Context: Pediatric obesity is associated with endothelial dysfunction and hypoadiponectinemia, but the relationship between these two conditions remains to be fully clarified. Whether enhanced release of endothelin-1 (ET-1) may directly impair adiponectin (Ad) production in obese children is not known. Objective: The aim of the study was to explore whether and how high circulating levels of ET-1 may contribute to impair Ad production, release, and vascular activity. Design and Participants: Sixty children were included into obese (Ob; n = 30), overweight (OW; n = 11), and lean (n = 19) groups. Total and high-molecular-weight Ad, ET-1, vascular cell adhesion molecule-1, and von Willebrand factor levels were measured in serum samples. Adipocytes were stimulated with exogenous ET-1 or with sera from lean, OW, and Ob, and Ad production and release measured in the absence or in the presence of ET A (BQ-123) and ETB (BQ-788) receptor blockers, p42/44 MAPK inhibitor PD-98059, or c-Jun NH2-terminal protein kinase inhibitor SP-600125. Vasodilation to Ad was evaluated in rat isolated arteries in the absence or in the presence of BQ-123/788. Results: Total and high-molecular-weight Ad was significantly decreased and ET-1 levels significantly increased in OW (P < .01) and Ob (P < .001) children. A statistically significant linear regression (P < .01) was found between Ad and ET-1. Exposure of adipocytes to exogenous ET-1 or serum from OW and Ob significantly decreased Ad mRNA and protein levels (P < 0.001). The inhibitory effect of ET-1 on Ad was reverted by BQ-123/788 or PD-98059 but not SP-600125. Admediated vasodilation was further increased in arteries pretreated with BQ-123/788. Conclusions: ET-1-mediated inhibition of Ad synthesis via p42/44 MAPK signaling may provide a possible explanation for hypoadiponectinemia in pediatric obesity and contribute to the development of cardiovascular complications.

AIM: Although the underlined mechanisms are still unknown, metabolic/coagulation alterations related to childhood obesity can induce vascular impairments. The aim of this study was to investigate the relationship between metabolic/coagulation parameters and endothelial function/vascular morphology in overweight/obese children. METHODS: Thirty-five obese/overweight children (22 pre-pubertal, mean age: 9.52±3.35 years) were enrolled. Body mass index (BMI), homeostasis model assessment index (HOMAIR), metabolic and coagulation parameters, [adiponectin, fibrinogen, high molecular weight adiponectin (HMW), endothelin-1, and vonWillebrand factor antigen] ultrasound early markers of atherosclerosis [flow-mediated dilatation (FMD), common carotid intima-media thickness (C-IMT), and anteroposterior diameter of infra-renal abdominal aorta (APAO)] were assessed. RESULTS: APAO was related to anthropometric (age: r=0.520, p=0.001; height: r=0.679, p＜0.001; weight: r=0.548, p=0.001; BMI: r=0.607, p＜0.001; SBP: r=0.377, p=0.026) and metabolic (HOMAIR: r=0.357, p=0.035; HMW: r=－0.355, p=0.036) parameters. Age, height, and systolic blood pressure were positively related to increased C-IMT (r=0.352, p=0.038; r=0.356, p=0.036; r=0.346, p=0.042, respectively). FMD was not related to any clinical and biochemical characteristics of the pediatric population. Age, HOMAIR, fasting glucose levels, and HMW were independent predictors for APAO increase. Each unit decrease in HMW concentrations (1 μg/ml) induced a 0.065 mm increase in APAO. CONCLUSION: High molecular weight adiponectin is related to cardiovascular risk in overweight/obese children.

Adiponectin (Ad) is an insulin-sensitizing adipocytokine with anti-inflammatory and vasoprotective properties. Cleavage of native full-length Ad (fAd) by elastases from activated monocytes generates globular Ad (gAd). Increased gAd levels are observed in the proximity of atherosclerotic lesions, but the physiological meaning of this proteolytic Ad fragment in the cardiovascular system is controversial. We compared molecular and biological properties of fAd and gAd in human aortic endothelial cells (HAEC). In control HAEC, both fAd and gAd acutely stimulated nitric oxide (NO) production by AMPK-dependent pathways. With respect to fAd, gAd more efficiently increased activation of NF-kB signaling pathways resulting in cyclo-oxygenase 2 (COX-2) overexpression and COX-2-dependent prostacyclin 2 (PGI2) release. In contrast with fAd, gAd also increased p38MAPK phosphorylation and VCAM-1 expression, ultimately enhancing adhesion of monocytes to endothelial cells. In HAEC lacking AdipoR1 (by siRNA), both activation of NF-kB as well as COX-2 overexpression by gAd were abrogated. Conversely, gAd-mediated p38MAPK activation and VCAM-1 expression were unaffected, and monocyte adhesion greatly enhanced. In HAEC lacking COX-2 (by siRNA), reduced levels of PGI2 further increased gAd-dependent monocyte adhesion. Our findings suggest that biological activities of fAd and gAd in endothelium do not completely overlap, with gAd possessing both AdipoR1- dependent ability to stimulate COX-2 expression and AdipoR1-independent effects related to expression of VCAM-1 and adhesion of monocytes to endothelium.

The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelial-derived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

The present invention relates to the use of compounds having a galloyl benzamide structure in the treatment and/or prevention of medical conditions mediated through c-Jun N-terminal kinases (JNKs) and to pharmaceutical compositions comprising said compounds.