Rapid in vivo PGC-1 mRNA upregulation in brown adipose tissue of Wistar rats by a beta(3)-adrenergic agonist and lack of effect of leptin.

Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) is highly expressed in brown adipose tissue (BAT) and plays an important role in adaptive thermogenesis. The aim of this study was to assess the acute effect of a β3-adrenergic agonist (Trecadrine) and leptin on the expression of PGC-1 and PPARγ2 mRNA in BAT. Trecadrine produced a marked increase (4.5-fold) in PGC-1 mRNA compared to controls (P<0.001) without changes in PPARγ2 mRNA, whereas leptin administration did not alter either PGC-1 or PPARγ2 expression. These results show that selective stimulation of the β3-adrenoceptor rapidly upregulates the expression of PGC-1 in brown adipocytes without a concomitant increase in PPARγ2. Moreover, our results show that PGC-1 and PPARγ2 expression in BAT seems not to be acutely regulated by leptin

Prevalencia de diabesidad en España: depende de cómo se defina la obesidad

La obesidad representa la enfermedad metabólica más prevalente a nivel mundial, conllevando un aumento de la morbi-mortalidad y la consiguiente disminución en la esperanza de vida1. A pesar de la magnitud del problema y de la atención que recibe en las publicaciones científicas, la pandemia sigue creciendo de forma imparable. Según un estudio reciente llevado a cabo en 200 países, la prevalencia de la obesidad en el mundo se ha multiplicado por seis en los últimos 40 años4. La prevalencia de obesidad en Europa varía entre el 12 y el 26%5, rango dentro del cual se encuentran también las cifras en la población adulta española, entorno al 22%6. La obesidad se ha convertido en una de las principales causas de muerte, ya que constituye el principal factor de riesgo para una serie de enfermedades no transmisibles, en particular la diabetes tipo 2 (DT2)7,8. Esta estrecha relación llevó hace unos años a acuñar el término diabesidad, destacando el hecho de que la mayoría de las personas con DT2 tienen obesidad

Adipose tissue as an endocrine organ: role of leptin and adiponectin in the pathogenesis of cardiovascular diseases

Obesity, the most common nutritional disorder in industrial countries, is associated with increased cardiovascular mortality and morbidity. Nevertheless, the molecular basis linking obesity with cardiovascular disturbances have not yet been fully clarified. Recent advances in the biology of adipose tissue indicate that it is not simply an energy storage organ, but also a secretory organ, producing a variety of bioactive substances, including leptin and adiponectin, that may influence the function as well as the structural integrity of the cardiovascular system. Leptin, besides being a satiety signal for the central nervous system and to be related to insulin and glucose metabolism, may also play an important role in regulating vascular tone because of the widespread distribution of functional receptors in the vascular cells. On the other hand, the more recently discovered protein, adiponectin, seems to play a protective role in experimental models of vascular injury, in probable relation to its ability to suppress the attachment of monocytes to endothelial cells, which is an early event in the atherosclerotic process. There is already considerable evidence linking altered production of some adipocyte hormones with the cardiovascular complications of obesity. Therefore, the knowledge of alterations in the endocrine function of adipose tissue may help to further understand the high cardiovascular risk associated with obesity

Leptin Inhibits Angiotensin II-Induced Intracellular Calcium Increase and Vasoconstriction in the Rat Aorta

Besides its role in body weight control leptin may also act as a vasoactive hormone. This study was designed to investigate whether leptin modifies angiotensin II (ANG II)-induced vascular responses. The expression of functional leptin receptors (OB-Rb) was detected in vascular smooth muscle cells (VSMCs) from adult Wistar rats by RT-PCR. Immunocytochemistry and Western blot analysis further showed the expression of OB-R protein in VSMCs. The ANG II (10(-7) mol/liter)-induced increase in intracellular Ca(2+) was blocked (P < 0.01) by leptin (10(-8) mol/liter). Moreover, in calcium-free buffer leptin was able to inhibit 65% of the ANG II-induced calcium release from intracellular stores. In endothelium-denuded aortic rings from adult Wistar rats no effect of leptin on basal tension was observed. However, the ANG II-induced isometric contraction was reduced (P < 0.05) by leptin (10(-8) mol/liter). The experiments were also performed in age- and sex-matched Zucker rats, in which no effect of leptin on ANG II-induced calcium increase and vasoconstriction was observed. It is concluded that leptin blocks the vasoconstrictor action of ANG II and inhibits the ANG II-induced increase in intracellular Ca(2+) in VSMCs through OB-Rb. These findings provide new insight into the physiological effects of leptin on blood pressure regulation

The inhibitory effect of leptin on angiotensin II-induced vasoconstriction in vascular smooth muscle cells is mediated via a nitric oxide-dependent mechanism

Leptin inhibits the contractile response induced by angiotensin (Ang) II in vascular smooth muscle cells (VSMCs) of the aorta. We studied in vitro and ex vivo the role of nitric oxide (NO) in the effect of leptin on the Ang II-induced vasoconstriction of the aorta of 10-wk-old Wistar rats. NO and nitric oxide synthase (NOS) activity were assessed by the Griess and (3)H-arginine/citrulline conversion assays, respectively. Stimulation of inducible NOS (iNOS) as well as Janus kinases/signal transducers and activators of transcription (JAK/STAT) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were determined by Western blot. The contractile responses to Ang II were evaluated in endothelium-denuded aortic rings using the organ bath system. Changes in intracellular Ca(2+) were measured in VSMCs using fura-2 fluorescence. Leptin significantly (P < or = 0.01) stimulated NO release and NOS activity in VSMCs. Leptin's effect on NO was abolished by the NOS inhibitor, N(G)-monomethyl l-arginine, or the iNOS selective inhibitor L-N(6)-(1-iminoethyl)-lysine. Accordingly, leptin increased iNOS protein expression, with a comparable time course with that of NO production and NOS activity. Leptin also significantly increased STAT3 (P < or = 0.01) and Akt (P < or = 0.001) phosphorylation. Moreover, either the JAK2 inhibitor, AG490, or the PI3K inhibitor, wortmannin, significantly (P < or = 0.05) abrogated the leptin-induced increase in iNOS protein. Finally, both N(G)-monomethyl L-arginine and L-N(6)-(1-iminoethyl)-lysine inhibitors completely blunted (P < or = 0.001) the leptin-mediated inhibition of the Ang II-induced VSMC activation and vasoconstriction. These findings suggest that the endothelium-independent depressor action of leptin is mediated by an increase of NO bioavailability in VSMCs. This process requires the up-regulation of iNOS through mechanisms involving JAK2/STAT3 and PI3K/Akt pathways

Association of increased Visfatin/PBEF/NAMPT circulating concentrations and gene expression levels in peripheral blood cells with lipid metabolism and fatty liver in human morbid obesity

BACKGROUND AND AIMS: Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine with physiological effects on the control of glucose homeostasis as well as potentially involved in inflammation. The association of circulating NAMPT concentrations with obesity has not been clearly established. The aim of the present work was to evaluate the effect of obesity on circulating concentrations and gene expression levels of NAMPT in human peripheral blood cells (PBCs) as well as its involvement in inflammation, glucose and lipid metabolism. METHODS AND RESULTS: Forty-four serum samples obtained from 14 lean and 30 obese volunteers were used to analyse the circulating concentrations of NAMPT. In addition, PBC, omental adipose tissue (OM) and liver biopsy samples obtained from a subgroup of subjects were used to determine transcript levels of NAMPT by Real-time PCR. Glucose and lipid profile as well as several inflammatory factors and hepatic enzymes were analysed. NAMPT circulating concentrations (P<0.01) and gene expression levels in PBC (P<0.05) were significantly increased in obese patients as compared to lean subjects. Total-cholesterol (P=0.016), HDL-cholesterol (P=0.036) and triglycerides (P=0.050) were significant and independent determinants of circulating concentrations of NAMPT (P<0.01). Moreover, a positive correlation (P<0.01) was found with the hepatic enzymes alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase after BMI adjustment. CONCLUSION: Our work shows that NAMPT circulating concentrations and mRNA expression levels in PBC are increased in obese patients and that plasma NAMPT levels are related to inflammation, lipid metabolism and hepatic enzymes suggesting a potential involvement in fatty liver disease and in the obesity-associated inflammatory stat

The obestatin receptor (GPR39) is expressed in human adipose tissue and is down-regulated in obesity-associated type 2 diabetes mellitus

The G protein-coupled receptor 39 (GPR39) has recently been identified as the receptor for obestatin, a peptidic hormone involved in energy homeostasis. However, the expression levels of this receptor in human adipose tissue in obesity and obesity-associated type 2 diabetes mellitus (T2DM) remain unknown. Therefore, we evaluated the actual presence of GPR39 mRNA in human adipose tissue and whether GPR39 expression levels are altered in obesity and obesity-associated T2DM. DESIGN: Omental adipose tissue biopsies obtained from 15 women were used in the study. Patients were classified as lean (body mass index 20.8 +/- 1.0 kg/m(2)), obese normoglycaemic (body mass index 48.4 +/- 2.1 kg/m(2)) and obese T2DM patients (body mass index 52.6 +/- 4.9 kg/m(2)). Anthropometric measurements and biochemical profiles were assessed for each subject. Real-time RT-PCR analyses were performed to quantify transcript levels of GPR39 and adiponectin. RESULTS: Obese T2DM patients exhibited significantly lower GPR39 expression levels compared to lean (P = 0.016) and obese normoglycaemic subjects (P = 0.008), while no differences between lean and obese normoglycaemic patients were observed. The mRNA expression levels of GPR39 were negatively correlated to fasting glucose concentrations (r = -0.581, P = 0.023), while exhibiting a positive correlation to adiponectin mRNA expression levels (r = 0.674, P = 0.006). CONCLUSION: GPR39 is expressed in human adipose tissue. The reduced expression levels of GPR39 in omental adipose tissue observed in obese patients with T2DM suggest an involvement of obestatin signalling in glucose homeostasis and T2DM development

Mejora en la calidad de vida tras cirugía bariátrica

La obesidad se ha convertido en las últimas décadas en una de las principales causas de morbi-mortalidad. A pesar de la alarma despertada, la pandemia sigue creciendo de forma imparable. La prevalencia de obesidad en la población adulta española se estima en un 23%. Las cifras en Navarra son similares a las encontradas en el resto del país. Tanto el sobrepeso como la obesidad se asocian a un mayor riesgo de padecer enfermedades cardiovasculares, diabetes tipo 2, dislipidemia, accidentes cerebrovasculares, síndrome de apneas obstructivas del sueño, y desarrollo de determinados tipos de cáncer. Diversos estudios apuntan que el impacto económico de la obesidad supone entre un 2 y un 7% del total del gasto sanitario, pudiendo conllevar un coste en todo el país de hasta 5.000 millones de euros anuales. A pesar del enorme problema de salud, se ha demostrado que en la práctica médica no le estamos prestando la atención necesari

Adiponectin-leptin Ratio is a Functional Biomarker of Adipose Tissue Inflammation

Obesity favors the development of cardiometabolic alterations such as type 2 diabetes (T2D) and the metabolic syndrome (MS). Obesity and the MS are distinguished by an increase in circulating leptin concentrations, in parallel to a drop in the levels of adiponectin. Consequently, the Adpn/Lep ratio has been suggested as a maker of dysfunctional adipose tissue. We aimed to investigate in humans (n = 292) the reliability of the Adpn/Lep ratio as a biomarker of adipose tissue dysfunction. We considered that an Adpn/Lep ratio of ≥1.0 can be considered normal, a ratio of ≥0.5 <1.0 suggests moderate-medium increased risk, and a ratio of <0.5 indicates a severe increase in cardiometabolic risk. Using these cut-offs, 5%, 54% and 48% of the lean, normoglycemic and without-MS subjects, respectively, fall within the group with an Adpn/Lep ratio below 0.5; while 89%, 86% and 90% of the obese, with T2D and with MS patients fall within the same group (p < 0.001). A significant negative correlation (r = -0.21, p = 0.005) between the Adpn/Lep ratio and serum amyloid A (SAA) concentrations, a marker of adipose tissue dysfunction, was found. We concluded that the Adpn/Lep ratio is a good indicator of a dysfunctional adipose tissue that may be a useful estimator of obesity- and MS-associated cardiometabolic risk, allowing the identification of a higher number of subjects at risk

Involvement of leptin in the association between percentage of body fat and cardiovascular risk factors

OBJECTIVES: Recent epidemiologic studies have shown that obesity is associated with elevated blood concentrations of prothrombotic-proinflammatory factors and markers of endothelial dysfunction such as fibrinogen, C-reactive protein (CRP), von Willebrand factor (vWF), and homocysteine. We have assessed whether these markers are associated with percentage of body fat (BF), insulin sensitivity as well as with leptin concentrations. DESIGN AND METHODS: Twenty-five men aged 49.6 +/- 12.7 yr (mean +/- SD) underwent whole-body air displacement plethysmography (Bod-Pod(R)) for estimating BF. Blood analyses for leptin and several other metabolic and cardiovascular markers were carried out. RESULTS: Obese subjects had higher levels as compared to controls of BF (37.5 +/- 5.1 vs. 26.0 +/- 6.6, p < 0.01), fibrinogen (3.30 +/- 0.43 vs. 2.67 +/- 0.11, p < 0.01), vWF (136.4 +/- 50.4% vs. 81.6 +/- 12.6%, p < 0.05), and leptin (17.6 +/- 8.7 vs. 6.2 +/- 3.3, p < 0.01), lower concentrations of HDL-cholesterol (1.09 +/- 0.20 vs. 1.51 +/- 0.10, p < 0.001) and lower QUICKI (1/[log(Ins(0)) + log(Glu(0))]) (0.31 +/- 0.03 vs. 0.34 +/- 0.02, p < 0.05). No significant changes were observed in CRP (5.7 +/- 3.4 vs. 3.8 +/- 1.6, p = 0.327) and homocysteine (9.4 +/- 4.2 vs. 8.3 +/- 0.9, p = 0.749). A positive correlation was observed between BF and fibrinogen (r = 0.67, p = 0.0003). Plasma leptin concentrations were correlated with fibrinogen (r = 0.71, p = 0.0001) and CRP (r = 0.43, p = 0.044). After adjustment for BF leptin emerged as a significant predictor of fibrinogen (beta = 0.47, p = 0.023; R(2) = 0.59, p < 0.001). QUICKI was positively correlated with HDL-cholesterol (r = 0.59, p = 0.010) and negatively with fibrinogen (r = -0.53, p = 0.025), CRP (r = -0.52, p = 0.028) and vWF (r = -0.56, p = 0.013). CONCLUSIONS: Increased BF and impaired insulin sensitivity are associated with increased concentrations of cardiovascular risk factors. Leptin seems to be involved in this elevation and emerges as a predictor of circulating fibrinogen concentrations