Metabolic Syndrome, Chronic Kidney, and Cardiovascular Diseases: Role of Adipokines

Obesity is a chronic disease, whose incidence is alarmingly growing. It is associated with metabolic abnormalities and cardiovascular complications. These complications are clustered in the metabolic syndrome (MetS) leading to high cardiovascular morbidity and mortality. Obesity predisposes to diabetic nephropathy, hypertensive nephrosclerosis, and focal and segmental glomerular sclerosis and represents an independent risk factor for the development and progression of chronic kidney disease (CKD). Albuminuria is a major risk factor for cardiovascular diseases (CVDs). Microalbuminuria has been described as early manifestation of MetS-associated kidney damage and diabetic nephropathy. Obesity and MetS affect renal physiology and metabolism through mechanisms which include altered levels of adipokines such as leptin and adiponectin, oxidative stress, and inflammation. Secretory products of adipose tissue also deeply and negatively influence endothelial function. A better understanding of these interactions will help in designing more effective treatments aimed to protect both renal and cardiovascular systems

Association between High Normal TSH Levels and Obesity in Women with Anti-Thyroid Autoantibodies (ATAs)

A positive correlation between Thyroid-Stimulating Hormone (TSH) and Body Mass Index (BMI) has been reported in many studies, but data on this topic remain controversial, especially when TSH values are in the normal range. Moreover, few studies have evaluated the co-existence of thyroid autoimmunity. This study investigated the role of thyroid autoimmunity in the interconnection between TSH, BMI, and waist circumference (WC) in euthyroid patients with overweight or obesity. We enrolled 902 patients (213 males; mean age +/- SD: 45 +/- 14 years; mean BMI +/- SD: 35.8 +/- 6.5 kg/m(2)), with normal serum TSH concentration; anti-thyroid autoantibodies (ATAs) were evaluated in 752 patients (186 males). Patients were divided into four BMI classes, based on WHO criteria, and the relationship between BMI, WC, and TSH was evaluated in the whole sample and compared to ATAs positivity, observed in 235 patients (44 males). No significant difference was found between TSH levels in the BMI classes. A statistically significant correlation between TSH and BMI was found only in ATAs-positive females (N = 191, Spearman rho: 0.149; p-value: 0.040). However, this finding was not confirmed when considering the WC. Our study shows a positive correlation only between TSH and BMI in obese women with positive ATAs, suggesting that in these patients, the high normal levels of TSH could be attributed to a mild thyroid failure with a possible worsening obesity-related effect, and both need a careful evaluation

Transcriptomic and morphological characterization of a first Zebrafish model of Limb Girdle Muscular Dystrophy D2

Limb Girdle Muscular Dystrophy D2 (LGMD D2) is a rare neuromuscular disorder caused by a heterozygous mutation in the termination codon of the TNPO3 gene. This gene encodes for Transportin-3 (TNPO3), an importin which normally mediates the translocation to the nucleus of SR proteins, a family of splicing factors and other proteins related to RNA metabolism. LGMD D2 is characterized by high variability in the onset and progression of the disorder, and the main clinical features are progressive muscle weakness and marked atrophy. Several mutations have been described as causative of LGMD D2, all resulting in a mutated protein that is 15-aminoacids longer in its C-terminal domain. However, the pathogenetic mechanism of this disorder remains unknown. This project aims at investigating the pathogenesis of LGMD D2 utilizing an in vivo approach based on the creation of a Zebrafish model of disease. We focused on the role of TNPO3 on muscle development to identify any potential molecular pathways linked to the disorder. Experimentally we proceeded with the microinjection of mRNAs encoding the wild type or mutated form of human TNPO3 into Zebrafish embryos, to follow their effects on the myogenic processes during development up to 48 hpf. The subsequent analysis showed abnormalities in the gene expression profiles of Myogenic Regulatory Factors (MRFs) and muscle-specific proteins, suggesting an unbalance in the normal myogenic process. Next, we analysed how the transcriptomic alterations were reflected at a morphological level by transmission electron microscopy studies. At ultrastructural level we observed a random organization of myofibrils limited to the embryos microinjected with the mutant form of human TNPO3. These results suggest that our approach could be effective in establishing a Zebrafish model of LGMD D2 and enabled us to gain an initial understanding of the role of TNPO3 in muscle development and the pathogenic mechanism of LGMD D2

Effects of eritoran on LPS-induced mRNA expression (arbitrary units) of TNFα (top left panel), CCL-2 (top right panel), IL-6 (middle left panel), IL-8 (middle right panel), VCAM (bottom left panel), and ICAM (bottom right panel).

<p>Values reported as mean±SD (n = 5 per group). CT: control; ER: eritoran; LPS: lipopolysaccharide; ER/LPS: eritoran/lipopolysaccharide. *p<0.05 vs CT, ER, and LPS/ER.</p

Flow-mediated dilation (top left panel) and plasma levels of IL-6 (top right panel), IL-8 (middle left panel), VCAM (middle right panel), ICAM (bottom left panel), and MCP-1 (bottom right panel) according to TLR4 genotype in study participants.

<p>Values reported as mean±SD.</p

Baseline Characteristics of Study Participants.

<p>DMARD: disease-modifying anti-rheumatic drug; anti-CCP: anti-cyclic citrullinated peptide antibodies; ESR: erythrocyte sedimentation rate. hsCRP: high sensitivity C-reactive protein; BMI: body mass index.</p><p>*p value calculated using Fisher exact test and ^#p value calculated using one way ANOVA; all other p values calculated using unpaired t test.</p><p>Values are reported as mean ± SD unless specified otherwise.</p

Representative Western blots (top panel) and bar graphs showing the effect of eritoran on LPS-induced phosphorylation of NF-κB p65 subunit (bottom left panel) and IκB-α (bottom right panel) (n = 5 per group).

<p>Bottom left panel: *p<0.05 vs CT; NS: p>0.05 vs LPS/ER. Bottom right panel: **p<0.005 vs CT; NS: p>0.05 vs LPS/ER.</p

Effects of eritoran on OxPAPC-induced mRNA expression (arbitrary units) of IL-6 (top panel) and IL-8 (middle panel) and on FFA-induced mRNA expression (arbitrary units) of IL-6 (bottom panel).

<p>Values reported as mean±SD (n = 5 per group). CT: control; ER: eritoran; OxPAPC: oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine; FFA: free fatty acids; OxPAPC/ER: oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine/eritoran. Top panel: *p<0.05 vs CT and ER; NS: p = 0.07 vs OxPAPC/ER. Middle panel: *p<0.05 vs CT, ER, and OxPAPC/ER. Bottom panel: *p<0.05 vs CT and ER; NS: p>0.05 vs FFA/ER.</p

Representative images of the baseline brachial ultrasound of a participant with the aa genotype (top left picture), of a participant with the ag genotype (top right picture), and of the baseline and post-hyperemic ultrasound of a healthy control (bottom pictures).

<p>The calculation of flow-mediated dilation (FMD) using the values collected in the healthy control is also reported.</p