The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the G protein-coupled family receptors and they were discovered ...while investigating the mode of action of ?(9)-tetrahydrocannabinol, a component of Cannabis sativa, to which they bind with high affinity. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food. At central nervous system level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to modulation of the release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell. Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism. Animal models have provided solid evidence that genetically induced obesity leads to long-lasting overstimulation of endocannabinoid system synthesis resulting in permanent overactivation of CB1, which may then contribute to the maintenance of this disease. Importantly, at peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance. Moreover, CB1 has been shown to be up-regulated in adipocytes derived from obese rodents. These results support the role of endocannabinoids in the development and maintenance of obesity, paving the way for the development of a new class of drugs such as the CB1 blockers as a therapy for tackling obesity and the associated major cardiovascular risk factors.
Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome (PCOS). Dietary-induced weight loss and the administration of insulin-lowering drugs, such ...as metformin, are usually followed by improved hyperandrogenism and related clinical abnormalities. This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight, fat distribution, the glucose-insulin system, and hormones in a group of 20 obese PCOS women body mass index (BMI) > 28 kg/m2 with the abdominal phenotype (waist to hip ratio >0.80), and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS. At baseline, we measured sex hormone, sex hormone-binding globulin (SHBG), and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography (CT) at the L4-L5 level, to measure sc adipose tissue area (SAT) and visceral adipose tissue area. All women were then given a low-calorie diet (1,200-1,400 kcal/day) alone for one month, after which anthropometric parameters and CT scan were newly measured. While continuing dietary treatment, PCOS women and obese controls were subsequently placed, in a random order, on metformin (850 mg/os, twice daily) (12 and 8, respectively) or placebo (8 and 12, respectively), according to a double-blind design, for the following 6 months. Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment. During the treatment period, 3 women of the control group (all treated with placebo) were excluded because of noncompliance; and 2 PCOS women, both treated with metformin, were also excluded because they became pregnant. Therefore, the women cohort available for final statistical analysis included 18 PCOS (10 treated with metformin and 8 with placebo) and 17 control women (8 treated with metformin and 9 with placebo). The treatment was well tolerated. In the PCOS group, metformin therapy improved hirsutism and menstrual cycles significantly more than placebo. Baseline anthropometric and CT parameters were similar in all groups. Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups, without any significant effect on CT scan parameters. In both PCOS and control women, however, metformin treatment reduced body weight and BMI significantly more than placebo. Changes in the waist-to-hip ratio values were similar in PCOS women and controls, regardless of pharmacological treatment. Metformin treatment significantly decreased SAT values in both PCOS and control groups, although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment. On the contrary, visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups, but only in the former was the effect of metformin treatment significantly higher than that of placebo. Fasting insulin significantly decreased in both PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin. Neither metformin or placebo significantly modified the levels of LH, FSH, dehydroepiandrosterone sulphate, and progesterone in any group, whereas testosterone concentrations decreased only in PCOS women treated with metformin. SHBG concentrations remained unchanged in all PCOS women; whereas in the control group, they significantly increased after both metformin and placebo. Leptin levels decreased only during metformin treatment in both PCOS and control groups. (ABSTRACT TRUNCATED)
We have previously shown that women with abdominal body fat
distribution (A-BFD) have a hyperactive hypothalamic-pituitary-adrenal
(HPA) axis. However, we did not consider the presence of anxiety ...and/or
depression, common manifestations in obese subjects. Anxiety and
depression may be associated with oversecretion of cortisol and could
represent a confounding factor in the evaluation of the HPA axis in
different obesity phenotypes. In this study nondepressed obese women
with abdominal and peripheral (P-BFD) body fat distribution and a
control lean group underwent a CRH/AVP stimulation test for ACTH and
cortisol determinations. Moreover, all women underwent metabolic
evaluation and had their urinary free cortisol (UFC) excretion
measured. After the stimuli, ACTH and cortisol responded more in the
A-BFD than in the P-BFD and control groups. A positive correlation was
found between either ACTH area under the curve (r2 =
0.366; P = 0.003) or cortisol area under the curve
(r2 = 0.378; P = 0.043) and the
homeostasis insulin resistance index in all obese patients.
Unexpectedly, A-BFD had significantly lower UFC per m2
values than P-BFD (P < 0.05). Lowered UFC
excretion in the A-BFD group is in keeping with an increased cortisol
clearance, which, in turn, may lead to HPA axis hyperactivity as an
appropriate compensatory mechanism. On the other hand, other
mechanisms, possibly central in origin, such as overdriving of the
CRH-ACTH system to chronic environmental stress factors, may be
involved in determining HPA overresponsiveness in abdominal obesity. In
conclusion, this study suggests that women with the abdominal obesity
phenotype are characterized by both central and peripheral alterations
of the HPA axis activity.
Leptin is a hormone produced in the adipose tissue and its concentrations in peripheral blood are significantly correlated with the amount of body fat. Whether other factors, including the pattern of ...body fat distribution and several hormones (such as insulin, sex steroids, and glucocorticoids), may be involved in the regulation of circulating blood leptin levels is controversial. Women with the polycystic ovary syndrome (PCOS) are hyperandrogenic and most of them are characterized by hyperinsulinemia, insulin resistance, and obesity, and particularly the visceral phenotype. To assess the potential contribution of anthropometric factors, androgens, and insulin in determining leptin levels, we examined their relationship with body-mass index (BMI), visceral (VAT) and subcutaneous (SAT) adipose tissue areas, basal androgen levels, and fasting and glucose-stimulated (AUC) insulin in different groups of obese women with PCOS (n = 23) and of age-matched obese (n = 16) and non-obese (n = 10) otherwise healthy controls. The
VAT
SAT
ratio was measured as a parameter of body fat distribution. Serum leptin levels were significantly higher in obese PCOS women than in obese and normal-weight healthy controls and, within the controls, in the obese than in the non-obese group. In all women considered together, and in each group separately, leptin concentrations were highly significantly correlated with BMI. In addition, after adjusting for BMI, both VAT and the
VAT
SAT
ratio were positively and significantly correlated with leptin. Partial correlatins with the
VAT
SAT
ratio remained significant in both the obese PCOS group and in controls considered separately, whereas the correlation with the SAT value was significant only in the control group. After adjusting for BMI, no correlation between leptin, androgens and fasting or stimulated (like AUC) insulin was found. These findings indicate that leptin levels in obese women with PCOS are higher than those observed in obese and non-obese controls. Moreover, they suggest that, other than BMI, the pattern of body fat distribution may be an independent factor related to circulating leptin levels, which, on the contrary, do not appear to be related to either androgen or insulin concentrations.
One of the most interesting pharmacological targets proposed in the past ten years for fighting obesity and related metabolic disorders is the endocannabinoid system. The role of the endocannabinoid ...system is crucial in regulating the rewarding properties of food, in controlling energy balance by acting at the hypothalamic circuitries involved in food intake, and in peripheral metabolism by influencing adipocytes, hepatocytes, myocytes and pancreatic endocrine cells. Obesity seems to be a condition associated with a pathological overactivation of the endocannabinoid system; therefore, restoring a normal endocannabinoid tone by antagonizing the cannabinoid receptor type 1 (CB
1) could help arrest both the development and the maintenance of obesity.
Arginine vasopressin (AVP) has a central role in the response of the hypothalamic-pituitary-adrenal (HPA) axis to stress conditions. A low dose of AVP has been shown to have a modest, but significant ...effect on ACTH response in normal weight subjects. The aim of this study was to test the response of the HPA axis in obese subjects in order to assess eventual primary neuroendocrine alterations, previously demonstrated by using AVP combined with corticotropin releasing hormone (CRH). In addition, given its central inhibitory action on the HPA axis, we investigated whether the suppressive capacity of alprazolam (APZ) pretreatment on the hormone response to low-dose AVP challenge and daily urinary free cortisol (UFC) excretion rate may be altered in the presence of obesity.
Fifteen overweight or obese women and eight normal-weight controls randomly underwent two low-dose AVP tests (0.3 UI iv bolus), one without (AVP test) and the other preceded by APZ administration (0.5 mg at midnight and 0.5 mg 90 min before the test in the morning at 08:30 h) (APZ/AVP test). Blood samples for ACTH and cortisol assay were obtained at baseline and throughout each test. The day before each test, 24h-UFC/ creatinine was also mea-sured.
Basal ACTH levels were similar in the two groups, whereas cortisol concentrations were significantly lower in the overweight/obese group. Overweight/obese women had higher ACTH and cortisol responses to the AVP tests and significantly greater hormone inhibition after APZ than controls. In both groups, AVP-induced delta-peak cortisol values before and after APZ pre-treatment were significantly correlated. Body fat distribution had no effect on the HPA axis response to AVP either before or after APZ. Moreover, APZ decreased 24h-UFC/creatinine values unsignificantly in controls and by approximately 50% in the overweight/obese subjects. These changes were unrelated to the cortisol response to the AVP test before and after APZ pretreatment. On the other hand, percent changes of 24h-UFC/creatinine after APZ were negatively related to the body mass index (BMI) but positively with waist circumference values, which indicates that the abdominal obesity phenotype may counteract the 24 h-UFC/creatinine that would be expected on the basis of BMI values.
Our data further support the concept that in women obesity may represent a condition of hyperresponsiveness or hypersensitivity of the HPA axis to neuroendocrine stimuli, which appear to be independent of feedback control. In addition, the data on the inhibiting capacity of APZ on UFC excretion confirm that the alterations of the HPA axis in obesity is particularly evident in the abdominal phenotype.
Objectives. In this study we investigated the relationships between blood lipids and menopausal status.
Setting and subjects. All data were obtained from the first cross‐sectional examination of the ...Virgilio Menopause Health Project in a large cohort of middle‐aged women in pre, peri‐, and postmenopausal age. The data refer to 426 women without metabolic or endocrine diseases, relevant hepatic, renal and cardiovascular abnormalities, none were dieting or taking medications.
Main outcome measures. A precoded questionnaire including full clinical history, socio‐economic and personal information, habitual diet, physical activity, drug use and smoking habits, careful recording of gynaecological events and family history for disease was completed. Several anthropometric parameters and the bioelectrical impedance analysis was used to measure free fatty mass. Blood samples for hormones and biochemistry were also obtained.
Results. There were no significant differences on body mass index, fatty mass, free fatty mass and parameters of body fat distribution between the three groups. Again, there were no differences in smoking habits, dietary intake or indices of physical activity amongst the groups. There was a significant increase from pre to postmenopause of LH and FSH and a decrease of oestradiol and testosterone, whereas no difference was found in sex hormone‐binding globulin. Age‐adjusted values of glucose, triglycerides and high density lipoprotein (HDL‐) cholesterol were similar in all groups, whereas postmenopausal women had significantly higher values of total and low density lipoprotein (LDL‐) cholesterol. On the contrary, there was a significant fall in insulin levels passing from pre to postmenopause. In multiple regression models, total and LDL‐cholesterol correlated positively with body mass index, waist‐to‐hip ratio and age, and negatively with free fatty mass and oestradiol blood levels.
Conclusions. These results are consistent with the hypothesis that menopausal status may have a significant and independent effect in determining increased total and LDL‐cholesterol concentrations in postmenopausal women.
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