The Role of Adipokines and Myokines in the Pathogenesis of Different Obesity Phenotypes-New Perspectives.

Obesity is a characteristic disease of the twenty-first century that is affecting an increasing percentage of society. Obesity expresses itself in different phenotypes: normal-weight obesity (NWO), metabolically obese normal-weight (MONW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). A range of pathophysiological mechanisms underlie the occurrence of obesity, including inflammation, oxidative stress, adipokine secretion, and other processes related to the pathophysiology of adipose tissue (AT). Body mass index (BMI) is the key indicator in the diagnosis of obesity; however, in the case of the NWO and MONW phenotypes, the metabolic disturbances are present despite BMI being within the normal range. On the other hand, MHO subjects with elevated BMI values do not present metabolic abnormalities. The MUO phenotype involves both a high BMI value and an abnormal metabolic profile. In this regard, attention has been focused on the variety of molecules produced by AT and their role in the development of obesity. Nesfatin-1, neuregulin 4, myonectin, irisin, and brain-derived neurotrophic factor (BDNF) all seem to have protective effects against obesity. The primary mechanism underlying the action of nesfatin-1 involves an increase in insulin sensitivity and reduced food intake. Neuregulin 4 sup-presses lipogenesis, decreases lipid accumulation, and reduces chronic low-grade inflammation. Myonectin lowers the amount of fatty acids in the bloodstream by increasing their absorption in the liver and AT. Irisin stimulates the browning of white adipose tissue (WAT) and consequently in-creases energy expenditure, additionally regulating glucose metabolism. Another molecule, BDNF, has anorexigenic effects. Decorin protects against the development of hyperglycemia, but may also contribute to proinflammatory processes. Similar effects are shown in the case of visfatin and chemerin, which may predispose to obesity. Visfatin increases adipogenesis, causes cholesterol accumulation in macrophages, and contributes to the development of glucose intolerance. Chemerin induces angiogenesis, which promotes the expansion of AT. This review aims to discuss the role of adipokines and myokines in the pathogenesis of the different obesity phenotypes.

The Relation between Resistin (-420C/G) Single Nucleotide Variant, Resistin Serum Concentration, Carbohydrate, and Lipid Parameters and Fried Food Taste Preference in Patients with Hypertriglyceridemia.

BACKGROUND: Resistin is a proinflammatory adipokine involved in metabolic disorders. Its interplay with hypertriglyceridemia remains to be elucidated. We aimed to evaluate the relationship between resistin (-420C/G) single nucleotide variant (SNV) and metabolic parameters and preference for fried food consumption in hypertriglyceridemia. METHODS: The study enrolled 179 hypertriglyceridemic (HTG) and 182 normotriglyceridemic (NTG) patients. Anthropometric measurements, serum resistin, insulin and fasting glucose concentration, a homeostatic model assessment-insulin resistance (HOMA-IR), triglycerides (TG), cholesterol concentration, and fried food taste preference (FP) or other cooking methods preference (OP) were assessed in the study. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: HTG and NTG groups did not differ significantly in serum resistin concentration; HTG individuals demonstrated significantly increased serum levels of TG, glucose, total cholesterol (TCH), and HOMA-IR and decreased HDL cholesterol. Resistin, insulin, glucose, HOMA-IR, and cholesterol fractions were similar among particular resistin genotypes in HTG, NTG, FP, or OP groups. TG and TCH concentrations differ significantly among CG and CC genotypes in the FP group. Considering the FP group, GG and CG genotypes appeared more frequently in hyperlipidemic (OR 2.6 95% CI; 1.16-5.82; p = 0.01; significant after Bonferroni correction) than in NTG patients. Multivariable logistic regression models showed that the G allele and CG genotype of SNV (-420C/G), adjusted for selected confounders such as fried food preference, increased the odds of hypertriglyceridemia about twofold. CONCLUSIONS: Allele G and CG genotype of resistin SNV (-420C/G) are linked with the preference for fried food taste in hypertriglyceridemic patients.

Association of GLP1R variants rs2268641 and rs6923761 with obesity and other metabolic parameters in a Polish cohort.

Introduction: Obesity is a complex disease associated with excessive fat accumulation and numerous metabolic complications. So far, many factors leading to the development of this disorder have been identified, including genetic susceptibility. Various studies linked GLP1R variants with anthropometric and metabolic parameters, suggesting the role of the variation in this gene in metabolic health. Objective: The aim of this study is to investigate the association of two single nucleotide variants of GLP1R gene, rs2268641 and rs6923761, with excessive weight, metabolic syndrome, anthropometric measurements and selected metabolic parameters. Methods: Normal-weight subjects (n= 340, control group) and subjects with excessive body mass (n = 600, study group) participated in this study. For all participants, anthropometric measurements and metabolic parameters were collected, and genotyping of the two single nucleotide variants of GLP1R gene, rs2268641 and rs6923761, was performed using the high-resolution melting curve analysis. Results: Significant differences in the genotype distribution of rs2268641 were found, where homozygous TT genotype was significantly less frequent in the study group with excessive body mass (OR=0.66; p=0.0298). For rs6923761, A allele and homozygous AA genotype were significantly more frequent in the study group with excessive weight than in the control group (OR=1.27; p=0.0239 and OR=1.69; p=0.0205, respectively). The association of studied variants with metabolic parameters was found for rs6923761. For this variant, AA carriers had higher body mass in comparison to GG carriers (p=0.0246), and AA carriers had higher glucose concentration in comparison to AG carriers (p=0.0498). We did not find an association of rs2268641 and rs6923761 with metabolic syndrome. Conclusion: In our study, AA carriers of rs6923761 had higher risk of excessive body mass, whereas TT carriers of rs2268641 had lower risk of being overweight. Moreover, homozygous carriers of the minor allele of rs6923761 had higher glucose concentration in comparison to heterozygous subjects. None of the studied variants were associated with metabolic syndrome in the studied population.

The Link between Three Single Nucleotide Variants of the GIPR Gene and Metabolic Health.

Single nucleotide variants (SNVs) of the GIPR gene have been associated with BMI and type 2 diabetes (T2D), suggesting the role of the variation in this gene in metabolic health. To increase our understanding of this relationship, we investigated the association of three GIPR SNVs, rs11672660, rs2334255 and rs10423928, with anthropometric measurements, selected metabolic parameters, and the risk of excessive body mass and metabolic syndrome (MS) in the Polish population. Normal-weight subjects (n = 340, control group) and subjects with excessive body mass (n = 600, study group) participated in this study. For all participants, anthropometric measurements and metabolic parameters were collected, and genotyping was performed using the high-resolution melting curve analysis. We did not find a significant association between rs11672660, rs2334255 and rs10423928 variants with the risk of being overweight. Differences in metabolic and anthropometric parameters were found for investigated subgroups. An association between rs11672660 and rs10423928 with MS was identified. Heterozygous CT genotype of rs11672660 and AT genotype of rs10423928 were significantly more frequent in the group with MS (OR = 1.38, 95%CI: 1.03-1.85; p = 0.0304 and OR = 1.4, 95%CI: 1.05-1.87; p = 0.0222, respectively). Moreover, TT genotype of rs10423928 was less frequent in the MS group (OR = 0.72, 95%CI: 0.54-0.95; p = 0.0221).

The Association between Serum Resistin Level, Resistin (-420C/G) Single Nucleotide Variant, and Markers of Endothelial Dysfunction, including Salt Taste Preference in Hypertensive Patients.

Background: Resistin action links to conditions such as diabetes, obesity, but its role in hypertension is less well understood. This study aimed to estimate the relationship between resistin (-420G/C) single nucleotide variant (SNV) and markers associated with endothelial dysfunction in hypertension. Methods: The study enrolled 162 hypertensive patients (HT) and 165 non-hypertensive (NHT) patients. Resistin serum concentration was estimated with immuoenzymatic assay. Anthropometric measurements, blood pressure and arterial stiffness index (SI), uric acid (UA) serum concentration, and salty taste preference of normal (NS) or high (HS) were assessed in the study. Genotyping was achieved by polymerase chain reaction-restriction fragment length polymorphism. Results: Resistin concentration and SI do not differ significantly between HT and NHT individuals; UA significantly increased in HT subjects. Resistin, UA, and SI did not differ among particular resistin genotypes in HT, NHT, NS, or HS groups. GG and CG genotypes were more frequent (OR 1.57 (95% CI; 1.01-2.43); p = 0.04) in hypertensive individuals than the NHT group, but less frequent (OR 0.58 (95% CI; 0.37-0.91); p = 0.01) in HS patients compared to NS individuals. Concerning HT patients with different salt preferences, GG + CG genotypes were less frequent (OR 0.50 (95% CI; 0.26-0.97); p = 0.04) in the HS group than in NS individuals. HT carriers of GG and CG genotype have significantly increased UA concentrations compared to the respective NHT subjects. HS individuals carrying GG and CG genotypes have higher SI values than the NS group. Allele G of SNV (-420G/C) adjusted for age, BMI, serum resistin, UA concentration, salt taste preference, SI, and HR values increased the risk of developing hypertensive phenotype 1.8 fold. Conclusions: Resistin SNV (-420G/C) is related to several markers associated with endothelial dysfunction, including salt taste preference in hypertensive patients.

Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective.

The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins-glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.

Association of serum omentin concentration with anthropometric, physiological, and biochemical parameters in obese individuals.

OBJECTIVE: Omentin is a secretory protein produced in visceral adipose tissue. The potential protective action of omentin in metabolic disorders is not yet fully understood. The aim of this study was to determine the association of omentin with anthropometric, physiologic, and biochemical parameters in obese individuals. METHODS: Sixty obese individuals and 40 normal weight controls were enrolled in the study. Anthropometric measurements were taken, systolic (SBP) and diastolic blood pressures (DBP) were recorded. Serum fasting glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), lipid profile, and serum omentin concentrations were determined. RESULTS: The concentration of omentin in obese individuals was significantly lower than in controls (145.5 ± 33.3 versus 383.6 ± 92.9; P < 0.001). Omentin correlated negatively with waist circumference (P < 0.01), hip circumference (P < 0.05), percent of adipose tissue (P < 0.001), fasting insulin (P < 0.001), HOMA-IR (P < 0.001), and SBP (P < 0.001) in the patients who were obese. A positive relationship was documented with high-density lipoprotein in both the obese patients (P < 0.01) and the overall population (P < 0.001). Multiple negative omentin correlations with body weight, body mass index, waist and hip circumference and its ratio, percent of adipose tissue, SBP, triacylglycerols, glucose, fasting insulin, and HOMA-IR were demonstrated in the entire population. In the multivariate linear regression model, insulin concentration (ß = -0.49; P < 0.001), percent of adipose tissue (ß = -0.31; P < 0.001), and waist circumference (ß = -0.21; P < 0.01) were independent predictors of omentin concentration in individuals who were obese. CONCLUSIONS: A concentration of omentin is associated with cardiometabolic risk-related factors in obesity. Fasting insulin, adipose tissue percentage, and waist circumference can be considered candidates for markers of omentin concentration in obese individuals.

The effect of nebivolol and ramipril on selected biochemical parameters, arterial stiffness, and circadian profile of blood pressure in young men with primary hypertension: A 12-week prospective randomized, open-label study trial.

BACKGROUND: The pleiotropic effects of hypotensive drugs should always be taken into consideration. There is limited data on the effect of such drugs on reducing global cardiovascular risk in young hypertensives. The aim of this study was to evaluate the effect of nebivolol and ramipril on biochemical parameters, arterial stiffness, and circadian profile of blood pressure (BP) in young men undergoing treatment for hypertension (HT). METHODS: A total of 80 patients aged 16 to 28 years of age with grade 1 HT were enrolled into the prospective randomized, open-label trial. They were randomized to receive 5 mg of nebivolol or 5 mg of ramipril, daily. Arterial stiffness index (SI), the circadian profile of BP registered in ambulatory blood pressure monitoring (ABPM), and biochemical parameters-including lipid profile, insulinemia, glycemia, and high sensitivity C-reactive protein (hsCRP) levels-were evaluated before and after the twelve-week period. RESULTS: After the treatment period, we observed significant decreases in both ABPM systolic blood pressure (SBP) in group of nebivolol (P = .0007) and ramipril (P = .0001) and in ABPM diastolic blood pressure (DBP) in group of nebivolol (P = .0018) and ramipril (P = .0006). Reductions in the nondippers percentage were found in group of nebivolol and ramipril (P = .0077, P = .0001 respectively). Ramipril treatment resulted in a significant plausible modification in high-density lipoprotein (HDL) (P = .0390), glucose (P = .0213), and hsCRP (P = .0053) concentrations, as well as decreased SI (P = .0009) value, while nebivolol treatment showed no such benefits. CONCLUSIONS: Despite the similar hypotensive effect of nebivolol and ramipril, ramipril seems to possess better clinical potential in reducing cardiovascular risk in young men with HT.

Plasma total homocysteine is a determinant of carotid intima-media thickness and circulating endothelial progenitor cells in patients with newly diagnosed hypertension.

BACKGROUND: Accumulating evidence suggests that elevated plasma homocysteine (Hcy), prevalent in hypertensive patients, affects oxidant/antioxidant balance of the body, and is linked to the development of atherosclerosis, inflammation, and endothelium injury. Our objective was to examine a hypothesis that Hcy is a predictor of total antioxidant status (TAS) and endothelial progenitor cells (EPCs), important in the repair of injured endothelium, in hypertensive patients. METHODS: This study was conducted with newly diagnosed essential hypertension patients (n=42) and healthy controls (n=20). Anthropometric and biochemical characteristics, including plasma Hcy, lipids, TAS, and C-reactive protein (CRP) were quantified. Intima-media thickness (IMT) was assessed in carotid arteries. Blood derived EPCs were quantified using an in vitro culture assay. RESULTS: Hcy, IMT, and CRP were significantly elevated while TAS and EPCs were significantly lower in hypertensive patients compared with controls. In multivariate regression analysis Hcy was a predictor of IMT of carotid artery and EPCs number. CONCLUSIONS: Our results suggest that Hcy might increase carotid artery IMT by reducing EPCs numbers. Possible involvement of Hcy in the reduction of EPCs number in hypertensive patients might be in part mediated by Hcy influence on the TAS.

Insulin resistance and oxidative stress influence colony-forming unit-endothelial cells capacity in obese patients.

The aim of this study was to investigate the relationship between a sub-population of endothelial progenitor cells (EPC), namely colony-forming unit-endothelial cells (CFU-EC), their colony-forming capacity and variable clinical parameters, including insulin resistance and oxidative stress, in obese individuals. Thirty-eight obese adults (aged 42.5 ± 12.7), with BMI 32.3 ± 4.0 and 13 normal-weight controls (aged 48.2 ± 12.9; BMI 23.2 ± 2.3) were studied. CFU-EC colony-forming capacity was impaired in the group of obese individuals compared to the normal-weight controls (P = 0.001). The inverse correlation between homeostasis model assessment-insulin resistance (HOMA(IR)) index and CFU-EC number (r = -0.558, P < 0.0001) as well as positive total antioxidant status of plasma (TAS)/CFU-EC relation were noticed during the study. Additionally, correlations between the concentration of triglycerides (TG), high-density lipoproteins (HDLs), and body composition parameters in the obese participants were established. Our results demonstrate that insulin resistance and oxidative stress have a significant impact on the CFU-EC colony formation in obesity. Moreover, in multivariate regression analysis, in both studied groups, the HOMA(IR) index and HDL concentration were independent predictors of the number of CFU-EC. Endothelium dysfunction, which can be present in obesity, may in part be caused by EPC function impairment in this condition.

Endothelial progenitor cells as a new agent contributing to vascular repair.

A special type of stem cells, defined as endothelial progenitor cells (EPCs), has been found in the bone marrow and peripheral blood. These EPCs are incorporated into injured vessels and become mature endothelial cells during re-endothelialization and neovascularization processes. Though a complete phenotypic description of EPCs remains unclear, these cells express several surface markers, the most relevant including CD34 and CD133 antigens. Furthermore, EPCs derived from other sources could also give rise to mature endothelial cells, which makes this group of cells more diverse. The recruitment of EPCs from the bone marrow to homing sites of vasculogenesis is subject to regulation by many factors, including chemokines and growth factors. The precise mechanism of EPC mobilization and differentiation is not entirely elucidated and is still under investigation. Recent studies have suggested that EPCs may promote local angiogenesis by secreting angiogenic growth factors in a paracrine manner. The number and function of EPCs can be affected during pathological conditions, including diabetes mellitus, cardiovascular risk factors for ischemic disease, and graft vasculopathy. Additionally, EPC number and migration capacity could be improved by such factors as drugs, physical exercise, and growth factors. Transplantation of EPCs into ischemic tissues may emerge as a promising approach in the therapy of diseases associated with blood vessel disorders.

[The role of platelet-derived growth factor A (PDGF-A) in hypertension and renal diseases. Part 1: Structure and regulation of the PDGF-A gene expression and its role in hypertension]. / Rola plytkowego czynnika wzrostu A (PDGF-a) w nadcisnieniu tetniczym i chorobach nerek. Cz. 1: Budowa i regulacja ekspresji genu PDGF-A i jego rola w nadcisnieniu tetniczym.

Platelet-derived growth factor is commonly known as a mitogen. There are four members of PDGF family known as PDGF-A chain, PDGF-B chain, PDGF-C chain and PDGF-D chain, which in active forms are dimers. As far as two receptors PDGF-alphaR and PDGF-betaR are known to bind PDGF There is a difference in binding affinity of various forms of PDGF by those receptors. Two different transcripts are derived from PDGF-A gene by alternative splicing. Transcription of PDGF-A gene is under control of many factors. Many research data suggest a role for PDGF-A in smooth muscle cell hyperplasia in hypertension and atherosclerosis. Since inhibition of PDGF-A transcription by a specific ribozyme represses smooth muscle cell proliferation in arteries, introduction of gene therapy might be of value in the treatment of hypertension and its complications.

[The role of platelet-derived growth factor A (PDGF-A) in hypertension and renal diseases. Part 2: a role of PDGF-A in kidney diseases]. / Rola plytkowego czynnika wzrostu A (PDGF-A) w nadcisnieniu tetniczym i chorobach nerek. Cz. 2: Rola PDGF-A w chorobach nerek.

Many studies have suggested deleterious effects of platelet-derived growth factor (PDGF) released by intrinsic renal cells during glomerulonephritis (GN). Increase in PDGF B chain expression has particularly been noted in glomeruli of patients with GN. Less known is the role of PDGF A chain both in the normal kidney and renal diseases. Several lines of evidence have indicated the involvement of PDGF-A in renal graft rejection. Furthermore, an increased expression of PDGF-A has also been observed in the course of human diabetic nephropathy. Still, the role of PDGF-A in the development and progression of GN remains unclear.

[Structure and function of PDGF-R-alpha and its expression in normal kidney and kidney diseases]. / Budowa i funkcja PDGF-alpha r oraz jego ekspresja w nerce prawidlowej i nerkach zmienionych chorobowo.

Platelet-derived growth factor is commonly known as a mitogen. Many research data suggest a role for PDGF-beta R in the mitogenic response of mesangial cells. There are four members of PDGF family known as PDGF-A chain, PDGF-B chain, PDGF-C chain and PDGF-D chain, which in active forms are dimers. As far as two receptors PDGF-alpha R and PDGF-beta R are known to bind PDGF. There is a difference in binding affinity of various forms of PDGF by these receptors. Two different promotors P1 and P2 can be used for PDGF-alpha R gene transcription. There are several different haplotypes of promotor P1 sequence. Transcription of PDGF-alpha R gene is under control of many factors. Interaction between a receptor and its ligand includes receptor dimerisation and autophosphorylation of tyrosine residues. PDGF AA is unique in that it can only be bound by alpha-receptor dimer. PDGF-AA expression has been confirmed in the normal kidney, as well as in several renal diseases. Although the expression of PDGF-alpha R has been found to accompany that of PDGF-AA, its actual relevance for the development of the glomerular pathology is not clear.