Giovanna Scartabelli

Melanocortin-4 receptor mutations in obesity

The current alarming spread of obesity in many parts of the world is caused by a sudden environmental shift characterized by replacement of a frugal diet with low cost, energy dense food, and little requests for physical activity during work and leisure time. Yet, not all people exposed to an obesogenic environment become obese, and individual differences in the propensity to gain weight as well as the occurrence of different obese phenotypes within the same environment indicate that the genetic heritage in this regard is significant and heterogeneous. The central melanocortin circuit has received much attention during the past decade, since mutations of genes expressing some key molecules in neurons of this system were discovered, which may cause monogenic forms of obesity in animals and humans. Within the arcuate nucleus of the hypothalamus the prohormone proopiomelanocortin is posttranslationally cleaved to produce the alpha-melanocyte stimulating hormone, a peptide with anorexigenic effects upon activation of the melanocortin-4 receptor (MC4R) expressed on the surface of target neurons. Studies regarding the frequency of MC4R mutations associated with human obesity have provided variable results (up to 6% of obese subjects). Various findings suggest an oligogenic and codominant mode of inheritance for MC4R deficiency, with modulation of expressivity and penetrance of the phenotype. The yield of MC4R testing in clinical diagnosis and treatment of obesity is at present undefined since the relatively low prevalence of MC4R pathogenic variants in the general population, along with the high number of sequence variants, has so far compromised the devising of systematic controlled intervention studies. Hopefully, in the future, MC4R testing will have practical implications for the development of new mechanism-based therapy of obesity as well as for the design of specific and more effective protocols, based on lifestyle intervention and current pharmacological or surgical approaches, for management of obesity in MC4R-mutated individuals.

Serum concentrations of adiponectin and leptin in patients with thyroid dysfunctions.

Thyroid dysfunction is associated with metabolic changes that affect mass and adipocyte function, as well as lipid and carbohydrate metabolism. Adipose tissue performs complex metabolic and endocrine functions. Leptin and adiponectin are two of the most important adipocytokines, both involved in the regulation of intermediate metabolism. The aim of this study was to evaluate the relationships between thyroid status and circulating levels of the two adipose tissue hormones. We studied 15 patients with hyperthyroidism, 15 patients with hypothyroidism and 15 euthyroid subjects, all matched by sex, age and body mass index (BMI). Serum concentrations of free thyroxine, free triiodothyronine, thyrotropin, leptin and adiponectin and anthropometric parameters (weight, height, BMI) were assessed. No significant difference was found among the 3 groups, as assessed by Student’s t-test, both for adiponectin and leptin. We conclude that metabolic changes associated with thyroid dysfunction are not related to variations in serum levels of adiponectin or leptin.

Effects of Bariatric Surgery on Early Myocardial Alterations in Adult Severely Obese Subjects

Objective: Aim of this study was to investigate the effect of weight loss on structural and functional myocardial alterations in severely obese subjects treated with bariatric surgery. Patients and Methods: Thirteen severely obese patients (2 males and 11 females) were enrolled in the study. All subjects underwent conventional 2D color Doppler echocardiography. The new ultrasonic techniques used were: (a) integrated backscatter for the analysis of myocardial reflectivity, referred to pericardial interface as expression of myocardial structure (increase in collagen content) and of cyclic variation index as expression of intrinsic myocardial contractility and (b) color Doppler myocardial imaging (CDMI) for the analysis of strain and strain rate (myocardial deformability). All subjects underwent bariatric surgery and were resubmitted to echocardiographic and biochemical examination 6–24 months after surgery. Results: The main finding of the present study was a quite complete normalization of myocardial functional and structural alterations after weight loss. In particular, the cyclic variation index at septum level improved from 14.6 ± 7.0 before to 25.7 ± 11.2 (means ± SD) after surgery (controls: 36.2 ± 9.1). Mean reflectivity at septum level significantly decreased from 55.8 ± 9.5 to 46.5 ± 8.8 (controls: 43.0 ± 8.0). Also, the strain at septum level significantly improved after surgery (from –11.9 ± 3.2 to –20.4 ± 5.3; controls: –23.4 ± 9). Conclusion: This study establishes: (a) the utility of new ultrasonic techniques to detect very early structural and functional myocardial alterations in severely obese patients, and (b) the regression of these subclinical abnormalities after weight loss achieved by bariatric surgery.

Ultrasonographic evaluation of liver volume and the metabolic syndrome in obese women

Non-alcoholic fatty liver disease is a common finding in obese subjects, and increasing evidence has been provided suggesting that it represents the hepatic component of the metabolic syndrome. The aim of this study was to evaluate whether the extent of liver enlargement is related to the severity of the metabolic syndrome in obese women. The relationship between ultrasound-measured hepatic left lobe volume (HLLV) and various features of the metabolic syndrome was evaluated in 85 obese women. The mean±SD value of HLLV in obese women was 431±214 ml (range 46–1019 ml) while it was 187±31 ml (range 143–258 ml) in lean subjects. In a multiple logistic regression analysis, ultrasound-measured intra-abdominal fat was the only anthropometric measure independently associated with HLLV. A strong positive association was found between HLLV and serum liver enzymes, triglycerides, glucose, insulin, uric acid, C reactive protein, systolic and diastolic blood pressure, while a negative correlation was observed between HLLV and HDL cholesterol. The values of HLLV corresponding to the cut-off values of various risk factors for the diagnosis of the metabolic syndrome were calculated, yielding a mean value of 465 ml. In conclusion, ultrasound measurement of HLLV represents a simple, reliable and low-cost tool for the evaluation of liver involvement in the metabolic syndrome. The strong association between liver enlargement and various cardiovascular risk factors associated with insulin resistance supports the role of liver steatosis as an important link among the many facets of the metabolic syndrome in human obesity.

Detection of a new de novo mutation at codon 251 of exon 8 of thyroid hormone receptor β gene in an Italian kindred with resistance to thyroid hormone

Resistance to thyroid hormone (RTH) is almost invariably associated with mutations of the thyroid hormone (TH) receptor β (hTRβ) gene and is inherited as an autosomal dominant disease. Mutations of hTRβ identified in patients affected by RTH cluster generally at two spots of the ligand binding domain. We investigated whether an Italian kindred with RTH had a mutation in the thyroid hormone (TH) receptor β gene. Blood samples were obtained from the available family members for biochemical and genetic analyses. Thyroid function tests in basal conditions, and in the case of the propositus also following incremental doses of T3, were performed. Exon 4 to 10 of hTRβ gene were amplified using the polymerase chain reaction (PCR) and the mutation was identified by direct sequence analysis. The affinity constant of this mutated receptor for T3 was measured by in vitro transcription-translation and was then compared with that of wild type. We identified a heterozygous G to A transition at nucleotide 1037 of exon 8 at codon 251, resulting in a glycine (G) to glutamic acid (E) substitution (G251E) in the patient affected by RTH and in his affected offspring, but not in the normal family members. This novel mutation represents a de novo mutation since both parents of the index case were unaffected and did not have this genomic mutation. When expressed in vitro, the mutant protein (G251E) showed a marked decrease of the affinity for T3, suggesting an impaired ligand-dependent transactivation activity of this mutant receptor. In vivo studies with incremental doses of L-T3 demonstrated a reduced sensitivity to TH in the index case, in particular at the pituitary level where the thyrotrophs’ activity was not completely inhibited even by 200 µg/day of L-T3. G251E mutation represents the fourth mutation described up to now in exon 8 of hTRβ among the subjects affected by RTH. A third cluster of mutations of the c-erbA β gene located proximally with respect to the other two so far described begins to emerge in RTH patients.

Description of an AGPAT2 pathologic allelic variant in a 54-year-old Caucasian woman with Berardinelli-Seip syndrome

A 54-year-old Italian female patient was admitted to our Department with the diagnosis of type 2 diabetes poorly controlled with insulin therapy. The patient was born by consanguineous parents (first degree cousins); she had acromegaloid features, diffuse lipoatrophy and muscular pseudo-hypertrophy since childhood. To confirm the clinical hypothesis of congenital generalized lipodystrophy (CGL) or Berardinelli-Seip syndrome, the sequences of AGPAT2 (encoding for 1-acyl-sn-glycerol-3-phosphate acyltransferase beta) and BSCL2 (encoding for seipin) candidate genes were analyzed. DNA analysis showed the presence of a homozygous mutation in exon 3 of the AGPAT2 gene (P112L). This is the first description of a Caucasian subject with CGL who carries the pathologic allelic variant P112L of the AGPAT2 gene.

Liver Enlargement Predicts Obstructive Sleep Apnea–Hypopnea Syndrome in Morbidly Obese Women

Obstructive sleep apnea–hypopnea syndrome (OSAHS) is frequently present in patients with severe obesity, but its prevalence especially in women is not well defined. OSAHS and non-alcoholic fatty liver disease are common conditions, frequently associated in patients with central obesity and metabolic syndrome and are both the result of the accumulation of ectopic fat mass. Identifying predictors of risk of OSAHS may be useful to select the subjects requiring instrumental sleep evaluation. In this cross-sectional study, we have investigated the potential role of hepatic left lobe volume (HLLV) in predicting the presence of OSAHS. OSAHS was quantified by the apnea/hypopnea index (AHI) and oxygen desaturation index in a cardiorespiratory inpatient sleep study of 97 obese women [age: 47 ± 11 years body mass index (BMI): 50 ± 8 kg/m2]. OSAHS was diagnosed when AHI was ≥5. HLLV, subcutaneous and intra-abdominal fat were measured by ultrasound. After adjustment for age and BMI, both HLLV and neck circumference (NC) were independent predictors of AHI. OSAHS was found in 72% of patients; HLLV ≥ 370 cm3 was a predictor of OSAHS with a sensitivity of 66%, a specificity of 70%, a positive and negative predictive values of 85 and 44%, respectively (AUC = 0.67, p < 0.005). A multivariate logistic model was used including age, BMI, NC, and HLLV (the only independent predictors of AHI in a multiple linear regression analyses), and a cut off value for the predicted probability of OSAHS equal to 0.7 provided the best diagnostic results (AUC = 0.79, p < 0.005) in terms of sensitivity (76%), specificity (89%), negative and positive predictive values (59 and 95%, respectively). All patients with severe OSAHS were identified by this prediction model. In conclusion, HLLV, an established index of visceral adiposity, represents an anthropometric parameter closely associated with OSAHS in severely obese women.

Frequency of the GPR7 Tyr135Phe allelic variant in lean and obese subjects

Background: GPR7, the endogenous coupled receptor for neuropeptide B and neuropeptide W, is expressed in several regions of the central nervous system, which are involved in the regulation of feeding behavior. GPR7 affects the regulation of energy balance through a mechanism independent of leptin and melanocortin pathways. Aim: Aim of this study was to investigate whether GPR7 gene mutations can be detected in human subjects and, in that event, if they are differently distributed among lean and obese subjects. Subjects and methods: The coding region of GPR7 were sequenced in 150 obese patients and 100 normal-weight unrelated controls. Functional studies of the allelic variants were performed. Results: One genetic GPR7 variant was found (Tyr135Phe — rs33977775) in obese subjects (13.3%) and lean control (25%). Functional studies did not reveal significant differences between the wild type and the Tyr135Phe allelic variants in their NPW-mediated capacity to inhibit forskolin-induced cAMP production. Conclusions: Screening of GPR7 gene mutations among lean and obese subjects revealed a Tyr135Phe allelic variant that was fairly common in the study population. As indicated by in vitro and in silico studies, this variant is unlikely to cause a functional derangement of the receptor.

Contents Vol. 109, 2008

E. Abadie, Saint Denis C.W. Akins, Boston, Mass. J.S. Alpert, Tucson, Ariz. E.A. Amsterdam, Sacramento, Calif. J.J. Badimon, New York, N.Y. A. Battler, Petah Tikva R. Becker, Durham, N.C. G.A. Beller, Charlottesville, Va. P.C. Block, Atlanta, Ga. R.O. Bonow, Chicago, Ill. J. Camm, London B. Carabello, Houston, Tex. K. Chatterjee, San Francisco, Calif. P.F. Cohn, Stony Brook, N.Y. M.H. Crawford, San Francisco, Calif. H. Cuénoud, Worcester, Mass. J.E. Dalen, Tucson, Ariz. S. Dalla Volta, Padova P.C. Deedwania, Fresno, Calif. A.N. De Maria, San Diego, Calif. P.S. Douglas, Durham, N.C. J.A. Eleft eriades, New Haven, Conn. U. Elkayam, Los Angeles, Calif. G. Ewy, Tucson, Ariz. M. Ezekowitz, Wynnewood, Pa. R. Ferrari, Milan G. Filippatos, Athens G.I. Fishman, New York, N.Y. K. Fox, London G.S. Francis, Cleveland, Ohio V. Fuster, New York, N.Y. B.J. Gersh, Rochester, Minn. W. Gersony, New York, N.Y. J. Gold, Toledo, Ohio R. Goldberg, Worcester, Mass. S. Goldberg, Philadelphia, Pa. M. Goldman, New York, N.Y. P.J. Goldschmidt, Miami, Fla. J. Gore, Worcester, Mass. T.H. Haghfelt, Odense J.L. Halperin, New York, N.Y. C.L. Hanis, Houston, Tex. S. Haunsø, Copenhagen Z.-X. He, Beijing