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Objective To analyze the reference range of thyroid-stimulating hormone (TSH) in different BMI categories and its impact on the classification of hypothyroidism. Methods The study included 3,928 individuals free of thyroid disease (without previous thyroid disease, no interfering medications, TSH

Background: The aim of this study was to investigate the national prevalence of thyroid dysfunction in Spain and its association with various clinical, environmental, and demographic variables. Methods: The study included 4554 subjects (42.4% men) with a mean age of 50 years (range 18-93 years), who were participants in a national, cross-sectional, population-based survey conducted in 2009-2010. Data gathered included clinical and demographic characteristics, physical examination, and blood sampling. Thyrotropin, free thyroxine, free triiodothyronine, and thyroid peroxidase antibody (TPOAb) concentrations were analyzed by electrochemiluminescence. Urinary iodine (UI) levels were measured in an isolated urine sample. Results: The prevalence of treated hypothyroidism, untreated subclinical hypothyroidism, and untreated clinical hypothyroidism was 4.2% [confidence interval (CI) 3.6-4.9%], 4.6% [CI 4.0-5.2%], and 0.3% [CI 0.1-0.5%], respectively. The prevalence of total hypothyroidism (including all fractions) was 9.1% [CI 8.2-10.0%]. The prevalence of total hyperthyroidism was 0.8% [CI 0.6-1.1]. A total of 7.5% [CI 6.7-8.3%] of the population tested positive for TPOAbs (>= 50 IU/mL). In multivariate logistic regression models, TPOAbs were strongly associated with both hypothyroidism (p < 0.001) and hyperthyroidism (p = 0.005), whereas high UI levels (> 200 mu g/g creatinine) were associated with hypothyroidism (p < 0.001). The positive association between UI and hypothyroidism remained for both treated (p < 0.001) and untreated (p < 0.05) hypothyroidism, whereas it was especially significant for non-autoimmune (TPOAbs negative) forms (p < 0.001). At UI levels >= 200 mu g/g, there was a positive correlation between UI and thyrotropin levels (beta = 0.152, p < 0.001) and a negative correlation between UI and free triiodothyronine levels (beta=-0.134, p = 0.001). Conclusion: According to the data, a large proportion (10%) of the Spanish population has some evidence of thyroid dysfunction. High TPOAb concentrations were associated with both hypo- and hyperthyroidism, whereas high UI concentrations were associated with hypothyroidism.

Te study was supported by CIBER in Diabetes and Associated Metabolic Disorders - CIBERDEM (ISCIII - Ministerio de Ciencia e Innovación), Ministerio de Sanidad y Consumo, Spanish Society of Diabetes – SED, Consejería de Salud Junta de Andalucía “Andalucía se mueve con Europa” (0256/2007), Instituto de Salud Carlos III and FEDER “Una manera de hacer Europa” (PI11/02755, PI14/00710, PI14/01104, PI14/00970, PI14/00874 and PI14/00465), Sociedad Andaluza de Endocrinología, Diabetes y Nutrición (Beca SAEDYN)., Maldonado-Araque, C., Valdés, S., Lago-Sampedro, A., Lillo-Muñoz, J.A., Garcia-Fuentes, E., Perez-Valero, V., Gutierrez-Repiso, C., Goday, A., Urrutia, I., Peláez, L., Calle-Pascual, A., Castaño, L., Castell, C., Delgado, E., Menendez, E., Franch-Nadal, J., Gaztambide, S., Girbés, J., Ortega, E., Vendrell, J., Chacón, M.R., Chaves, F.J., Soriguer, F., Rojo-Martínez, G.

Objective The effects of C-peptide on adipose tissue, an organ involved in the development of obesity and insulin resistance, are not yet well known. The aim of this study was to determine whether C-peptide could be involved in the regulation of the adipocytokine synthesis in human visceral adipose tissue. Methods The association between C-peptide and different serum adipocytokines, with an intravenous glucose tolerance test (IVGTT), and in an in vitro study in subjects without obesity and in subjects with morbid obesity were analyzed. Results In different multiple regression analysis models, C-peptide and C-peptide increase above basal levels during total IVGTT and between 0 and 10 min were associated positively with leptin and negatively with visfatin. Rhodamine-labeled C-peptide binds to human adipocytes, and this binding was blocked with excess of unlabeled C-peptide. Exposure of human visceral explants and adipocytes from subjects with morbid obesity to C-peptide at 1 and 10 nM induced a significant increase in leptin and a decrease in visfatin secretion. In subjects without obesity, these C-peptide effects were found mainly at 10 nM. These effects can be inhibited by phosphatidylinositol 3-kinase (PI3K) or protein kinase B (PKB) inhibitors. Conclusions C-peptide may be involved in the regulation of leptin and visfatin secretion, molecules intimately involved in energy homeostasis processes, through PI3K or PKB pathways.

Enhancement of adiponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponectin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance.

BACKGROUND AND PURPOSE Peripheral blockade of cannabinoid CB1 receptors has been proposed as a safe and effective therapy against obesity, putatively devoid of the adverse psychiatric side effects of centrally acting CB1 receptor antagonists. In this study we analysed the effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist with poor brain penetration, in an animal model of diet-induced obesity. EXPERIMENTAL APPROACH To induce obesity, male Wistar rats were fed a high-fat diet (HFD; 60 kcal% fat) whereas controls received a standard diet (SD; 10 kcal% fat). Following 10 weeks of feeding, animals received a daily i.p. injection of vehicle or 3 mg·kg−1 LH-21 for 10 days. Plasma and liver samples were used for biochemical analyses whereas visceral fat-pad samples were analysed for lipid metabolism gene expression using real-time RT-PCR. In addition, the potential of LH-21 to interact with hepatic cytochrome P450 isoforms and cardiac human Ether-a-go-go Related Gene (hERG) channels was evaluated. KEY RESULTS LH-21 reduced feeding and body weight gain in HFD-fed animals compared with the control group fed SD. In adipose tissue, this effect was associated with decreased gene expression of: (i) leptin; (ii) lipogenic enzymes, including SCD-1; (iii) CB1 receptors; and (iv) both PPARα and PPARγ. Although there were no significant differences in plasma parameters between HFD- and SD-fed rats, LH-21 did not seem to induce hepatic, cardiac or renal toxicity. CONCLUSIONS AND IMPLICATIONS These results support the hypothesis that treatment with the peripherally neutral acting CB1 receptor antagonist, LH-21, may promote weight loss through modulation of visceral adipose tissue.

BACKGROUND AND PURPOSE The lack of safe and effective treatments for obesity has increased interest in natural products that may serve as alternative therapies. From this perspective, we have analysed the effects of daidzein, one of the main soy isoflavones, on diet-induced obesity in rats. EXPERIMENTAL APPROACH Rats made obese after exposure to a very (60%) high fat-content diet were treated with daidzein (50 mg·kg−1) for 14 days. The dose was selected on the basis of the acute effects of this isoflavone on a feeding test. After 14 days, animals were killed and plasma, white and brown adipose tissue, muscle and liver studied for the levels and expression of metabolites, proteins and genes relevant to lipid metabolism. KEY RESULTS A single treatment (acute) with daidzein dose-dependently reduced food intake. Chronic treatment (daily for 14 days) reduced weight gain and fat content in liver, accompanied by high leptin and low adiponectin levels in plasma. While skeletal muscle was weakly affected by treatment, both adipose tissue and liver displayed marked changes after treatment with daidzein, affecting transcription factors and lipogenic enzymes, particularly stearoyl coenzyme A desaturase 1, a pivotal enzyme in obesity. Expression of uncoupling protein 1, an important enzyme for thermogenesis, was increased in brown adipose tissue after daidzein treatment. CONCLUSIONS AND IMPLICATIONS These results support the use of isoflavones in diet-induced obesity, especially when hepatic steatosis is present and open a new field of use for these natural products.

Fundamento y objetivo Evaluar la hipotesis de que valores elevados de glucemia se asocian con menores valores sericos de acido urico, en 2 poblaciones independientes. Pacientes y metodo La primera poblacion procede del Estudio Pizarra, estudio prospectivo con 1.226 sujetos que se clasificaron segun su situacion metabolica tras una sobrecarga oral de glucosa. Se midieron variables antropometricas, valores basales de insulina, acido urico y resistencia a la insulina segun el Homeostasis Model Assessment (HOMA-IR). La segunda muestra procede de la base de datos del Hospital Universitario Carlos Haya (Malaga), que recoge 81.754 sucesivas peticiones analiticas de hemoglobina glucosilada (HbA1c) realizadas a lo largo de 30 meses. Resultados En el Estudio Pizarra los valores de glucosa se relacionaron con los valores de acido urico en ambos sexos. En la segunda muestra los valores de acido urico de mujeres siguieron una relacion en forma de campana con la HbA1c, incrementandose hasta valores de HbA1c del 7% y descendiendo a medida que la HbA1c aumentaba (p

The aim of this study was to assess the relationship between obesity and vitamin D status cross-sectionally, the relationship between obesity and the incidence of hypovitaminosis D prospectively and inversely the relationship between vitamin D status and incidence of obesity in a population-based cohort study in Spain. At baseline (1996-1998), 1226 subjects were evaluated and follow-up assessments were performed in 2002-2004 and 2005-2007, participants undergoing an interview and clinical examination with an oral glucose tolerance test. At the second visit, 25-hydroxyvitamin D and intact parathyroid hormone concentrations were also measured. Prevalence of obesity at the three visits was 28.1, 36.2 and 39.5%, respectively. The prevalence of vitamin D deficiency (25-hydroxyvitamin D ≤ 20 ng/ml (≤ 50 nmol/l)) was 34.7%. Neither obesity at baseline (OR=0.98, 95% CI: 0.69-1.40, P=0.93) nor the development of obesity between baseline and the second evaluation (OR=0.80, 95% CI: 0.48-1.33, P=0.39) were significantly associated with vitamin D status. In subjects who were non-obese (BMI30 kg/m²) at the second evaluation, 25-hydroxyvitamin D values ≤ 17 ng/ml (≤ 42.5 nmol/l) were significantly associated with an increased risk of developing obesity in the next 4 years (OR=2.35, 95% CI: 1.03-5.4, P=0.040 after diverse adjustments). We conclude that vitamin D deficiency is associated with an increased risk of developing obesity.

The effects of C-peptide on adipose tissue, an organ involved in the development of obesity and insulin resistance, are not yet well known. The aim of this study was to determine whether C-peptide could be involved in the regulation of the adipocytokine synthesis in human visceral adipose tissue.The association between C-peptide and different serum adipocytokines, with an intravenous glucose tolerance test (IVGTT), and in an in vitro study in subjects without obesity and in subjects with morbid obesity were analyzed.In different multiple regression analysis models, C-peptide and C-peptide increase above basal levels during total IVGTT and between 0 and 10 min were associated positively with leptin and negatively with visfatin. Rhodamine-labeled C-peptide binds to human adipocytes, and this binding was blocked with excess of unlabeled C-peptide. Exposure of human visceral explants and adipocytes from subjects with morbid obesity to C-peptide at 1 and 10 nM induced a significant increase in leptin and a decrease in visfatin secretion. In subjects without obesity, these C-peptide effects were found mainly at 10 nM. These effects can be inhibited by phosphatidylinositol 3-kinase (PI3K) or protein kinase B (PKB) inhibitors.C-peptide may be involved in the regulation of leptin and visfatin secretion, molecules intimately involved in energy homeostasis processes, through PI3K or PKB pathways.

Summary Background Results of studies examining the influence of age on thyroid function and TSH levels, in the absence of thyroid disease, remain controversial. The aim of this study was to determine the course of thyroid function over 11 years in a population with normal thyroid function. Methods This is a population-based prospective study started in 1995–1997 (first phase), and reassessed 6 (second phase) and 11 years later (third phase). Results The TSH and FT4 in the third phase were significantly increased (p = 0.001 and p = 0.001, respectively), with the values being higher particularly from the age of 50 years. In those persons with a baseline TSH ≥ 1.2 and

Introduction Irisin activates the thermogenic function in adipose tissues. However, little is known on the association between human irisin and different cardiometabolic risk factors. We analyse the influence of morbid obesity on irisin levels and its relation with leptin and different cardiovascular risk factors. Material and methods We measured the serum irisin level and the fibronectin type III domain containing 5 (FNDC5) expression in adipose tissue from 33 morbidly obese subjects and 12 nonobese subjects. We also studied the effect of leptin on FNDC5 expression. Results Serum irisin was higher in the nonobese subjects than in morbidly obese subjects, both before (P = 0·043) and after bariatric surgery (P = 0·042). The variable that best explained the serum irisin levels in a multiple linear regression model was the waist-to-hip ratio (WHR) (R2 = 0·201) (Beta = −0·357, P = 0·046). Those morbidly obese subjects with android-type obesity had lower serum irisin levels than those with gynecoid-type obesity, both before (P = 0·027) and after bariatric surgery (P = 0·006). Only the percentage change in WHR was associated with serum irisin levels after bariatric surgery (r = −0·529, P = 0·005). FNDC5 expression levels in subcutaneous adipose tissue (SAT) were higher in the nonobese than in the morbidly obese subjects (P = 0·042). In SAT explants from nonobese subjects, leptin (20 and 150 ng/mL) produced a decrease in FNDC5 expression (P = 0·009 and P = 0·037, respectively). Conclusions We showed decreased serum irisin levels in morbidly obese subjects, related mainly to WHR. FNDC5 expression could be regulated by leptin.

Peripheral blockade of cannabinoid CB(1) receptors has been proposed as a safe and effective therapy against obesity, putatively devoid of the adverse psychiatric side effects of centrally acting CB(1) receptor antagonists. In this study we analysed the effects of LH-21, a peripherally acting neutral cannabinoid receptor antagonist with poor brain penetration, in an animal model of diet-induced obesity.To induce obesity, male Wistar rats were fed a high-fat diet (HFD; 60 kcal% fat) whereas controls received a standard diet (SD; 10 kcal% fat). Following 10 weeks of feeding, animals received a daily i.p. injection of vehicle or 3 mg·kg(-1) LH-21 for 10 days. Plasma and liver samples were used for biochemical analyses whereas visceral fat-pad samples were analysed for lipid metabolism gene expression using real-time RT-PCR. In addition, the potential of LH-21 to interact with hepatic cytochrome P450 isoforms and cardiac human Ether-à-go-go Related Gene (hERG) channels was evaluated.LH-21 reduced feeding and body weight gain in HFD-fed animals compared with the control group fed SD. In adipose tissue, this effect was associated with decreased gene expression of: (i) leptin; (ii) lipogenic enzymes, including SCD-1; (iii) CB(1) receptors; and (iv) both PPARα and PPARγ. Although there were no significant differences in plasma parameters between HFD- and SD-fed rats, LH-21 did not seem to induce hepatic, cardiac or renal toxicity.These results support the hypothesis that treatment with the peripherally neutral acting CB(1) receptor antagonist, LH-21, may promote weight loss through modulation of visceral adipose tissue.

International audience; ABSTRACT Background: Vitamin D deficiency is common worldwide. No homogenous reference values have yet been established and no studies of values have been done in Spain involving a large number of participants. Objective: To study the population concentrations of vitamin D in a representative sample of the Spanish population. Subjects/Methods: The study involved two cohorts from Spain. The Asturias Study and the Pizarra Study are two prospective, population-based studies with 2260 participants. In 1262 subjects(age:20-83 years) we studied 25-hydroxyvitamin D, intact parathyroid hormone (PTHi), calcium, phosphorus and creatinine. Results: The median population values of 25-hydroxyvitamin D and PTHi were 22.46 ng/mL and 42.29 pg/mL, respectively. The values of 25-hydroxyvitamin D were significantly higher in summer and correlated with age (beta=-0.050.01, p

The endogenous cannabinoid system plays an important modulatory role in feeding behaviour and metabolism, acting at both central and peripheral levels. Chronic administration of cannabinoid CB1 receptor antagonists has been found to be effective in experimental obesity. However, clinically available cannabinoid receptor antagonists are inverse agonists that can target CB1 receptors located in both central circuits regulating appetite and motivation and in peripheral organs regulating metabolism and energy expenditure. This profile complicates understanding of cannabinoid CB1 receptor blockade as a therapeutic strategy in obesity and metabolic disorders. This review aims to explore the relevance of both inverse agonism and peripheral cannabinoid receptor blockade on the beneficial actions of chronic cannabinoid receptor blockade, by comparing the actions of the reference antagonist ⁄ inverse agonist rimonabant and the newly designed drug LH-21. LH-21 is a triazol derivative and a neutral cannabinoid receptor antagonist; it has a poor penetration rate into the central nervous system. When given acutely it decreases food intake and enhances the anorectic actions of oleoylethanolamide, a feeding suppressant lipid that acts on peripheral sensory terminals in a similar way as rimonabant. Unlike rimonabant, chronic administration of LH-21 (3 mg ⁄ kg) reduces feeding but does not improve hypertriglyceridaemia or hypercholesterolaemia; nor does it reduce liver fat deposits in Zucker rats. These results suggest that the inverse agonism and ⁄ or the antagonism of central cannabinoid CB1 receptors are necessary for the metabolic benefits of cannabinoid CB1 receptor blockade, but not for the appetite reduction, This work has been supported by MEC SAF 2004 ⁄ 07762, MEC SAF 2003 ⁄ 08003 ⁄ C02, MEC SAF 2003 ⁄ 02262, FIS 04 ⁄ 0834, FIS CP 04 ⁄ 0039; CB 06 ⁄ 03 ⁄ 0018, Plan Nacional Sobre Drogas, ISCIII Redes Tema´ticas RD06 ⁄ 001, Proyectos de Excelencia de la Consejeria de Innovación, Plan Andaluz de Investigación, Junta de Andalucía, and Fundacion Eugenio Rodriguez Pascual.