β-HSD1 in the pathogenesis of the metabolic syndrome has emerged over the past three decades. However, the precise impact of 11β-HSD1 in obesity-related diseases remains uncertain. Many studies from animal experiments to clinical studies have investigated liver and adipose tissue 11β-HSD1 in relation to obesity and its metabolic disorders including insulin resistance. But the relevance of 11β-HSD1 in skeletal muscle has been less extensively studied. On the other hand, skeletal muscle is assumed to be the main site of peripheral insulin resistance, but the biological relevance of 11β-HSD1 in skeletal muscle is unclear. This mini-review will focus on 11β-HSD1 in skeletal muscle and its postulated link to obesity and insulin-resistance.
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Affiliation(s)
- Christine Loerz
- Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Kiel, Germany
| | - Edmund Maser
- Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Kiel, Germany.
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Beck KR, Kaserer T, Schuster D, Odermatt A. Virtual screening applications in short-chain dehydrogenase/reductase research. J Steroid Biochem Mol Biol 2017; 171:157-177. [PMID: 28286207 PMCID: PMC6831487 DOI: 10.1016/j.jsbmb.2017.03.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 03/06/2017] [Accepted: 03/08/2017] [Indexed: 02/06/2023]
Abstract
Several members of the short-chain dehydrogenase/reductase (SDR) enzyme family play fundamental roles in adrenal and gonadal steroidogenesis as well as in the metabolism of steroids, oxysterols, bile acids, and retinoids in peripheral tissues, thereby controlling the local activation of their cognate receptors. Some of these SDRs are considered as promising therapeutic targets, for example to treat estrogen-/androgen-dependent and corticosteroid-related diseases, whereas others are considered as anti-targets as their inhibition may lead to disturbances of endocrine functions, thereby contributing to the development and progression of diseases. Nevertheless, the physiological functions of about half of all SDR members are still unknown. In this respect, in silico tools are highly valuable in drug discovery for lead molecule identification, in toxicology screenings to facilitate the identification of hazardous chemicals, and in fundamental research for substrate identification and enzyme characterization. Regarding SDRs, computational methods have been employed for a variety of applications including drug discovery, enzyme characterization and substrate identification, as well as identification of potential endocrine disrupting chemicals (EDC). This review provides an overview of the efforts undertaken in the field of virtual screening supported identification of bioactive molecules in SDR research. In addition, it presents an outlook and addresses the opportunities and limitations of computational modeling and in vitro validation methods.
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Affiliation(s)
- Katharina R Beck
- Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
| | - Teresa Kaserer
- Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria
| | - Daniela Schuster
- Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), Computer Aided Molecular Design Group, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
| | - Alex Odermatt
- Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
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Delitala AP, Capobianco G, Delitala G, Cherchi PL, Dessole S. Polycystic ovary syndrome, adipose tissue and metabolic syndrome. Arch Gynecol Obstet 2017. [DOI: 10.1007/s00404-017-4429-2] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Kosicka K, Siemiątkowska A, Pałka D, Szpera-Goździewicz A, Bręborowicz GH, Główka FK. Detailed analysis of cortisol, cortisone and their tetrahydro- and allo-tetrahydrometabolites in human urine by LC–MS/MS. J Pharm Biomed Anal 2017; 140:174-181. [DOI: 10.1016/j.jpba.2017.03.039] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 03/17/2017] [Accepted: 03/18/2017] [Indexed: 11/28/2022]
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Thiazolopyridines Improve Adipocyte Function by Inhibiting 11 Beta-HSD1 Oxoreductase Activity. J CHEM-NY 2017. [DOI: 10.1155/2017/3182129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background. Glucocorticoid excess has been linked to clinical observations associated with the pathophysiology of metabolic syndrome. The intracellular glucocorticoid levels are primarily modulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme that is highly expressed in key metabolic tissues including fat, liver, and the central nervous system. Methods. In this study we synthesized a set of novel tetrahydrothiazolopyridine derivatives, TR-01–4, that specifically target 11β-HSD1 and studied their ability to interfere with the glucocorticoid and lipid metabolism in the 3T3-L1 adipocytes. Results. Based on the docking model and structure-activity relationships, tetrahydrothiazolopyridine derivatives TR-02 and TR-04 showed the highest potency against 11β-HSD1 by dose-dependently inhibiting conversion of cortisone to cortisol (IC50 values of 1.8 μM and 0.095 μM, resp.). Incubation of fat cells with 0.1–10 μM TR-01–4 significantly decreased cortisone-induced lipid accumulation in adipocytes and suppressed 11β-HSD1 mRNA expression. Observed reduction in adipocyte fat stores could be partially explained by decreased expression levels of adipogenic markers (PPAR-γ, aP2) and key enzymes of lipid metabolism, including fatty acid synthase (FAS), hormone sensitive lipase (HSL), and lipoprotein lipase (LPL). Conclusions. The tetrahydrothiazolopyridine moiety served as an active pharmacophore for inhibiting 11β-HSD1 and offered a novel therapeutic strategy to ameliorate metabolic alterations found in obesity and diabetes.
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Anderson AJ, Andrew R, Homer NZ, Jones GC, Smith K, Livingstone DE, Walker BR, Stimson RH. Metformin Increases Cortisol Regeneration by 11βHSD1 in Obese Men With and Without Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 2016; 101:3787-3793. [PMID: 27459533 PMCID: PMC5052341 DOI: 10.1210/jc.2016-2069] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
CONTEXT The mechanism of action of metformin remains unclear. Given the regulation of the cortisol-regenerating enzyme 11βhydroxysteroid dehydrogenase 1 (11βHSD1) by insulin and the limited efficacy of selective 11βHSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11βHSD1 activity. OBJECTIVE To determine whether metformin regulates 11βHSD1 activity in vivo in obese men with and without type 2 diabetes mellitus. DESIGN Double-blind, randomized, placebo-controlled, crossover study. SETTING A hospital clinical research facility. PARTICIPANTS Eight obese nondiabetic (OND) men and eight obese men with type 2 diabetes (ODM). INTERVENTION Participants received 28 days of metformin (1 g twice daily), placebo, or (in the ODM group) gliclazide (80 mg twice daily) in random order. A deuterated cortisol infusion at the end of each phase measured cortisol regeneration by 11βHSD1. Oral cortisone was given to measure hepatic 11βHSD1 activity in the ODM group. The effect of metformin on 11βHSD1 was also assessed in human hepatocytes and Simpson-Golabi-Behmel syndrome adipocytes. MAIN OUTCOME MEASURES The effect of metformin on whole-body and hepatic 11βHSD1 activity. RESULTS Whole-body 11βHSD1 activity was approximately 25% higher in the ODM group than the OND group. Metformin increased whole-body cortisol regeneration by 11βHSD1 in both groups compared with placebo and gliclazide and tended to increase hepatic 11βHSD1 activity. In vitro, metformin did not increase 11βHSD1 activity in hepatocytes or adipocytes. CONCLUSIONS Metformin increases whole-body cortisol generation by 11βHSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11βHSD1 inhibitors.
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Affiliation(s)
- Anna J Anderson
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
| | - Ruth Andrew
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
| | - Natalie Z Homer
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
| | - Gregory C Jones
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
| | - Kenneth Smith
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
| | - Dawn E Livingstone
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
| | - Brian R Walker
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
| | - Roland H Stimson
- University/British Heart Foundation Centre for Cardiovascular Science (A.J.A., R.A., N.Z.H., G.C.J., K.S., D.E.L., B.R.W., R.H.S), University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom; Diabetes Centre, Gartnavel General Hospital (G.C.J.), Glasgow, Scotland, United Kingdom; and Division of Medical Sciences and Graduate Entry Medicine (K.S.), School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom
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Robert O, Boujedidi H, Bigorgne A, Ferrere G, Voican CS, Vettorazzi S, Tuckermann JP, Bouchet-Delbos L, Tran T, Hemon P, Puchois V, Dagher I, Douard R, Gaudin F, Gary-Gouy H, Capel F, Durand-Gasselin I, Prévot S, Rousset S, Naveau S, Godot V, Emilie D, Lombès M, Perlemuter G, Cassard AM. Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice. J Hepatol 2016; 64:916-24. [PMID: 26639395 DOI: 10.1016/j.jhep.2015.11.023] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 11/12/2015] [Accepted: 11/13/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Kupffer cells (KC) play a key role in the onset of inflammation in non-alcoholic steatohepatitis (NASH). The glucocorticoid receptor (GR) induces glucocorticoid-induced leucine zipper (GILZ) expression in monocytes/macrophages and is involved in several inflammatory processes. We hypothesized that the GR-GILZ axis in KC may contribute to the pathophysiology of obesity-induced liver inflammation. METHODS By using a combination of primary cell culture, pharmacological experiments, mice deficient for the Gr specifically in macrophages and transgenic mice overexpressing Gilz in macrophages, we explored the involvement of the Gr-Gilz axis in KC in the pathophysiology of obesity-induced liver inflammation. RESULTS Obesity was associated with a downregulation of the Gr and Gilz, and an impairment of Gilz induction by lipopolysaccharide (LPS) and dexamethasone (DEX) in KC. Inhibition of Gilz expression in isolated KC transfected with Gilz siRNA demonstrated that Gilz downregulation was sufficient to sensitize KC to LPS. Conversely, liver inflammation was decreased in obese transgenic mice specifically overexpressing Gilz in macrophages. Pharmacological inhibition of the Gr showed that impairment of Gilz induction in KC by LPS and DEX in obesity was driven by a downregulation of the Gr. In mice specifically deficient for Gr in macrophages, Gilz expression was low, leading to an exacerbation of obesity-induced liver inflammation. CONCLUSIONS Obesity is associated with a downregulation of the Gr-Gilz axis in KC, which promotes liver inflammation. The Gr-Gilz axis in KC is an important target for the regulation of liver inflammation in obesity.
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Affiliation(s)
- Olivier Robert
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France
| | - Hédia Boujedidi
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France
| | - Amélie Bigorgne
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France
| | - Gladys Ferrere
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France
| | | | - Sabine Vettorazzi
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany
| | - Jan Peter Tuckermann
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, 89081 Ulm, Germany
| | | | - Thi Tran
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France
| | - Patrice Hemon
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France
| | - Virginie Puchois
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France
| | - Ibrahim Dagher
- Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service de chirurgie minimale invasive, DHU Hépatinov, Clamart, France
| | - Richard Douard
- AP-HP, Hôpital Européen Georges Pompidou, Service de chirurgie, Paris, France; AP-HP, Hôpital Avicenne, Service de chirurgie, Bobigny, France
| | - Francoise Gaudin
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; IFR 141 Institut Paris-Sud d'Innovation Thérapeutique, Châtenay-Malabry, France
| | - Hélène Gary-Gouy
- IFR 141 Institut Paris-Sud d'Innovation Thérapeutique, Châtenay-Malabry, France
| | - Francis Capel
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France
| | | | - Sophie Prévot
- AP-HP, Hôpital Antoine-Béclère, Service d'anatomie pathologique, Clamart, France
| | - Sophie Rousset
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France
| | - Sylvie Naveau
- AP-HP, Hôpital Antoine-Béclère, Service d'hépato-gastroentérologie, Clamart, France
| | - Véronique Godot
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France
| | - Dominique Emilie
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France
| | - Marc Lombès
- Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; INSERM, U693, Le Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service d'anatomie pathologique, Clamart, France; AP-HP, Hôpital Bicêtre, Service d'Endocrinologie et Maladies de la Reproduction, Le Kremlin-Bicêtre, France
| | - Gabriel Perlemuter
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France; AP-HP, Hôpital Antoine-Béclère, Service d'hépato-gastroentérologie, Clamart, France.
| | - Anne-Marie Cassard
- INSERM UMR996 - Inflammation, Chemokines and Immunopathology, Clamart, France; Univ Paris-Sud, Univ Paris-Saclay, DHU Hepatinov, Labex Lermit, Kremlin-Bicêtre, France.
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Máčová L, Sosvorová L, Vítků J, Bičíková M, Hill M, Zamrazilová H, Sedláčková B, Stárka L. Steroid hormones related to 11beta-hydroxysteroid dehydrogenase type 1 in treated obesity. Physiol Res 2015; 64:S121-33. [PMID: 26680473 DOI: 10.33549/physiolres.933073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
The local concentration of glucocorticoids is intensively regulated by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1). Human 11beta-HSD 1 also reversibly catalyzes the inter-conversion of 7alpha-hydroxy- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) into 7-oxo-DHEA. The cohort of 282 obese adolescents, 154 girls (median age 15.31 years, range 14.17-16.68 years) and 128 boys (median age 14.95 years, range 13.87-16.16 years), BMI (Body Mass Index) >90th percentile was examined. In samples collected before and after one month of reductive diet therapy, circulating levels of steroids were analyzed by liquid chromatography-tandem mass spectrometry and radioimmunoassay methods. The model of the treatment efficacy prediction was calculated. A significant reduction in circulating levels of cortisone, E2 and increased levels of 7beta-hydroxy-DHEA after the reductive treatment was observed. Levels of cortisol, DHEA, DHT sustained without any significant change. The predictive Orthogonal Projections to Latent Structures (OPLS) model explained 20.1 % of variability of BMI, z-score change by the basal levels of 7alpha-hydroxy-DHEA, DHEA, cortisol and E2 as the strongest predictors. Reduced levels of circulating cortisone and reduced ratios of oxygenated/reduced metabolites reflect increased reductase activity of 11beta-HSD 1 with reduced BMI, z-score. We hypothesize whether these changes can be attributed to the altered activity of 11beta-HSD 1 in the liver.
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Affiliation(s)
- L Máčová
- Department of Steroids and Proteofactors, Institute of Endocrinology, Prague, Czech Republic.
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Pharmacophore Models and Pharmacophore-Based Virtual Screening: Concepts and Applications Exemplified on Hydroxysteroid Dehydrogenases. Molecules 2015; 20:22799-832. [PMID: 26703541 PMCID: PMC6332202 DOI: 10.3390/molecules201219880] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 12/03/2015] [Accepted: 12/09/2015] [Indexed: 01/06/2023] Open
Abstract
Computational methods are well-established tools in the drug discovery process and can be employed for a variety of tasks. Common applications include lead identification and scaffold hopping, as well as lead optimization by structure-activity relationship analysis and selectivity profiling. In addition, compound-target interactions associated with potentially harmful effects can be identified and investigated. This review focuses on pharmacophore-based virtual screening campaigns specifically addressing the target class of hydroxysteroid dehydrogenases. Many members of this enzyme family are associated with specific pathological conditions, and pharmacological modulation of their activity may represent promising therapeutic strategies. On the other hand, unintended interference with their biological functions, e.g., upon inhibition by xenobiotics, can disrupt steroid hormone-mediated effects, thereby contributing to the development and progression of major diseases. Besides a general introduction to pharmacophore modeling and pharmacophore-based virtual screening, exemplary case studies from the field of short-chain dehydrogenase/reductase (SDR) research are presented. These success stories highlight the suitability of pharmacophore modeling for the various application fields and suggest its application also in futures studies.
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Valverde E, Seira C, McBride A, Binnie M, Luque FJ, Webster SP, Bidon-Chanal A, Vázquez S. Searching for novel applications of the benzohomoadamantane scaffold in medicinal chemistry: Synthesis of novel 11β-HSD1 inhibitors. Bioorg Med Chem 2015; 23:7607-17. [DOI: 10.1016/j.bmc.2015.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 10/30/2015] [Accepted: 11/05/2015] [Indexed: 12/28/2022]
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Xiang L, Mittwede PN, Clemmer JS. Glucose Homeostasis and Cardiovascular Alterations in Diabetes. Compr Physiol 2015; 5:1815-39. [PMID: 26426468 DOI: 10.1002/cphy.c150001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Pardina E, Baena-Fustegueras JA, Fort JM, Ferrer R, Rossell J, Esteve M, Peinado-Onsurbe J, Grasa M. Hepatic and visceral adipose tissue 11βHSD1 expressions are markers of body weight loss after bariatric surgery. Obesity (Silver Spring) 2015; 23:1856-63. [PMID: 26239572 DOI: 10.1002/oby.21173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 05/06/2015] [Indexed: 11/12/2022]
Abstract
OBJECTIVE Cortisolemia and 11βHSD1 in liver and adipose tissue are altered in obesity. However, their participation in the development of obesity remains unclear. This study analyzed these parameters in the transition from morbid to type 1 obesity after bariatric surgery. METHODS A group of 34 patients with morbid obesity and 22 nonobese subjects were recruited. Initial hypothalamus-pituitary-adrenal (HPA) basal activity and 11βHSD1 mRNA expression in liver, subcutaneous (SAT), and visceral adipose tissue (VAT) were evaluated. A year after bariatric surgery (weight loss of 48 kg), these parameters were reappraised in plasma, SAT, and liver. RESULTS Body weight loss was accompanied by a downshift in basal HPA activity and 11βHSD1 expression in SAT. In patients with morbid obesity, 11βHSD1 expression correlated positively with BMI in VAT and negatively in liver at 6 and 12 months after surgery. In SAT, a correlation was observed with body weight only when patients showed type 1 obesity. Insulin, glucose, and HOMA correlated positively with all the HPA indicators and 11βHSD1 expression in SAT. CONCLUSIONS Body weight loss after bariatric surgery is accompanied by a downshift in basal HPA activity. Hepatic and VAT 11βHSD1 expressions in morbid obesity are predictors of body weight loss.
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Affiliation(s)
- Eva Pardina
- Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
| | | | - José Manuel Fort
- Endocrinology Surgery Unit, Institut De Recerca Hospital Universitari Vall D'Hebron, Barcelona, Spain
| | - Roser Ferrer
- Biochemistry Department, Institut De Recerca Hospital Universitari Vall D'Hebron, Barcelona, Spain
| | - Joana Rossell
- Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
| | - Montserrat Esteve
- Department of Nutrition and Food Science, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER Obesity and Nutrition, Institute of Health Carlos III, Madrid, Spain
| | - Julia Peinado-Onsurbe
- Department of Biochemistry and Molecular Biology, University of Barcelona, Barcelona, Spain
| | - Mar Grasa
- Department of Nutrition and Food Science, University of Barcelona, Barcelona, Spain
- Institute of Biomedicine, University of Barcelona, Barcelona, Spain
- CIBER Obesity and Nutrition, Institute of Health Carlos III, Madrid, Spain
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Abstract
PURPOSE OF REVIEW The present review highlights recent investigations in the prior 18 months focusing on the role of dysregulated cortisol physiology in obesity as a potential modifiable mechanism in the pathogenesis of obesity-related cardiometabolic disorders. RECENT FINDINGS Given the clinical resemblance of obesity-related metabolic disorders with the Cushing's syndrome, new studies have investigated the intracellular regulation and metabolism of cortisol, new measurements of cortisol in scalp hair as a tool for long-term exposure to cortisol, and the cortisol-mineralocorticoid receptor pathway. Thus, current and future pharmacological interventions in obesity may include specific inhibition of steroidogenic and regulatory enzymes as well as antagonists of the mineralocorticoid and glucocorticoid receptors. SUMMARY The understanding of how adrenal function is challenged by the interplay of our genetic and environmental milieu has highlighted the importance of inappropriate cortisol regulation in cardiometabolic disorders. Increased adipose tissue in obesity is associated with hypothalamic-pituitary-adrenal axis overactivation, increased cortisol production at the local tissue level, and probably higher mineralocorticoid receptor activation in certain tissues.
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Affiliation(s)
- Rene Baudrand
- Department of Endocrinology, School Of Medicine, Pontificia Universidad Catolica De Chile, Santiago 8330074, Chile
- Director of the Endocrine Hypertension and Adrenal Disease Program, School Of Medicine, Pontificia Universidad Catolica De Chile, Santiago 8330074, Chile
| | - Anand Vaidya
- Center for Adrenal Disorders, Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School. Boston, MA 02115, USA
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do Nascimento FV, Piccoli V, Beer MA, von Frankenberg AD, Crispim D, Gerchman F. Association of HSD11B1 polymorphic variants and adipose tissue gene expression with metabolic syndrome, obesity and type 2 diabetes mellitus: a systematic review. Diabetol Metab Syndr 2015; 7:38. [PMID: 26056536 PMCID: PMC4459686 DOI: 10.1186/s13098-015-0036-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Accepted: 04/21/2015] [Indexed: 01/11/2023] Open
Abstract
The HSD11B1 gene is highly expressed in abdominal adipose tissue, and the enzyme it encodes catalyzes the interconversion of inactive cortisone to hormonally active cortisol. Genetic abnormalities of HSD11B1 have been associated with the development of abnormal glucose metabolism and body fat distribution. To systematically review studies evaluating the association of HSD11B1 gene expression in abdominal adipose tissue and HSD11B1 polymorphisms with obesity, the metabolic syndrome (MetS), and type 2 diabetes (T2DM), we conducted a search in MEDLINE, SCOPUS, and Cochrane Library databases in April 2015. The inclusion criteria were observational studies (cross-sectional, cohort, or case-control), conducted in adults, which analyzed the relationship of HSD11B1 polymorphisms and/or HSD11B1 expression in abdominal adipose tissue with obesity, MetS, or T2DM. Of 802 studies retrieved, 32 met the inclusion criteria (23 gene expression and 9 polymorphism studies). Twenty one studies analyzed the relationship between abdominal subcutaneous and/or visceral HSD11B1 expression with central and/or generalized obesity. Most studies reported that abdominal adipose HSD11B1 expression increased with increasing body mass index (15 studies) and abnormalities of glucose metabolism (7 studies), and varied with the presence of MetS (3 studies). Nine studies analyzed the association of 26 different HSD11B1 polymorphic variants with obesity, MetS, and T2DM. Only an Indian study found an association between a polymorphic variant at the HSD11B1 gene with MetS whereas in Pima Indians another polymorphic variant was found to be associated with T2DM. While the literature suggests that HSD11B1 is hyperexpressed in abdominal adipose tissue in subjects with obesity and abnormal glucose metabolism, this seems to be not true for HSD11B1 gene expression and MetS. Although an association of polymorphic variants of HSD11B1 with MetS in Indians and in the T2DM population of Pima Indians were found, most studies did not find a relationship between genetic polymorphic variants of HSD11B1 and obesity, MetS, and T2DM. Their reported conflicting and inconclusive results, suggesting that polymorphic variants of HSD11B1 may have only a small role in the development of metabolic abnormalities of susceptible populations in the development of MetS and T2DM.
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Affiliation(s)
- Filipe Valvassori do Nascimento
- />Postgraduate Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, 2° andar, PPG Endocrinologia, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
| | - Vanessa Piccoli
- />Postgraduate Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, 2° andar, PPG Endocrinologia, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
| | - Mayara Abichequer Beer
- />Postgraduate Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, 2° andar, PPG Endocrinologia, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
| | - Anize Delfino von Frankenberg
- />Postgraduate Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, 2° andar, PPG Endocrinologia, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
| | - Daisy Crispim
- />Division of Endocrinology, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Prédio 12, 4° andar, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
- />Postgraduate Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, 2° andar, PPG Endocrinologia, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
| | - Fernando Gerchman
- />Division of Endocrinology, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Prédio 12, 4° andar, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
- />Postgraduate Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2400, 2° andar, PPG Endocrinologia, Bairro Santana, Porto Alegre, RS 90035-003 Brazil
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Woods C, Tomlinson JW. The Dehydrogenase Hypothesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015. [DOI: 10.1007/978-1-4939-2895-8_16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Dube S, Norby BJ, Pattan V, Carter RE, Basu A, Basu R. 11β-hydroxysteroid dehydrogenase types 1 and 2 activity in subcutaneous adipose tissue in humans: implications in obesity and diabetes. J Clin Endocrinol Metab 2015; 100:E70-6. [PMID: 25303491 PMCID: PMC4283013 DOI: 10.1210/jc.2014-3017] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
CONTEXT The role of 11β-hydroxysteroid dehydrogenase types 1 (11β-HSD-1) and 2 (11β-HSD-2) enzymes in sc adipose tissue is controversial. OBJECTIVE The objective of the study was to determine the activity of 11β-HSD-1 and -2 enzymes in the abdominal and leg sc adipose tissue in obesity and diabetes. DESIGN 11β-HSD-1 and -2 enzyme activities in abdominal and leg sc adipose tissue were measured by infusing [2,2,4,6,6,12,12-(2)H7] cortisone (D7 cortisone) and [9,12,12-(2)H3] cortisol (D3 cortisol) via microdialysis catheters placed in sc fat depots. SETTING The study was conducted at the Mayo Clinic Clinical Research Unit. PARTICIPANTS Lean nondiabetic (n = 13), overweight/obese nondiabetic (n = 15), and overweight/obese participants with type 2 diabetes mellitus (n = 15) participated in the study. MAIN OUTCOME MEASURES The conversion of infused D7 cortisone to D7 cortisol (via 11β-HSD reductase activity) and D3 cortisol to D3 cortisone (via 11β-HSD dehydrogenase activity) in sc adipose tissue. RESULTS Enrichment of D7 cortisone and D3 cortisol were similar in the effluents from both sites in all groups. D3 cortisone enrichment did not differ in the three cohorts, indicating that 11β-HSD-2 enzyme activity (conversion of cortisol to cortisone) occurs equally in all groups. However, D7 cortisol enrichment was detectable in abdominal sc fat of overweight/obese participants with type 2 diabetes mellitus only, implying 11β-HSD-1 reductase activity (conversion of cortisone to cortisol) occurs in obese subjects with type 2 diabetes. CONCLUSIONS There is conversion of cortisone to cortisol via the 11β-HSD-1 enzyme pathway in abdominal sc fat depots in overweight/obese participants with type 2 diabetes mellitus. This observation has significant implications for developing tissue-specific 11β-HSD-1 inhibitors in type 2 diabetes mellitus.
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Affiliation(s)
- Simmi Dube
- Endocrine Research Unit (S.D., B.J.N., V.P., A.B., R.B.), Division of Endocrinology, Diabetes, Metabolism, and Nutrition, and Division of Biomedical Statistics and Informatics (R.E.C.), Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905
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Di Luigi L, Botrè F, Sabatini S, Sansone M, Mazzarino M, Guidetti L, Baldari C, Lenzi A, Caporossi D, Romanelli F, Sgrò P. Acute effects of physical exercise and phosphodiesterase's type 5 inhibition on serum 11β-hydroxysteroid dehydrogenases related glucocorticoids metabolites: a pilot study. Endocrine 2014; 47:952-8. [PMID: 24532078 DOI: 10.1007/s12020-014-0185-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 01/25/2014] [Indexed: 12/11/2022]
Abstract
Endogenous glucocorticoids (GC) rapidly increase after acute exercise, and the phosphodiesterase's type 5 inhibitor (PDE5i) tadalafil influences this physiological adaptation. No data exist on acute effects of both acute exercise and PDE5i administration on 11β-hydroxysteroid dehydrogenases (11β-HSDs)-related GC metabolites. We aimed to investigate the rapid effects of exercise on serum GC metabolites, with and without tadalafil administration. A double blind crossover study was performed in eleven healthy male volunteers. After the volunteers randomly received a short-term administration of placebo or tadalafil (20 mg/die for 2 days), a maximal exercise test to exhaustion on cycle ergometer was performed. Then, after a 2-week washout period, the volunteers were crossed over. Blood samples were collected before starting exercise and at 5 and 30 min of recovery (+5-Rec, +30-Rec). Serum ACTH, corticosterone (Cn), cortisol (F), cortisone (E), tetrahydrocortisol (THF), tetrahydrocortisone (THE), cortols, cortolones and respective ratios were evaluated. Pre-Ex THF was higher after tadalafil. Exercise increased ACTH, Cn, F, E, THE, cortols and cortolones after both placebo and tadalafil, and THF after placebo. The F/E ratio increased at +5-Rec and decreased at +30-Rec after placebo. Compared to placebo, after tadalafil lower ACTH, F and Cn, higher THF/F and THE/E, and not E (at +5-Rec) and F/E modifications were observed. Acute exercise rapidly influences serum GC metabolites concentrations. Tadalafil influences both GC adaptation and 11β-HSDs activity during acute exercise. Additional researches on the effects of both exercise and PDE5i on tissue-specific 11β-HSDs activity at rest and during physiological adaptation are warranted.
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Affiliation(s)
- Luigi Di Luigi
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis, 15, 00135, Rome, Italy,
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Tirabassi G, Boscaro M, Arnaldi G. Harmful effects of functional hypercortisolism: a working hypothesis. Endocrine 2014; 46:370-86. [PMID: 24282037 DOI: 10.1007/s12020-013-0112-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 10/31/2013] [Indexed: 01/15/2023]
Abstract
Functional hypercortisolism (FH) is caused by conditions able to chronically activate hypothalamic-pituitary-adrenal axis and usually occurs in cases of major depression, anorexia nervosa, bulimia nervosa, alcoholism, diabetes mellitus, simple obesity, polycystic ovary syndrome, obstructive sleep apnea syndrome, panic disorder, generalized anxiety disorder, shift work, and end-stage renal disease. Most of these states belong to pseudo-Cushing disease, a condition which is difficult to distinguish from Cushing's syndrome and characterized not only by biochemical findings but also by objective ones that can be attributed to hypercortisolism (e.g., striae rubrae, central obesity, skin atrophy, easy bruising, etc.). This hormonal imbalance, although reversible and generally mild, could mediate some systemic complications, mainly but not only of a metabolic/cardiovascular nature, which are present in these states and are largely the same as those present in Cushing's syndrome. In this review we aim to discuss the evidence suggesting the emerging negative role for FH.
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Affiliation(s)
- Giacomo Tirabassi
- Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, Polytechnic University of Marche, Ancona, Italy
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Cuzzola A, Mazzini F, Petri A. A comprehensive study for the validation of a LC–MS/MS method for the determination of free and total forms of urinary cortisol and its metabolites. J Pharm Biomed Anal 2014; 94:203-9. [DOI: 10.1016/j.jpba.2014.02.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 02/07/2014] [Accepted: 02/09/2014] [Indexed: 11/28/2022]
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Geer EB, Islam J, Buettner C. Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrinol Metab Clin North Am 2014; 43:75-102. [PMID: 24582093 PMCID: PMC3942672 DOI: 10.1016/j.ecl.2013.10.005] [Citation(s) in RCA: 257] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Glucocorticoids (GCs) are critical in the regulation of the stress response, inflammation and energy homeostasis. Excessive GC exposure results in whole-body insulin resistance, obesity, cardiovascular disease, and ultimately decreased survival, despite their potent anti-inflammatory effects. This apparent paradox may be explained by the complex actions of GCs on adipose tissue functionality. The wide prevalence of oral GC therapy makes their adverse systemic effects an important yet incompletely understood clinical problem. This article reviews the mechanisms by which supraphysiologic GC exposure promotes insulin resistance, focusing in particular on the effects on adipose tissue function and lipid metabolism.
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Affiliation(s)
- Eliza B Geer
- Division of Endocrinology, Mount Sinai Medical Center, One Gustave Levy Place, Box 1055, New York, NY 10029, USA.
| | - Julie Islam
- Division of Endocrinology and Metabolism, Beth Israel Medical Center, 317 East 17th Street, 8th Floor, New York, NY 10003, USA
| | - Christoph Buettner
- Division of Endocrinology, Mount Sinai Medical Center, One Gustave Levy Place, Box 1055, New York, NY 10029, USA
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Takaya J, Yamanouchi S, Kaneko K. A calcium-deficient diet in rat dams during gestation and nursing affects hepatic 11β-hydroxysteroid dehydrogenase-1 expression in the offspring. PLoS One 2014; 9:e84125. [PMID: 24427280 PMCID: PMC3888454 DOI: 10.1371/journal.pone.0084125] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 11/12/2013] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Prenatal malnutrition can affect the phenotype of offspring by changing epigenetic regulation of specific genes. Several lines of evidence demonstrate that calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. We hypothesized that pregnant female rats fed a Ca-deficient diet would have offspring with altered hepatic glucocorticoid-related gene expression and that lactation would modify these alterations. METHODOLOGY We determined the effects of Ca deficiency during pregnancy and/or lactation on hepatic 11β-hydroxysteroid dehydrogenase-1 (Hsd11b1) expression in offspring. Female Wistar rats consumed either a Ca-deficient (D: 0.008% Ca) or control (C: 0.90% Ca) diet ad libitum from 3 weeks preconception to 21 days postparturition. On postnatal day 1, pups were cross-fostered to the same or opposite dams and divided into the following four groups: CC, DD, CD, and DC (first letter: original mother's diet; second letter: nursing mother's diet). All offspring were fed a control diet beginning at weaning (day 21) and were killed on day 200 ± 7. Serum insulin and adipokines in offspring were measured using ELISA kits. PRINCIPAL FINDINGS In males, mean levels of insulin, glucose, and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were higher in the DD and DC groups than in the CC group. We found no difference in HOMA-IR between the CC and CD groups in either males or females. Expression of Hsd11b1 was lower in male DD rats than in CC rats. Hsd11b1 expression in male offspring nursed by cross-fostered dams was higher than that in those nursed by dams fed the same diet; CC vs. CD and DD vs. DC. In females, Hsd11b1 expression in DC rats was higher than that in CC rats. CONCLUSIONS These findings indicated that maternal Ca restriction during pregnancy and/or lactation alters postnatal growth, Hsd11b1 expression, and insulin resistance in a sex-specific manner.
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Affiliation(s)
- Junji Takaya
- Department of Pediatrics, Kansai Medical University, Moriguchi, Osaka, Japan
- * E-mail:
| | - Sohsaku Yamanouchi
- Department of Pediatrics, Kansai Medical University, Moriguchi, Osaka, Japan
| | - Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, Moriguchi, Osaka, Japan
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Annaloro C, Airaghi L, Saporiti G, Onida F, Cortelezzi A, Deliliers GL. Metabolic syndrome in patients with hematological diseases. Expert Rev Hematol 2014; 5:439-58. [DOI: 10.1586/ehm.12.35] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Bays H, Blonde L, Rosenson R. Adiposopathy: how do diet, exercise and weight loss drug therapies improve metabolic disease in overweight patients? Expert Rev Cardiovasc Ther 2014; 4:871-95. [PMID: 17173503 DOI: 10.1586/14779072.4.6.871] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
An increase in bodyweight is generally associated with an increased risk of excessive fat-related metabolic diseases (EFRMD), including Type 2 diabetes mellitus, hypertension and dyslipidemia. However, not all patients who are overweight have EFRMD, and not all patients with EFRMD are significantly overweight. The adipocentric paradigm provides the basis for a unifying, pathophysiological process whereby fat gain in susceptible patients leads to fat dysfunction ('sick fat'), and wherein pathological abnormalities in fat function (adiposopathy) are more directly related to the onset of EFRMD than increases in fat mass (adiposity) alone. But just as worsening fat function worsens EFRMD, improved fat function improves EFRMD. Peroxisome proliferator-activated receptor-gamma agonists increase the recruitment, proliferation and differentiation of preadipocytes ('healthy fat') and cause apoptosis of hypertrophic and dysfunctional (including visceral) adipocytes resulting in improved fat function and improved metabolic parameters associated with EFRMD. Weight loss interventions, such as a hypocaloric diet and physical exercise, in addition to agents such as orlistat, sibutramine and cannabinoid receptor antagonists, may have favorable effects upon fat storage (lipogenesis and fat distribution), nutrient metabolism (such as free fatty acids), favorable effects upon adipose tissue factors involved in metabolic processes and inflammation, and enhanced 'cross-talk' with other major organ systems. In some cases, weight loss therapeutic agents may even affect metabolic parameters and adipocyte function independently of weight loss alone, suggesting that the benefit of these agents in improving EFRMD may go beyond their efficacy in weight reduction. This review describes how adiposopathy interventions may affect fat function, and thus improve EFRMD.
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Affiliation(s)
- Harold Bays
- L-MARC Research Center, Medical Director/President, 3288 Illinois Avenue, Louisville, KY 40213, USA.
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Scott JS, Goldberg FW, Turnbull AV. Medicinal Chemistry of Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1). J Med Chem 2013; 57:4466-86. [DOI: 10.1021/jm4014746] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- James S. Scott
- AstraZeneca Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K
| | - Frederick W. Goldberg
- AstraZeneca Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K
| | - Andrew V. Turnbull
- AstraZeneca Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K
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Harno E, Cottrell EC, Yu A, DeSchoolmeester J, Gutierrez PM, Denn M, Swales JG, Goldberg FW, Bohlooly-Y M, Andersén H, Wild MJ, Turnbull AV, Leighton B, White A. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors still improve metabolic phenotype in male 11β-HSD1 knockout mice suggesting off-target mechanisms. Endocrinology 2013; 154:4580-93. [PMID: 24169553 PMCID: PMC4192288 DOI: 10.1210/en.2013-1613] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 10/11/2013] [Indexed: 12/23/2022]
Abstract
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)-fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting "off-target" mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11β-HSD1 inhibitors occurs via 11β-HSD1-independent pathways, and only limited efficacy is achievable from selective 11β-HSD1 inhibition. These data challenge the concept that inhibition of 11β-HSD1 is likely to produce a "step-change" treatment for diabetes and/or obesity.
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Affiliation(s)
- Erika Harno
- Faculty of Life Sciences and Faculty of Medical and Human Sciences, AV Hill Building, University of Manchester, Manchester, M13 9PT, United Kingdom.
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Tarantino G, Finelli C. Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease. World J Gastroenterol 2013; 19:6735-6743. [PMID: 24187449 PMCID: PMC3812473 DOI: 10.3748/wjg.v19.i40.6735] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 09/10/2013] [Accepted: 09/16/2013] [Indexed: 02/06/2023] Open
Abstract
Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of patients with Cushing's syndrome have hepatic steatosis. Aiming at clarifying the reasons whereby patients suffering from Cushing's syndrome - a condition characterized by profound metabolic changes - present low prevalence of hepatic steatosis, the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome. They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing's syndrome could result from the inhibition of the so-called low-grade chronic-inflammation, mainly mediated by Interleukin 6, due to an excess of cortisol, a hormone characterized by an anti-inflammatory effect. The Cushing's syndrome, speculatively considered as an in vivo model of the hepatic steatosis, could also help clarify the mechanisms of non alcoholic fatty liver disease.
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Majumdar SK, Inzucchi SE. Investigational anti-hyperglycemic agents: the future of type 2 diabetes therapy? Endocrine 2013; 44:47-58. [PMID: 23354728 DOI: 10.1007/s12020-013-9884-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Accepted: 01/11/2013] [Indexed: 12/18/2022]
Abstract
As the pandemic of type 2 diabetes spreads globally, clinicians face many challenges in treating an increasingly diverse patient population varying in age, comorbidities, and socioeconomic status. Current therapies for type 2 diabetes are often unable to alter the natural course of the disease and provide durable glycemic control, and side effects in the context of individual patient characteristics often limit treatment choices. This often results in the progression to insulin use and complex regimens that are difficult to maintain. Therefore, a number of agents are being developed to better address the pathogenesis of type 2 diabetes and to overcome limitations of current therapies. The hope is to provide more options for glucose lowering and complication reduction with less risk for hypoglycemia and other adverse effects. These agents include newer incretin-based therapies and PPAR agonists, as well as new therapeutic classes such as sodium-coupled glucose cotransporter 2 inhibitors, free fatty acid receptor agonists, 11-β-hydroxysteroid dehydrogenase type 1 inhibitors, glucokinase activators, and several others that may enter clinical use over the next decade. Herein we review these agents that are advancing through clinical trials and describe the rationale behind their use, mechanisms of action, and potential for glucose lowering, as well as what is known of their limitations.
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Affiliation(s)
- Sachin K Majumdar
- Section of Endocrinology, Department of Medicine, Bridgeport Hospital, Yale New Haven Health, 267 Grant Street, Bridgeport, CT 06610-0120, USA.
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Gathercole LL, Lavery GG, Morgan SA, Cooper MS, Sinclair AJ, Tomlinson JW, Stewart PM. 11β-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects. Endocr Rev 2013; 34:525-55. [PMID: 23612224 DOI: 10.1210/er.2012-1050] [Citation(s) in RCA: 136] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.
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Affiliation(s)
- Laura L Gathercole
- School of Clinical and Experimental Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston B15 2TH, United Kingdom
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44
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Gibbs JP, Emery MG, McCaffery I, Smith B, Gibbs MA, Akrami A, Rossi J, Paweletz K, Gastonguay MR, Bautista E, Wang M, Perfetti R, Daniels O. Population Pharmacokinetic/Pharmacodynamic Model of Subcutaneous Adipose 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Activity After Oral Administration of AMG 221, a Selective 11β-HSD1 Inhibitor. J Clin Pharmacol 2013; 51:830-41. [DOI: 10.1177/0091270010374470] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Han Y, Staab-Weijnitz CA, Xiong G, Maser E. Identification of microRNAs as a potential novel regulatory mechanism in HSD11B1 expression. J Steroid Biochem Mol Biol 2013; 133:129-39. [PMID: 23017470 DOI: 10.1016/j.jsbmb.2012.09.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 08/20/2012] [Accepted: 09/07/2012] [Indexed: 11/23/2022]
Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1, gene HSD11B1) converts glucocorticoid receptor-inert cortisone to receptor-active cortisol. Multiple evidence supports a causal role for 11β-HSD1 in the current obesity epidemic. In obese, HSD11B1 expression is increased in adipose tissue but typically decreased in liver, and the underlying tissue-specific mechanisms are largely unknown. In this context, we investigated a potential role of microRNAs (miRNAs). We used several miRNA target prediction tools to identify possible candidates and a publicly available miRNA expression atlas to further select candidates expressed in hepatocytes. Using a dual luciferase reporter assay, we identified three potential miRNAs, hsa-miR-340, -561 and -579, as potential negative regulators of HSD11B1 expression. Disruption of the corresponding microRNA response elements abolished repression of luciferase activity for hsa-miR-561 and -579, but not for hsa-miR-340. Furthermore, levels of firefly luciferase mRNA were not changed by miR-561 and -579, indicating a mechanism based on translational repression rather than mRNA degradation. Finally, we were able to detect both, miR-561 and -579, in human total liver RNA by reverse-transcription-polymerase chain reaction (RT-PCR). According to the presented results, miR-561 and -579 are likely to be involved in the tissue-specific regulation of HSD11B1 expression. Moreover, literature findings and a pathway enrichment analysis support a potential role of these two miRNAs in glucocorticoid metabolism and signalling and associated diseases.
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Affiliation(s)
- Yanyan Han
- Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, 24105 Kiel, Germany
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Chen G, Li S, Dong X, Bai Y, Chen A, Yang S, Fang M, Zamaratskaia G, Doran O. Investigation of testosterone, androstenone, and estradiol metabolism in HepG2 cells and primary culture pig hepatocytes and their effects on 17βHSD7 gene expression. PLoS One 2012; 7:e52255. [PMID: 23300627 PMCID: PMC3530596 DOI: 10.1371/journal.pone.0052255] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2012] [Accepted: 11/09/2012] [Indexed: 11/18/2022] Open
Abstract
Steroid metabolism is important in various species. The accumulation of androgen metabolite, androstenone, in pig adipose tissue is negatively associated with pork flavor, odour and makes the meat unfit for human consumption. The 17β-hydroxysteroid dehydrogenase type 7 (17βHSD7) expressed abundantly in porcine liver, and it was previously suggested to be associated with androstenone levels. Understanding the enzymes and metabolic pathways responsible for androstenone as well as other steroids metabolism is important for improving the meat quality. At the same time, metabolism of steroids is known to be species- and tissue-specific. Therefore it is important to investigate between-species variations in the hepatic steroid metabolism and to elucidate the role of 17βHSD7 in this process. Here we used an effective methodological approach, liquid chromatography coupled with mass spectrometry, to investigate species-specific metabolism of androstenone, testosterone and beta-estradiol in HepG2 cell line, and pig cultured hepatocytes. Species- and concentration-depended effect of steroids on 17βHSD7 gene expression was also investigated. It was demonstrated that the investigated steroids can regulate the 17βHSD7 gene expression in HepG2 and primary cultured porcine hepatocytes in a concentration-dependent and species-dependent pattern. Investigation of steroid metabolites demonstrated that androstenone formed a 3′-hydroxy compound 3β-hydroxy-5α-androst-16-ene. Testosterone was metabolized to 4-androstene-3,17-dione. Estrone was found as the metabolite for β-estradiol. Inhibition study with 17βHSD inhibitor apigenin showed that apigenin didn’t affect androstenone metabolism. Apigenin at high concentration (50 µM) tends to inhibit testosterone metabolism but this inhibition effect was negligible. Beta-estradiol metabolism was notably inhibited with apigenin at high concentration. The study also established that the level of testosterone and β-estradiol metabolites was markedly increased after co-incubation with high concentration of apigenin. This study established that 17βHSD7 is not the key enzyme responsible for androstenone and testosterone metabolism in porcine liver cells.
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Affiliation(s)
- Gang Chen
- Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Sicong Li
- Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Xinxing Dong
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Ying Bai
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Ailiang Chen
- Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Shuming Yang
- Key Laboratory of Agro-Product Quality and Safety, Institute of Quality Standards and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Meiying Fang
- College of Animal Science and Technology, China Agricultural University, Beijing, China
- * E-mail:
| | - Galia Zamaratskaia
- Department of Food Science, Swedish University of Agriculture Science (SLU), Uppsala, Sweden
| | - Olena Doran
- Centre for Research in Biosciences, Faculty of Health and Life Sciences, University of the West of England, Bristol, United Kingdom
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Pereira CD, Azevedo I, Monteiro R, Martins MJ. 11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Diabetes Obes Metab 2012; 14:869-81. [PMID: 22321826 DOI: 10.1111/j.1463-1326.2012.01582.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11β-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11β-HSD1 modulation. We intend to review and discuss 11β-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases.
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Affiliation(s)
- C D Pereira
- Department of Biochemistry (U38/FCT), Faculty of Medicine, University of Porto, Portugal
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Janesick A, Blumberg B. Obesogens, stem cells and the developmental programming of obesity. INTERNATIONAL JOURNAL OF ANDROLOGY 2012; 35:437-48. [PMID: 22372658 PMCID: PMC3358413 DOI: 10.1111/j.1365-2605.2012.01247.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Obesogens are chemicals that directly or indirectly lead to increased fat accumulation and obesity. Obesogens have the potential to disrupt multiple metabolic signalling pathways in the developing organism that can result in permanent changes in adult physiology. Prenatal or perinatal exposure to obesogenic endocrine disrupting chemicals has been shown to predispose an organism to store more fat from the beginning of its life. For example, excess oestrogen or cortisol exposure in the womb or during early life resulted in an increased susceptibility to obesity and metabolic syndrome later in life. This review focuses on the effects of environmental chemicals, such as the model obesogen, tributyltin (TBT), on the development of obesity. We discuss evidence linking the obesogenic effects of TBT with its ability to activate the peroxisome proliferator-activated receptor gamma and stimulate adipogenesis. We also discuss how TBT and other environmental obesogens may lead to epigenetic changes that predispose exposed individuals to subsequent weight gain and obesity. This suggests that humans, who have been exposed to obesogenic chemicals during sensitive windows of development, might be pre-programmed to store increased amounts of fat, resulting in a lifelong struggle to maintain a healthy weight and exacerbating the deleterious effects of poor diet and inadequate exercise.
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Affiliation(s)
- A Janesick
- Departments of Developmental and Cell Biology, University of California, Irvine, CA 92697-2300, USA.
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Liver upregulation of genes involved in cortisol production and action is associated with metabolic syndrome in morbidly obese patients. Obes Surg 2012; 22:478-86. [PMID: 21964795 DOI: 10.1007/s11695-011-0524-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which converts cortisone (inactive) to cortisol, is downregulated in obesity. However, this compensation fails in obese with metabolic abnormalities, such as diabetes. To further characterize the tissue-specific cortisol regeneration in obesity, we have investigated the mRNA expression of genes related to local cortisol production, i.e., 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PDH) and cortisol action, glucocorticoid receptor (GR) and a cortisol target gene, phosphoenolpyruvate carboxykinase (PEPCK) in the liver, and visceral (VAT) and subcutaneous (SAT) adipose tissues from morbidly obese patients with and without metabolic syndrome (MS). METHODS Fifty morbidly obese patients undergoing bariatric surgery, 14 men (mean age, 41.3 ± 3.5 years; BMI, 48.0 ± 3.6 kg/m(2)) and 36 women (mean age, 44.6 ± 1.9 years; BMI, 44.9 ± 1.2 kg/m(2)), were classified as having MS (MS+, n = 20) or not (MS-, n = 30). Tissue mRNA levels were measured by real-time polymerase chain reaction. RESULTS Hepatic mRNA levels of these genes were higher in obese patients with MS (11β-HSD1, P = 0.002; H6PDH, P = 0.043; GR, P = 0.033; PEPCK, P = 0.032) and positively correlated with the number of clinical characteristics that define the MS. The expression of the four genes positively correlated among them. In contrast to the liver, these genes were not differently expressed in VAT or SAT, when MS+ and MS- obese patients were compared. CONCLUSIONS Coordinated liver-specific upregulation of genes involved in local cortisol regeneration and action support the concept that local hepatic hypercortisolism contributes to development of MS in morbidly obese patients.
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Czegle I, Csala M, Mandl J, Benedetti A, Karádi I, Bánhegyi G. G6PT-H6PDH-11βHSD1 triad in the liver and its implication in the pathomechanism of the metabolic syndrome. World J Hepatol 2012; 4:129-38. [PMID: 22567185 PMCID: PMC3345537 DOI: 10.4254/wjh.v4.i4.129] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Revised: 11/16/2011] [Accepted: 04/24/2012] [Indexed: 02/06/2023] Open
Abstract
The metabolic syndrome, one of the most common clinical conditions in recent times, represents a combination of cardiometabolic risk determinants, including central obesity, glucose intolerance, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease and hypertension. Prevalence of the metabolic syndrome is rapidly increasing worldwide as a consequence of common overnutrition and consequent obesity. Although a unifying picture of the pathomechanism is still missing, the key role of the pre-receptor glucocorticoid activation has emerged recently. Local glucocorticoid activation is catalyzed by a triad composed of glucose-6-phosphate-transporter, hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1 in the endoplasmic reticulum. The elements of this system can be found in various cell types, including adipocytes and hepatocytes. While the contribution of glucocorticoid activation in adipose tissue to the pathomechanism of the metabolic syndrome has been well established, the relative importance of the hepatic process is less understood. This review summarizes the available data on the role of the hepatic triad and its role in the metabolic syndrome, by confronting experimental findings with clinical observations.
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Affiliation(s)
- Ibolya Czegle
- Ibolya Czegle, István Karádi, 3rd Department of Internal Medicine, Semmelweis University, 1125 Budapest, Hungary
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