Our findings show that, in human obesity, plasma visfatin is reduced, whereas visfatin mRNA is differentially regulated in SAT and VAT. Visfatin is not related to insulin resistance either as assessed by homeostasis model assessment or during lipid infusion.

Abstract-Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, nϭ380) and peripheral (APA, nϭ344; bilateral adrenal hyperplasia, nϭ174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; PϽ10 Ϫ3) and in younger patients (42.1Ϯ1.0 versus 47.6Ϯ0.7 years; PϽ10 Ϫ3 ) and were associated with higher preoperative aldosterone levels (455Ϯ26 versus 376Ϯ17 ng/L; Pϭ0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism. H ypertension is a major cardiovascular risk factor that affects between 10% and 40% of the population in industrialized countries. Detection of secondary forms of hypertension is particularly important because it allows for the targeted management of the underlying disease. Primary aldosteronism (PA) is the most common form of secondary hypertension, with an estimated prevalence between 6% and 12% of hypertensives and as high as 20% in patients with resistant hypertension. 1-5 PA occurs as the result of a dysregulation of the mechanisms controlling adrenal aldosterone production, ultimately leading to hypertension with low plasma renin and elevated aldosterone sometimes associated with hypokalemia. Among subtypes of PA, aldosteroneproducing adenoma (APA) and bilateral adrenal hyperplasia (BAH; also known as idiopathic hyperaldosteronism) together account for Ϸ95% of cases. [1][2][3] Aldosterone production from the adrenal zona glomerulosa is tightly controlled to maintain electrolyte and fluid homeostasis by the kidney. Thus, the two most important physiological stimuli of aldosterone secretion are angiotensin II and serum potassium. Glomerulosa cell membrane depolarization leads to openi...

These results indicate a role for the local endocannabinoids in the regulation of glucose metabolism in human adipocytes and suggest a role in channeling excess energy fuels to adipose tissue in obese humans.

Both NAFLD and obese patients had lower adiponectin levels, whereas leptin was increased only in the obese group. No correlation was found between resistin and high-sensitivity C-reactive protein, BMI, homeostasis model assessment, insulin, glucose, transaminases, and lipid values. A positive correlation was found between resistin and histological inflammatory score. These data report increased resistin in NAFLD patients that is related to the histological severity of the disease, but do not support a link between resistin and insulin resistance or BMI in these patients.

Our data support a pathophysiological link between ucOCN and cOCN balance and obesity. OCN is present in the first phases of adipogenesis but also in human AT ex vivo. AT releases, in vitro, both ucOCN and cOCN, suggesting a possible link between AT and OCN in the regulation of metabolism.

Abstract-Aldosterone-producing adenomas (APA) are a frequent cause of secondary hypertension characterized by autonomous hypersecretion of aldosterone. However, the molecular mechanisms involved in adrenal tumorigenesis and deregulated aldosterone secretion are currently unknown. To identify putative functional genes, a transcriptional screening was performed on 8 APA and 3 normal adrenals (NA) using oligonucleotide microarrays. Data were next validated on an expanded set of samples by real-time PCR (APA, nϭ19; NA, nϭ10). The epidermal growth factor-like teratocarcinoma-derived growth factor-1 (TDGF-1) was upregulated in APA compared with NA (14.7-fold and 21.4-fold by microarray and real-time PCR, respectively). In vitro studies and Western blot analysis using the NCI H295R adrenocortical cell line showed that TDGF-1 increased Akt phosphorylation on Thr308 and Ser473, consistent with activation of phosphatidylinositol 3-kinase/Akt signaling, and also demonstrated a concomitant inactivation of the Akt substrate glycogen synthesis kinase-3␤ via Ser9 phosphorylation. Furthermore, TDGF-1 mediated a 3.8Ϯ0.4-fold increase in aldosterone secretion (nϭ4) that was specifically blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nmol/L) and LY294002 (20 mol/L). Finally, TDGF-1 protected H295R cells from apoptosis induced by staurosporine, causing a decrease in caspase-3 activity, a reduction in the inactivation of poly(ADP-ribose) polymerase, and an inhibition of DNA fragmentation, detected by the TUNEL reaction and fluorescence microscopy that was blocked by LY294002. Taken together, our data suggest that TDGF-1, which is significantly upregulated in APA and mediates aldosterone hypersecretion and deregulated growth in adrenocortical cells in vitro, may represent a key player in the development and pathophysiology of primary aldosteronism. (Hypertension. 2010;55:1468-1475.)Key Words: aldosterone-producing adenoma Ⅲ aldosterone Ⅲ NCI H295R cells Ⅲ teratocarcinoma-derived growth factor Ⅲ phosphatidylinositol 3-kinase/Akt signaling P rimary aldosteronism (PA) is the most frequent form of endocrine hypertension, accounting for up to 5% to 10% of all hypertensive patients, 1 and is characterized by the chronic, excessive, and autonomous secretion of aldosterone by the adrenal gland. The diagnosis of this form of hypertension is fundamental because, compared with essential hypertensives with similar risk profiles, patients with PA are more prone to stroke and myocardial infarction 2 and display an increase in cardiovascular damage and metabolic complications. 3 Aldosterone-producing adenomas (APA) are a common underlying cause of PA and are found in 30% to 40% of PA patients, whereas bilateral adrenal hyperplasia is present in 60% to 70% of patients. 4 Unilateral adrenalectomy normalizes, or at least markedly improves, the blood pressure in patients with APA, and therefore, APA is the most common, specifically treatable, and potentially curable form of hypertension. 4,5 However, the molecular mechanisms...

Myostatin is a member of transforming growth factor-beta superfamily that plays an important inhibitory role during muscle development; in fact mutations of myostatin gene result in a hypermuscular phenotype. Moreover myostatin-deficient mice have a significant reduction in fat depots and a depression of adipogenesis. Little is known about myostatin function in muscle growth regulation in humans and in particular during caloric restriction. In the present work we quantified by real-time RT-PCR myostatin expression in muscle biopsies of a group of morbidly obese patients before and after weight loss obtained by biliopancreatic diversion (BPD). The patients reduced body weight by 38.9%, mostly due to fat-mass loss, showing also a significant reduction in the 24-hour EE as assessed by the respiratory chamber. Myostatin mRNA levels result clearly decreased after weight loss, suggesting a role in counteracting the progressive decline of muscle mass after BPD. Myostatin may provide therefore another mechanistic explanation for the control of energy partitioning between protein and fat, working against muscle wasting. Our data suggest that myostatin might represent an important regulator of skeletal muscle size also in conditions of food restriction in obese subjects.

These results support a link between circulating resistin and obesity in humans but do not support a role for resistin in human insulin resistance.