A. Liuzzi

The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients

objective  We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low‐dose dexamethasone (0·25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a BclI restriction site polymorphism in a group of Italian patients with severe obesity.

Relationship between blood pressure and glucose tolerance in acromegaly

Hypertension represents a well‐known risk factor for cardiovascular diseases. The pathogenesis of hypertension in acromegaly is commonly viewed as multifactorial, but the possible influence of metabolic disorders on blood pressure (BP) in affected patients is largely unknown.

Bone mineral density in acromegaly: the effect of gender, disease activity and gonadal status

objective Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status.

Skeletal involvement in female acromegalic subjects : The effects of growth hormone excess in amenorrheal and menstruating patients

Bone involvement is a common clinical feature in acromegalic patients, though previous studies gave divergent results possibly because of the different gonadal status of the patients studied. To study the influence of estrogen milieu in these patients, we evaluated 23 acromegalic patients with active disease, subdivided into two groups: menstruating and amenorrheal patients, comparable for duration and activity of disease. Forty‐two matched women served as controls. Skeletal involvement was studied by measuring: (a) the main biomarkers of bone turnover: serum alkaline phosphatase total activity (AP), bone GLA protein (BGP), serum carboxy‐terminal propeptide of type I collagen (PICP), serum type I cross‐linked N‐telopeptide (ICTP), and urinary pyridinoline and deoxypyridinoline corrected for creatinine (Pyr/Cr, D‐Pyr/Cr) and urinary calcium/creatinine ratio (Ca/Cr); (b) bone mineral density (BMD), as measured by quantitative computed tomography both at lumbar spine and distal radius, and by dual X‐ray absorptiometry both at lumbar spine and at three femoral sites (Wards triangle, femoral neck, and great trochanter). AP, BGP, ICTP, Pyr/Cr, D‐Pyr/Cr were significantly higher in patients than in controls, independent of the menstrual pattern. Higher PICP levels were found in the whole group and in menstruating acromegalics when compared with control women; no difference was found in amenorrheal patients, who in turn showed higher urinary Ca/Cr values. When patients were considered all together, BMD at spine, femoral neck, and trochanter was higher than in controls. In contrast, when the gonadal status was taking into account and, menstruating and amenorrheal subjects were considered separately, BMD at spine, but not in other sites, was significantly higher in menstruating patients than in controls. In contrast, no difference of BMD values at any site was observed between amenorrheal patients and controls. The mean BMD Z scores allowed us to detect an unequal involvement of different skeletal sites. Our results show that bone turnover is increased in acromegalic women and suggest that GH anabolic effect on bone is more evident in the presence of estrogens and that different skeletal sites may be affected differently by hormone excess.

Rare melanocortin-3 receptor mutations with in vitro functional consequences are associated with human obesity

In contrast to the melanocortin 4 receptor, the possible role of the melanocortin 3 receptor (MC3R) in regulating body weight is still debated. We have previously reported three mutations in the MC3R gene showing association with human obesity, but these results were not confirmed in a study of severe obese North American adults. In this study, we evaluated the entire coding region of MC3R in 839 severely obese subjects and 967 lean controls of Italian and French origin. In vitro functional analysis of the mutations detected was also performed. The total prevalence of rare MC3R variants was not significantly different in obese subjects when compared with controls (P= 0.18). However, the prevalence of mutations with functional alterations was significantly higher in the obese group (P= 0.022). In conclusions, the results of this large study demonstrate that in the populations studied functionally significant MC3R variants are associated with obesity supporting the current hypothesis that rare variants might have a stronger impact on the individual susceptibility to gain weight. They also underline the importance of detailed in vitro functional studies in order to prove the pathogenic effect of such variants. Further investigations in larger cohorts will be needed in order to define the specific phenotypic characteristics potentially correlated with reduced MC3R signalling.

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

BACKGROUND:It is known that cholinergic anti-inflammatory reflex regulates inflammation in peripheral tissues. Nicotinic acetylcholine receptors (nAChRs) are mediators of this anti-inflammatory pathway and also non-neuronal cells express functional nAChrs. A role for α7-subtype acetylcholine cholinergic receptor (α7nAChR) in insulin sensitivity improvement has already been shown in rodents both in vivo and in vitro. However, no data are available on α7nAChR expression in human adipocytes.OBJECTIVE:To investigate the expression and protein content of α7nAChR in human subcutaneous adipose tissue (SAT) and in isolated mature adipocytes.DESIGN:A total of 39 SAT biopsy specimens obtained from obese and normal-weight subjects were used to assess α7nAChR messenger RNA levels and to stimulate α7nAChR with a specific agonist and antagonist in vitro. Additional SATs from eight non-diabetic obese subjects were also studied, before and after a 3-month lifestyle intervention.RESULTS:α7nAChR expression was significantly lower in the SAT of obese subjects compared with that of normal-weight subjects. In mature adipocytes isolated from morbidly obese subjects (body mass index>40 kg m−2), α7nAChR expression was 75% lower compared with adipocytes from normal-weight subjects. In adipocytes of obese subjects, α7nAChR was downregulated also at protein level. In eight non-diabetic obese subjects, a lifestyle intervention (3 months of diet and physical activity) induced a significant weight loss and an increase in α7nAChR SAT expression. In vitro stimulation of adipocytes with the specific α7nAChR agonist PNU282987 induced a significant anti-inflammatory effect. Furthermore, a similar downregulation of the inflammatory profile, associated with a significant increase in α7nAChR protein level, was observed after genistein stimulation.CONCLUSIONS:These results provide evidence that α7nAChR expression levels are significantly decreased in obese subjects, and that this receptor modulates inflammatory gene expression in human adipocytes. The upregulation of α7nAChR by genistein stimulation opens new insights for the management of low-grade inflammation linked to human obesity.

EVIDENCE FOR A DOPAMINERGIC ACTIVITY OF METHYSERGIDE IN HUMANS

The acute administration of 2 mg of methysergide significantly reduced plasma prolactin levels in nine normal subjects and in seven hyperprolactinaemic patients. The prolactin lowering effect of this drug was abolished by sulpiride. Moreover methysergide lowered plasma GH levels in four out of nine acromegalic patients, who were also responsive to a dopaminergic drug such as bromocriptine. Although methysergide did not significantly blunt the TRH‐induced prolactin release, our data suggest that this drug may affect GH and prolactin release through a dopaminergic mechanism of action. This effect should be taken into account when methysergide is employed as antiserotoninergic drug in neuroendocrinological studies.

TECNOB Study: Ad Interim Results of a Randomized Controlled Trial of a Multidisciplinary Telecare Intervention for Obese Patients with Type-2 Diabetes

Background: Obesity increases the risk of many health complications such as hypertension, coronary heart disease and type 2 diabetes, needs long-lasting treatment for effective results and involves high public and private care-costs. Therefore, it is imperative that enduring and low-cost clinical programs for obesity and related co-morbidities are developed and evaluated. Information and communication technologies (ICT) can help clinicians to deliver treatment in a cost-effective and time-saving manner to a large number of obese individuals with co-morbidities. Objective: To examine ad interim effectiveness of a 12-month multidisciplinary telecare intervention for weight loss provided to obese patients with type 2 diabetes. Design, Setting, and Participants: A single-center randomized controlled trial (TECNOB study) started in December 2008. At present, 72 obese patients with type 2 diabetes have been recruited and randomly allocated to the TECNOB program (n=37) or to a control condition (n=39). However, only 34 participants have completed at least the 3-month follow-up and have been included in this ad interim analysis. 21 out of them have reached also the 6-month follow-up and 13 have achieved the end of the program. Study is still on-going. Intervention: All participants attended 1-month inpatient intensive program that involved individualized medical care, diet therapy, physical training and brief psychological counseling. At discharge, participants allocated to the TECNOB program were instructed to use a weight-loss web-site, a web-based videoconference tool, a dietary software installed into their cellular phones and an electronic armband measuring daily steps and energy expenditure. Main Outcome Measures: Weight and disordered eating-related behaviors and cognitions (EDI-2) at entry to hospital, at discharge from hospital, at 3,6 and 12 months. Results: Ad interim analysis of data from 34 participants showed no statistically significant difference between groups in weight change at any time-point. However, within-group analysis revealed significant reductions of initial weight at discharge from hospital, at 3 months, at 6 months but not at 12 months. Control group had higher scores in Interpersonal distrust at 12 months. Conclusion: This ad interim findings revealed that the effect of the inpatient treatment was high and probably overwhelmed the effect of the TECNOB intervention. Much statistical power and long-term follow-up may enhance the probability to detect the TECNOB effect over and above the great one exerted by the inpatient program.

Permanence of molecular features of obesity in subcutaneous adipose tissue of ex-obese subjects

Objective:Bariatric surgery represents a powerful tool for morbid obesity treatment. However, after stabilization of weight loss that follows surgical interventions, ex-obese patients face the problem of residual tissues removal. Actually, it is unknown whether the characteristics of this residual subcutaneous adipose tissue (SAT) are ‘restored’ with regard to molecular and morphological features.Design:To clarify this issue, we compared the SAT gene expression profile of ex-obese patients (ExOB-SAT, mean body mass index (BMI): 27.2±1.3 kg m−2) with that of lean (normal weight, NW-SAT, mean BMI: 22.6±1.1 kg m−2), overweight (OW-SAT, BMI: 27.65±0.2 kg m−2) and obese patients, according to BMI classes (OB1-SAT: 30⩾BMI⩽34.9, OB2-SAT: 35⩾BMI⩽39.9, OB3-SAT: BMI⩾40).Subjects and Methods:A total of 58 samples of SAT were collected during surgical interventions. Gene expression levels were assessed by microarrays and significant genes were validated by RT–qPCR. Adipocyte hypertrophy, inflammatory infiltration and fibrosis were assessed by morphological techniques.Results:Global gene expression in ExOB-SAT was closely related to gene expression of OB3-SAT by hierarchical clustering procedures, in spite of different BMI. Metallothioneins (MT1A and MT2A) were the key over-expressed genes in both groups. At morphologic level, adipocyte hypertrophy and inflammatory infiltration improved after weight loss in ExOB-SAT, despite a persistence of fibrosis.Conclusions:Taken together, these results demonstrate that SAT gene expression is not fully restored, even after an extensive and stable weight loss. The persistence of ‘obesity molecular features’ in ExOB-SAT suggests that the molecular signature of adipose tissue is not solely dependent on weight loss and may need longer time period to completely disappear.

Use of the ICF to describe functioning and disability in obese patients

Purpose. To describe the functioning and disability in adult patients with severe obesity through an implementation of ICF-based tools in a clinical inpatient setting, and to highlight the most relevant domains of functioning. Methods. Adult obese inpatients with BMI ≥ 35 kg/m2 were enrolled and underwent a clinical evaluation following a standardized diagnostic protocol. ICF categories were filled according to established coding rules, on the basis of an extended list composed by ICF Core Set for obesity, the ICF checklist and other categories linked to the diagnostic protocol. Categories reported as a problem by at least 20% of patients were considered relevant for describing functional profiles of obese patients. Results. Fifty-one patients were enrolled and 43 ICF categories were selected: 11 body functions (26% out of the total selected categories), 3 body structures (7%), 15 activities and participation (35%) and 14 environmental factors (32%). Six ICF categories were not included in the Core-Set for obesity. Conclusions. Our study shows the applicability of an extended list of ICF categories to describe functioning and disability of obese patients, and provide a preliminary indication to expanding the ICF Core Set for obesity.