Activity of the hypothalamic–pituitary–adrenal axis in different obesity phenotypes

Pasquali, Renato; Vicennati, Valentina

doi:10.1038/sj.ijo.0801277

Cited by 121 publications

(77 citation statements)

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“…The time-limited nature of the hormonal response ensures that the accompanying behavioral, metabolic and immunosuppressive effects induced by CRH and cortisol are short-lived and therefore beneficial, with no adverse sequelae (Caldji et al 2000;Koob 1999;Sapolsky 2000a). However, over a lifetime, persons with enhanced stress responsivity experience bouts of inappropriate hypercortisolism resulting in insulin resistance, immuno-suppression, osteoporosis and hippocampal injury (Pasquali and Vicennati 2000;Sapolsky 2000b;Sapolsky 2000c). Among many of its actions, cortisol acts permissively to heighten the effects of catecholamines.…”

Section: Discussionmentioning

confidence: 99%

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

Wand

2002

Neuropsychopharmacology

230

167

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An A118G nucleotide exchange in exon 1 of the mu-opioid receptor causes an Asn40Asp substitution polymorphism in the receptor's extracellular domain. In vitro studies show that the Asp40 variant of the mu-opioid receptor binds ␤ -endorphin three times more avidly than the more commonStress threatens homeostasis and is counteracted by a series of physiological and behavioral responses that improve the chances for survival. A successful response to stress plays an important role in maintaining health and well-being. Abnormalities in the stress response heighten an individual's vulnerability to endocrine, metabolic, psychiatric, and immunological disorders (Kreek and Koob 1998; Bjorntorp and Rosmond 2000a,b;Chrousos 2000). The unique characteristics of an individual's stress response are the product of genetic and environmental determinants (Francis et al. 1999;Wust et al. 2000).Corticotropin releasing factor (CRF) neurons within the paraventricular nucleus of the hypothalamus initiate activation of the hypothalamic-pituitary-adrenal (HPA) axis (Bell et al. 1998 (Wand et al. 1998). Recently, a common A118G nucleotide exchange in exon 1 of the muopioid receptor has been identified that causes an Asn40Asp substitution polymorphism in the extracellular N-terminal domain of the mu-opioid receptor (Bergen et al. 1997;Wendel and Hoehe 1998). In vitro studies show that the Asp40 variant of the mu-opioid receptor binds ␤ -endorphin three times more avidly than the common Asn40 variant and also induces a 3-fold increase in agonist-induced activation of G protein-coupled potassium channels (Bond et al. 1998). Because the Asn40Asp substitution alters receptor binding and signal transduction, it is plausible that this polymorphism alters processes under opioidergic regulation (LaForge et al. 2000a,b). The CRF neuron is also modulated by serotonergic fibers (Contesse et al. 2000;Isogawa et al. 2000). As opposed to ␤ -endorphin, which inhibits CRF secretion, serotonin activates the CRF neuron and stimulates CRF release. The serotonin transporter regulates the concentration of serotonin within the synaptic cleft and thereby modulates magnitude and duration of serotonin-induced postsynaptic mediated signals (Lesch and Mossner 1998). Recently a functional polymorphism has been described in the promoter region of the transporter, which modulates transcriptional activity of this gene as well as tissue expression of transporter activity (Hanna et al. 1998;Heils et al. 1997;Little et al. 1998). Like the A118G polymorphism in the mu-opioid receptor, it is plausible that this functional polymorphism within the serotonin transporter is associated with altered HPA axis dynamics.The present study was designed to test whether the Asn40Asp substitution polymorphism in the mu-opioid receptor or a functional mutation in the polymorphic region of serotonin transporter influences HPA axis activation induced by opioid receptor blockade. METHODS SubjectsHealthy men were recruited by newspaper from the Baltimore area. Respondents gave informed conse...

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Section: Discussionmentioning

confidence: 99%

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

Wand

2002

Neuropsychopharmacology

230

167

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“…4 Although PCOS per se may be associated with alterations of both lipid and lipoprotein metabolism, the presence of obesity usually leads to a more atherogenic lipoprotein pattern. A greater reduction of highdensity lipoproteins (HDL)s 44,73 together with a higher increase of both triglycerides 44,67,73 and total cholesterol 44 levels were in fact observed in obese with respect to the normal-weight PCOS women.…”

Section: Androgen Abnormalitiesmentioning

confidence: 99%

“…An increased b-endorphin response to acute CRH administration has also been found in women with abdominal obesity. 67 However, there are no studies investigating the net contribution of obesity to the opioid tone and its ability to regulate insulin in PCOS women.…”

Section: Neuroendocrine Factorsmentioning

confidence: 99%

Obesity and the polycystic ovary syndrome

et al. 2002

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The polycystic ovary syndrome (PCOS) is a condition characterized by hyperandrogenism and chronic oligo-anovulation. However, many features of the metabolic syndrome are inconsistently present in the majority of women with PCOS. Approximately 50% of PCOS women are overweight or obese and most of them have the abdominal phenotype. Obesity may play a pathogenetic role in the development of the syndrome in susceptible individuals. In fact, insulin possesses true gonadotrophic function and an increased insulin availability at the level of ovarian tissue may favour excess androgen synthesis. Obesity, particularly the abdominal phenotype, may be partly responsible for insulin resistance and associated hyperinsulinemia in women with PCOS. Therefore, obesity-related hyperinsulinemia may play a key role in favouring hyperandrogenism in these women. Other factors such as increased estrogen production rate, increased activity of the opioid system and of the hypothalamic-pituitary-adrenal axis, decreased sex hormone binding globulin synthesis and, possibly, high dietary lipid intake, may be additional mechanisms by which obesity favours the development of hyperandrogenism in PCOS. Irrespective of the pathogenetic mechanism involved, obese PCOS women have more severe hyperandrogenism and related clinical features (such as hirsutism, menstrual abnormalities and anovulation) than normal-weight PCOS women. This picture tends to be more pronounced in obese PCOS women with the abdominal phenotype.Body weight loss is associated with beneficial effects on hormones, metabolism and clinical features. A further clinical and endocrinological improvement can also be achieved by adding insulin-sensitizing agents and=or antiandrogens to weight reduction programmes. These obviously emphasize the role of obesity in the pathophysiology of PCOS.

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“…In obesity, estimation of plasma cortisol does not reflect the function of the HPA axis (7), and levels of cortisol in obese patients have been reported to be normal (8), low (9), or increased (10). On the contrary, response to different stimuli (high secretion of cortisol after laboratory stress tests or after different exogenous neuropeptides) has been found to be altered (11). Compared with these tests, the dexamethasone suppression test (DEX-ST), mainly used in the diagnosis of Cushing's disease, appears to be inadequate.…”

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confidence: 99%

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients

et al. 2007

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OBJECTIVE -Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women.RESEARCH DESIGN AND METHODS -Ten glucose-normotolerant, fertile, obese women (BMI Ͼ40 kg/m 2 , aged 38.66 Ϯ 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method. RESULTS-No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P ϭ 0.05) and postobese women (P Յ 0.01) as was the decrease in dehydroepiandrosterone (P Յ 0.05 and P Յ 0.01, respectively). CBG decreased from 51.50 Ϯ 12.76 to 34.33 Ϯ 7.24 mg/l (P Յ 0.01) following BPD. FCI increased from 11.15 Ϯ 2.85 to 18.16 Ϯ 6.82 (P Յ 0.05). Insulin secretion decreased (52.04 Ϯ 16.71 vs. 30.62 Ϯ 16.32 nmol/m Ϫ2 ; P Յ 0.05), and insulin sensitivity increased by 163% (P Յ 0.0001). Serum CBG was related to BMI (r 0 ϭ 0.708; P ϭ 0.0001), body weight (r 0 ϭ 0.643; P ϭ 0.0001), body fat percent (r 0 ϭ 0.462; P ϭ 0.001), C-reactive protein (r 0 ϭ 0.619; P ϭ 0.004), and leptin (r 0 ϭ 0.579; P ϭ 0.007) and negatively to M value (r 0 ϭ Ϫ0.603; P ϭ 0.005).CONCLUSIONS -After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity. Diabetes Care 30:1494-1500, 2007N utritional status and activity of the hypothalamic-pituitary-adrenal (HPA) axis are strictly associated (1,2). However, little is known about the effect of starvation and intentional calorie deprivation on the HPA axis (3,4). The HPA axis controls the secretion of cortisol with excessive secretion being inhibited by negative feedback. Several studies suggest that abnormalities in cortisol action and HPA axis control may be a factor that links disturbances of carbohydrate metabolism (which characterize insulin resistance) and obesity (5-6). In obesity, estimation of plasma cortisol does not reflect the function of the HPA axis (7), and levels of cortisol in obese patients have been reported to be normal (8), low (9), or increased (10). On the contrary, response to different stimuli (high secretion of cortisol after laboratory stress tests or after different exo...

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Activity of the hypothalamic–pituitary–adrenal axis in different obesity phenotypes

Cited by 121 publications

References 1 publication

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

The Mu-Opioid Receptor Gene Polymorphism (A118G) Alters HPA Axis Activation Induced by Opioid Receptor Blockade

Obesity and the polycystic ovary syndrome

Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients

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