Changes in Adenosine 5′-Monophosphate-Activated Protein Kinase as a Mechanism of Visceral Obesity in Cushing’s Syndrome

Kola, Blerina; Lolli, Francesca; Arnaldi, Giorgio; Giacchetti, Gilberta; Boscaro, Marco; Grossman, Ashley; Korbonits, Márta

doi:10.1210/jc.2008-1297

Cited by 76 publications

(63 citation statements)

References 22 publications

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“…These can be combined with agents that increase postprandial insulin secretion such as sulphonylureas and meglitinides. The effect of metformin (and possibly thiazolidinediones) on fat tissue and other organ AMP-activated protein kinases (AMPK) could be beneficial (44,45). Pioglitazone may have a potential negative effect on heart and bone (46).…”

Section: Gcs and Glucose Metabolismmentioning

confidence: 99%

Metabolic comorbidities in Cushing's syndrome

Ferraú

Korbonits

2015

European Journal of Endocrinology

149

121

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Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall.

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Section: Gcs and Glucose Metabolismmentioning

confidence: 99%

Metabolic comorbidities in Cushing's syndrome

Ferraú

Korbonits

2015

European Journal of Endocrinology

149

121

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“…is hypothesis is based on the simple observation that patients with Cushing's syndrome develop central obesity, which improves with the resolution of hypercortisolism [10,11].…”

confidence: 99%

“…Cross-sectional studies showed that morning cortisol levels are signi cantly correlated with the symptoms of metabolic syndrome, such as visceral obesity, high blood pressure and a poor lipid pro le [3][4][5]. Further studies suggest that metabolic syndrome is a less profound form of Cushing's syndrome, which is characterized by a rise in serum cortisol levels [4,[6][7][8][9].is hypothesis is based on the simple observation that patients with Cushing's syndrome develop central obesity, which improves with the resolution of hypercortisolism [10,11].It is known that men with metabolic syndrome are more frequently a ected with android obesity. Central fat distribution is signi cantly associated with increased cortisol levels [12,13], so it could be hypothesized that men with metabolic syndrome have a higher serum cortisol levels, due to increased abdominal obesity compared with women.…”

mentioning

confidence: 99%

Association of serum cortisol levels with parameters of metabolic syndrome in men and women

Esteghamati¹,

Morteza²,

Khalilzadeh³

et al. 2011

CIM

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Association of serum cortisol levels with parameters of metabolic syndrome in men and women Abstract Purpose: Central fat distribution is signi cantly associated with an increased cortisol levels. We hypothesized that men with metabolic syndrome have a higher serum cortisol levels compared to women. e purpose of this study was to compare serum cortisol levels, and its correlation with serum leptin levels, between men and women with and without metabolic syndrome.Methods: A cross sectional study was performed with 120 untreated patients with metabolic syndrome and 165 healthy volunteers as controls. Serum lipid pro le, fasting blood sugar, insulin, cortisol and leptin levels were measured for both groups.Results: Men with metabolic syndrome had a higher serum cortisol levels, while serum leptin levels were signi cantly higher in women. e higher serum cortisol level in men with metabolic syndrome was signi cant a er multiple adjustments for age, BMI and waist circumference (17.74±5.1 vs 14.07±4.3; p<0.05) using general linear model; however, these di erence were no longer signi cant when the waist-to-hip ratio was added as one of the adjustment factors (16.7±1.2 vs. 14.9±0.5; p<0.2). Serum cortisol levels was signicantly correlated with serum leptin (r=0.33, p<0.05), cholesterol (r=0.35, p<0.05), triglyceride (r=0.25, p<0.05), waist circumference (r=0.41, p<0.01) and waist-to-hip ratio (r=0.32, p<0.01) in women with metabolic syndrome, a er controlling for age and BMI.Conclusion: Serum cortisol levels are signi cantly higher in men with metabolic syndrome. is e ect is independent of waist circumference. ORIGINAL RESEARCH © 2011 CIMClin In E131 Metabolic syndrome is a cluster of metabolic risk factors associated with cardiovascular disease and type 2 diabetes [1]. e major components of metabolic syndrome include excess abdominal fat, dyslipidemia, hypertension, hyperglycemia and increased in ammatory state [1]. For any given body mass index (BMI), mortality is higher if fat is distributed centrally, which is the major component of metabolic syndrome [2]. Cross-sectional studies showed that morning cortisol levels are signi cantly correlated with the symptoms of metabolic syndrome, such as visceral obesity, high blood pressure and a poor lipid pro le [3][4][5]. Further studies suggest that metabolic syndrome is a less profound form of Cushing's syndrome, which is characterized by a rise in serum cortisol levels [4,[6][7][8][9].is hypothesis is based on the simple observation that patients with Cushing's syndrome develop central obesity, which improves with the resolution of hypercortisolism [10,11].It is known that men with metabolic syndrome are more frequently a ected with android obesity. Central fat distribution is signi cantly associated with increased cortisol levels [12,13], so it could be hypothesized that men with metabolic syndrome have a higher serum cortisol levels, due to increased abdominal obesity compared with women. On the other hand, adipose tissue is known as an endocrine organ, producing a number...

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“…Several physiological and pharmacological stimuli have been reported to stimulate rodent adipose tissue AMPK, including exercise, starvation, troglitazone and adrenaline (epinephrine) [10,[18][19][20], whereas AMPK is inhibited in response to ghrelin, corticosterone and a high-fat diet [21][22][23] in vivo. However, only one study has investigated AMPK activity in human adipose in vivo; in this study, insulin-resistant patients with Cushing's syndrome exhibited reduced AMPK activity compared with controls [24].…”

Section: Introductionmentioning

confidence: 97%

AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study

et al. 2011

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Aims/hypothesis The hypoglycaemic actions of metformin have been proposed to be mediated by hepatic AMP-activated protein kinase (AMPK). As the effects of metformin and the role of AMPK in adipose tissue remain poorly characterised, we examined the effect of metformin on AMPK activity in adipose tissue of individuals with type 2 diabetes in a randomised glycaemia-controlled crossover study. Methods Twenty men with type 2 diabetes (aged 50-70 years) treated with diet, metformin or sulfonylurea alone were recruited from North Glasgow University National Health Service Trusts' diabetes clinics and randomised to either metformin or gliclazide for 10 weeks. Randomisation codes, generated by computer, were put into sealed envelopes and stored by the hospital pharmacist. Medication bottles were numbered, and allocation was done in sequence. The participants and investigators were blinded to group assignment. At the end of each phase of therapy adipose biopsy, AMPK activity (primary endpoint) and levels of lipid metabolism and signalling proteins were assessed. In parallel, the effect of metformin on AMPK and insulinsignalling pathways was investigated in 3T3-L1 adipocytes. Results Ten participants were initially randomised to metformin and subsequently crossed over to gliclazide, while ten participants were initially randomised to gliclazide and subsequently crossed over to metformin. No participants discontinued the intervention and the adipose tissue AMPK activity was analysed in all 20 participants. There were no adverse events or side effects in the study group. Adipose AMPK activity was increased following metformin compared with gliclazide therapy (0. ; p< 0.005), independent of AMPK level, glycaemia or plasma adiponectin concentrations. The increase was associated with reduced levels of acetyl-CoA carboxylase (ACC) protein and increased ACC Ser80 phosphorylation. In 3T3-L1 adipocytes, metformin reduced levels of ACC protein and stimulated phosphorylation of AMPK Thr172 and hormone-sensitive lipase Ser565. Conclusions These results provide the first evidence that metformin activates AMPK and reduces ACC protein levels in human adipose tissue in vivo. Future studies are required to assess the role of adipose AMPK activation in the pharmacological effects of metformin.Trial registration ISRCTN51336867

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Changes in Adenosine 5′-Monophosphate-Activated Protein Kinase as a Mechanism of Visceral Obesity in Cushing’s Syndrome

Abstract: Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushing's syndrome.

Cited by 76 publications

References 22 publications

Metabolic comorbidities in Cushing's syndrome

Metabolic comorbidities in Cushing's syndrome

Association of serum cortisol levels with parameters of metabolic syndrome in men and women

AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study

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