Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

Morton, Nicholas M.

doi:10.1016/j.mce.2009.09.024

Cited by 149 publications

(165 citation statements)

References 153 publications

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“…Many tissues, including adipose tissue, can convert the inactive cortisol metabolite cortisone back to biologically active cortisol via the enzyme 11‐β‐hydroxysteroid dehydrogenase type 1 (11‐β‐HSD1), resulting in increased tissue and intracellular levels of cortisol 34, 42. Rodent models and human studies both demonstrate 11‐β‐HSD1 overexpression in adipose tissue and associations between increases in local and systemic cortisol and development of insulin dysregulation and diabetes in the Metabolic Syndrome in people 43, 44, 45, 46, 47…”

Section: Discussionmentioning

confidence: 99%

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses

Hart

Wochele

Norton

et al. 2016

Veterinary Internal Medicne

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BackgroundIncreased free cortisol fraction is associated with insulin dysregulation (ID) in people with Metabolic Syndrome and Cushing's Disease. Free cortisol has not been investigated in equine endocrine disorders.Hypotheses(1) In healthy horses, sex, age, body condition score (BCS), and season impact free cortisol; (2) free cortisol is increased in horses with Pituitary Pars Intermedia Dysfunction (PPID) or Equine Metabolic Syndrome (EMS).AnimalsFifty‐seven healthy horses; 40 horses and ponies with PPID (n = 20) or EMS (n = 20).MethodsProspective study. Serum collected seasonally from healthy animals and archived serum from PPID and EMS animals was analyzed for insulin, total and free cortisol concentrations, and free cortisol fraction (FCF). Linear mixed models were used to determine effects of age, sex, season, and BCS on hormones in controls. Hormone measurements were compared between disease groups and age‐ and season‐matched controls with t‐tests. EMS and hyperinsulinemic PPID animals were combined in an ID (hyperinsulinemia) group.ResultsFree cortisol concentrations were increased in overweight/obese controls (0.3 ± 0.1 μg/dL) compared to lean controls (0.2 ± 0.1 μg/dL; P = .017). Mean FCF was significantly higher in animals with PPID (8.8 ± 5.8 μg/dL, P = .005) or ID (8.8 ± 10.2 μg/dL, P = .039) than controls (5.0 ± 0.9 μg/dL), but total cortisol concentrations were similar (P ≥ .350) (PPID: 4.2 ± 4.3 μg/dL; ID: 5.0 ± 4.5 μg/dL; controls: 4.6 ± 1.7 and 5.1 ± 2.1 μg/dL).Conclusions and Clinical ImportanceIncreased FCF is associated with obesity in healthy horses and with ID (hyperinsulinemia) in horses and ponies with endocrine disease. Decreased plasma cortisol‐binding capacity could be a component of these endocrine disorders in horses.

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Section: Discussionmentioning

confidence: 99%

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses

Hart

Wochele

Norton

et al. 2016

Veterinary Internal Medicne

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“…Various cortisol-regulated physiological processes depend on glucocorticoid receptor (GR), which is activated upon cortisol binding (20,21). On the pre-receptor level, cortisol action is additionally regulated by the intracellular enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) (20,22,23) that comes in two isoforms: type 1 (11β-HSD1) and type 2 (11β-HSD2). Type 1 catalyses the conversion of the inactive form cortisone into active cortisol, while type 2 converts active cortisol into its inactive form cortisone to lower the levels of active glucocorticoid and to inhibit cortisol activity (22,24).…”

Section: Endocrine Factors and Metsmentioning

confidence: 99%

“…Together with excess glucocorticoid secretion by the HPA axis (through increased peripheral glucocorticoidal signalling and cortisol reactivation) this may contribute to higher cortisol level observed in MetS. Centrally distributed fat or central obesity is characteristic of MetS, and adipose tissue not only stores fat but works as an endocrine organ, as it produces pro-infl ammatory cytokines (adipokines) such as tumour necrosis factor α (TNFα) and interleukin-6 (IL-6) (1,23). In other terms, MetS is a state of chronic, low-grade infl ammation (23).…”

Section: Endocrine Factors and Metsmentioning

confidence: 99%

“…Centrally distributed fat or central obesity is characteristic of MetS, and adipose tissue not only stores fat but works as an endocrine organ, as it produces pro-infl ammatory cytokines (adipokines) such as tumour necrosis factor α (TNFα) and interleukin-6 (IL-6) (1,23). In other terms, MetS is a state of chronic, low-grade infl ammation (23). How does this explain the involvement of cortisol?…”

Section: Endocrine Factors and Metsmentioning

confidence: 99%

“…For two, central obesity can affect insulin action, as adipose tissue releases TNF-α, IL-6, and free fatty acids, which block normal insulin signalling pathway (2,18). In addition, adiposity is characterised by low levels of adiponectin (a tissue-specifi c circulating adipokine with insulinsensitising and anti-atherogenic properties), which contributes to systematic insulin resistance (18, 15, 23). Long-term elevation of insulin levels causes desensitisation of insulin receptors, which in turn may lead to hyperglycaemia, smooth muscle hypertrophy, hypertension and many other physiological disorders (33).…”

Section: Endocrine Factors and Metsmentioning

confidence: 99%

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Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

Slanovic-Kuzmanović

Kos

Domijan

2013

Archives of Industrial Hygiene and Toxicology

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Metabolic syndrome (MetS) is a chronic, multi-component disease characterised by central obesity, hyperglycaemia, dyslipidaemia, and hypertension. Since MetS leads to type 2 diabetes, cardiovascular disease, development of certain cancers, and eventually to premature death, it is not surprising that it draws the attention of scientists around the world. The aetiopathology of MetS is complex and still not fully understood. This review focuses on the role of endocrine factors such as cortisol and insulin in the development of MetS. It also takes a look at some of the contributing lifestyle and genetic factors as well as at the current knowledge about its treatment. Slanovic-Kuzmanović Z, et al. ENDOCRINE, LIFESTYLE, AND GENETIC RISK FACTORS FOR METS Arh Hig Rada Toksikol 2013;64:581-591 Metabolic syndrome (MetS) is a modern disease characterised by the clustering of abnormalities such as central obesity, high levels of fasting glucose and triglyceride, low levels of high-density lipoprotein (HDL), and hypertension (1, 2). The prevalence of MetS has been increasing over the past two decades (1), and recent studies (3-5) suggest that it has reached 25 % among the adults worldwide. Reports vary from 21.9 % in men and 16.8 % in women in north-eastern Italy, and 24.6 % in alcohol-dependent male patients in north India to 31.25 % in rural women from Bangladesh. A small study on salt intake with 92 participants in Croatia reports the prevalence of 31.5 % (6). Among obese adolescents and pubertal children, the prevalence of MetS could be around 15 %, judging by the reports of 14 % in Danish obese adolescents (7) and of 9.7 % to 41.2 % in obese pubertal children and 8.3 % to 34.2 % in obese prepubertal children in Spain (8). KEY WORDS: cardiovascular diseases, circadian rhythm, cortisol, hyperglycaemia, hypertension, insulin, MetS, type 2 diabetes

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Design and Synthesis of (R)‐1‐Arylsulfonylpiperidine‐2‐carboxamides as 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitors

Xia

Liu

et al. 2013

ChemMedChem

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R adamantly beats S: 11β-HSD1 is a target for treating metabolic syndrome. The R isomer 5 was selected as a starting point for optimization and SAR studies. Inhibitor 8 w emerged after several rounds of optimization, showing cross-species inhibition of human and mouse 11β-HSD1. It also displays a good DMPK profile in vitro, and was advanced to PK/PD evaluations in vivo. The results confirmed its dose-dependent activity in mice.

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Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

Cited by 149 publications

References 153 publications

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses

Effect of Age, Season, Body Condition, and Endocrine Status on Serum Free Cortisol Fraction and Insulin Concentration in Horses

Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome

Design and Synthesis of (R)‐1‐Arylsulfonylpiperidine‐2‐carboxamides as 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitors

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