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Background: Obesity is linked with heightened cardiovascular risk, especially when accompanied by metabolic abnormalities. Lipocalin (LCN) 2 and retinol-binding protein (RBP) 4, two members of the lipocalin family, may be upregulated in insulin resistance and atherosclerosis. We analyzed whether changes in circulating LCN2 and RBP4 in obese individuals relate with impaired vasodilator reactivity, an early stage in atherosclerosis. Methods: Obese individuals ( n = 165), without ( n = 48) or with ( n = 117) metabolic abnormalities, and lean subjects ( n = 42) participated in this study. LCN2 and RBP4 were measured by Luminex assay. Endothelium-dependent and -independent vasodilation to acetylcholine and sodium nitroprusside, respectively, was assessed by strain-gauge plethysmography. Results: Circulating LCN2 was higher in obese than in lean subjects ( p < 0.001), whereas RBP4 was not different between the two groups ( p = 0.12). The vasodilator responses to both acetylcholine and nitroprusside were impaired in obese individuals ( p < 0.001 vs lean subjects), with no difference between those with metabolically healthy or unhealthy obesity ( p > 0.05). In the whole population, vasodilator responses to acetylcholine ( R = 0.23, p = 0.01) and nitroprusside ( R = 0.38, p < 0.001) had an inverse, linear relationship with circulating LCN2; no correlation, by contrast, was observed between circulating RBP4 and vasodilator reactivity (both p > 0.05). In a subgroup of obese patients with diabetes ( n = 20), treatment with metformin ( n = 10) or pioglitazone ( n = 10) did not modify circulating LCN2 and RBP4 or vascular reactivity (all p > 0.05). Conclusions: Circulating LCN2, but not RBP4, is higher in obese than in lean individuals. Interestingly, changes in LCN2 inversely relate to those in vasodilator function, thereby making this protein a potential biomarker for risk stratification in obesity.

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116–734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals ( P =0.02). The vasorelaxing response to canagliflozin was not modified ( P =0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H 2 O 2 scavenging (catalase); also, canagliflozin-induced relaxation was similar ( P =0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na + /H + exchanger 1 inhibitor BIX ( P =0.67), but greater than that to the Na + /Ca ++ exchanger inhibitor SEA 0400 ( P =0.001), hinting a role of Na + /H + exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide ( P =0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.

As inadequate perfusion has emerged as a key determinant of adipose tissue dysfunction in obesity, interest has grown regarding possible pharmacological interventions to prevent this process. Mirabegron has proved to improve insulin sensitivity and glucose homeostasis in obese humans via stimulation of βSmall arteries (116-734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone in response to mirabegron were determined under different conditions.Mirabegron did not elicit vasorelaxation in vessels contracted with U46619 or high-KMirabegron induces endothelium-independent vasorelaxation in arteries from visceral adipose tissue, likely through antagonism of α

Metabolic syndrome is a cluster of the most dangerous cardiovascular (CV) risk factors including visceral obesity, insulin resistance, hyperglycemia, alterations in lipid metabolism and arterial hypertension (AH). In particular, AH plays a key role in the complications associated with metabolic syndrome. High salt intake is a well-known risk factor for AH and CV diseases. Vasoconstriction, impaired vasodilation, extracellular volume expansion, inflammation, and an increased sympathetic nervous system (SNS) activity are the mechanisms involved in the pathogenesis of AH, induced by Western diet. Gut dysbiosis in AH is associated with reduction of short chain fatty acid-producing bacteria: acetate, butyrate and propionate, which activate different pathways, causing vasoconstriction, impaired vasodilation, salt and water retention and a consequent high blood pressure. Moreover, increased trimethylamine N-oxide and lipopolysaccharides trigger chronic inflammation, which contributes to endothelial dysfunction and target organs damage. Additionally, a high salt-intake diet impacts negatively on gut microbiota composition. A bidirectional neuronal pathway determines the “brain–gut” axis, which, in turn, influences blood pressure levels. Then, we discuss the possible adjuvant novel treatments related to gut microbiota modulation for AH control.

Flavonoids display a broad range of structures and are responsible for the major organoleptic characteristics of plant-derived foods and beverages. Recent data showed their activity, and in particular of luteolin-7-O-glucoside (LUT-7G), in reduction of oxidative stress and inflammatory mechanisms in different physiological systems. In this paper, we tried to elucidate how LUT-7G could exert both antioxidant and anti-inflammatory effects in endothelial cells cultured in vitro. Here, we showed that LUT-7G is able to inhibit the STAT3 pathway, to have an antiproliferative action, and an important antioxidant property in HUVEC cells. These properties are exerted by the flavone in endothelial through the transcriptional repression of a number of inflammatory cytokines and their receptors, and by the inhibition of ROS generation. ROS and STAT3 activation has been correlated with the production of oxysterols and other hydroxylated fatty acids, and they have been recognized important as players of atherogenesis and cardiocirculatory system diseases. The analysis of the general production pathway of these hydroxylated species, showed a strong decrease of cholesterol hydroxylated species such as 7-alpha-hydroxicholesterol, 7-beta-hydroxicholesterol by the treatment with LUT-7G. This confirms the anti-inflammatory properties of LUT-7G also in the endothelial district, showing for the first time the molecular pathway that verify previous postulated cardiovascular benefits of this flavone.

Human obesity is associated with insulin resistance and often results in a number of metabolic abnormalities and cardiovascular complications. Over the past decades, substantial advances in the understanding of the cellular and molecular pathophysiological pathways underlying the obesity-related vascular dysfunction have facilitated better identification of several players participating in this abnormality. However, the complex interplay between the disparate mechanisms involved has not yet been fully elucidated. Moreover, in medical practice, the clinical syndromes stemming from obesity-related vascular dysfunction still carry a substantial burden of morbidity and mortality; thus, early identification and personalized clinical management seem of the essence. Here we will initially describe the alterations of intravascular homeostatic mechanisms occurring in arteries of obese patients. Then, we will briefly enumerate those recognized causative factors of obesity-related vasodilator dysfunction, such as vascular insulin resistance, lipotoxicity, visceral adipose tissue expansion and perivascular adipose tissue abnormalities; next, we will discuss in greater detail some emerging pathophysiological mechanisms, including skeletal muscle inflammation, signals from gut microbiome, and the role of extracellular vesicles and microRNAs. Finally, it will touch upon some gaps in knowledge, as well as some current acquisitions in terms of specific treatment regimens, such as glucagon-like peptide (GLP)-1 enhancers and sodium-glucose transporter (SGLT)2 inhibitors, that could arrest or slow the progression of this abnormality full of unwanted consequences.

Obesity associates with premature atherosclerosis and an increased burden of cardiovascular disease, especially when accompanied by abnormalities of lipid and glucose metabolism. Angiopoietin-like (ANGPTL)3 and ANGPTL4 are metabolic regulators, whose upregulation is associated with dyslipidemia, insulin resistance and atherosclerosis. We analyzed, therefore, changes in circulating ANGPTL3 and ANGPTL4 in obese patients with different metabolic phenotypes and their relation with impaired vasodilator reactivity, an early abnormality in atherosclerosis. Compared to the lean subjects (n = 42), circulating ANGPTL3 was elevated (both p &gt, 0.001) in the patients with metabolically unhealthy obesity (MUO, n = 87) and type 2 diabetes (T2D, n = 31), but not in those with metabolically healthy obesity (MHO, n = 48, p &gt, 0.05). Circulating ANGPTL4, by contrast, was increased in all obese subgroups (all p &lt, 0.001 vs. lean subjects). Vasodilator responses to both acetylcholine and sodium nitroprusside were reduced in the three obese subgroups vs. lean subjects (all p &lt, 0.001), with greater impairment in the patients with T2D than in those with MHO and MUO (all p &lt, 0.05). In the whole population, an inverse relationship (r = 0.27, p = 0.003) was observed between circulating ANGPTL4 and endothelium-dependent vasorelaxation. Circulating ANGPTL3 and ANGPTL4 undergo variable changes in obese patients with different metabolic phenotypes, changes in ANGPTL4 relate to endothelial dysfunction, making this protein a possible target for vascular prevention in these patients.

Adipokines have been postulated as the potential mediators of the relationship between excess adiposity and vascular dysfunction. In obese patients, vascular dysfunction, characterized by impaired vasodilator responsiveness and/or increased endothelin (ET)-1-dependent vasoconstriction, is, in turn, a predominant abnormality in the atherogenic process. We hypothesized, therefore, that in human obesity vascular dysfunction could be associated with changes in circulating concentrations of adipokines. To test this hypothesis, we compared plasma levels of a panel of adipokines (Luminex assay) in lean subjects (n=42) and obese patients (n=134), and tested their relationship with the forearm flow response (strain-gauge plethysmography) to intra-arterial infusion of endothelium-dependent (acetylcholine; ACh) and -independent (sodium nitroprusside; SNP) vasodilators or ETA receptor antagonism (BQ-123, 10 nmol/min). Compared to lean subjects (n=42), obese patients (n=134) had higher plasma levels of chemerin (4.0±0.1 vs. 2.9±0.2 ng/ml; P0.05); similarly, no correlation was seen between plasma adipokines and the vasodilator response to SNP (all P>0.05). On the other hand, a significant linear relationship was observed between the vasodilation elicited by B-123 and plasma levels of chemerin (R=0.30, P=0.012) and adipsin (R=0.38, P0.05). In conclusion, circulating concentrations of selected adipokines, such as visfatin, chemerin and adipsin, are variably associated with obesity-related decrease in endothelium-dependent vasodilation and increase in ET-1-dependent vasoconstriction. These findings are consistent with the notion that adipokines may influence vascular dysfunction and make these molecules promising targets for prevention. Funding Acknowledgement Type of funding source: None

Adrenocortical oncocytomas are rare and mostly nonfunctioning neoplasms. We report the case of a 27-year-old woman diagnosed with an ACTH-independent Cushing’s syndrome due to left adrenal oncocytoma. She underwent laparoscopic adrenalectomy. Histopathological examination revealed an oncocytoma of uncertain malignant potential with a low Ki-67 proliferation index, inhibin A positivity, and chromogranin A negativity. Electron micrographs confirmed adrenal oncocytoma cells, characterized by the presence of a large amount of mitochondria. The postoperative course was uneventful, and the patient experienced a progressive regression of Cushing-related symptoms. Periodical follow-ups with MRI and cortisol dosage are required due to the neoplasm’s uncertain malignant potential. Considerations on the diagnosis, pathology findings, clinical remarks, and interventions are made.

Activation of the vascular endothelin-1 (ET-1) system is a key abnormality in vascular dysfunction of human obesity, especially in patients developing complications, such as the metabolic syndrome, diabetes, and atherosclerosis. Vascular insulin resistance, an increased insulin-stimulated endothelial production of ET-1 combined with impaired nitric oxide availability, is the hallmark of obesity-related vasculopathy, but dysregulated adipokine release from obese adipose tissue may contribute to the predominance of ET-1-dependent vasoconstriction. ET-1, in turn, might determine unhealthy obese adipose tissue expansion, with visceral and perivascular adipose tissue changes driving the release of inflammatory cytokines and atherogenic chemokines. In addition, ET-1 might also play a role in the development of the metabolic complications of obesity. Studies have shown inhibition of lipoprotein lipase activity by ET-1, with consequent hypertriglyceridemia. Also, ET-1 in pancreatic islets seems to contribute to beta cell dysfunction, hence affecting insulin production and development of diabetes. Moreover, ET-1 may play a role in nonalcoholic steatohepatitis. Recent clinical trials using innovative design have demonstrated that antagonism of ET-type A receptors protects against some complications of obesity and diabetes, such as nephropathy. These findings encourage further investigation to evaluate whether targeting the ET-1 system could afford better protection against other consequences of the obesity epidemic.

Interest in adipose tissue pathophysiology and biochemistry have expanded considerably in the past two decades due to the ever increasing and alarming rates of global obesity and its critical outcome defined as metabolic syndrome (MS). This obesity-linked systemic dysfunction generates high risk factors of developing perilous diseases like type 2 diabetes, cardiovascular disease or cancer. Amino acids could play a crucial role in the pathophysiology of the MS onset. Focus of this study was to fully characterize amino acids metabolome modulations in visceral adipose tissues (VAT) from three adult cohorts: (i) obese patients (BMI 43-48) with metabolic syndrome (PO), (ii) obese subjects metabolically well (O), and (iii) non obese individuals (H). 128 metabolites identified as 20 protein amino acids, 85 related compounds and 13 dipeptides were measured by ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) and gas chromatography-/mass spectrometry GC/MS, in visceral fat samples from a total of 53 patients. Our analysis indicates a probable enhanced BCAA (leucine, isoleucine, valine) degradation in both VAT from O and PO subjects, while levels of their oxidation products are increased. Also PO and O VAT samples were characterized by: elevated levels of kynurenine, a catabolic product of tryptophan and precursor of diabetogenic substances, a significant increase of cysteine sulfinic acid levels, a decrease of 1-methylhistidine, and an up regulating trend of 3-methylhistidine levels. We hope this profiling can aid in novel clinical strategies development against the progression from obesity to metabolic syndrome.

A 65-year-old Italian physician affected by Familial Mediterranean fever (FMF) was hospitalized due to progressive abdominal enlargement, which had begun 6 months before admission. Physical examination revealed ascites and bilateral leg edema. Abdominal CT scan showed ascitic fluid and extensive multiple peritoneal implants; peritoneal CT-guided biopsy revealed an epithelial-type malignant mesothelioma. The patient's past medical history revealed recurrent episodes of abdominal pain and fever from the age of 2. Clinical diagnosis of FMF was suspected at the age of 25, while genetic analysis, performed at the age of 50, confirmed homozygosity for the M694I mutation in the MEFV gene. Treatment with the first line FMF drug colchicine was started and stopped several times because of worsened leukopenia. The patient in fact had a history of asymptomatic leukopenia/lymphopenia from an early age; the intake of colchicine aggravated his pre-existing problem until the definitive suspension of the drug. As for second-line drugs, canakinumab was first prescribed, but due to prescription issues, it was not possible to be administered. When he was given anakinra, there was a worsening of leukopenia leading to septic fever. Systematic literature review indicates that, in most cases, recurrent peritoneal inflammation results in benign peritoneal fibrosis or less commonly in encapsulating peritonitis. There are only a few reported cases of recurrent peritoneal inflammation progressing from FMF to peritoneal mesothelioma (MST). In such cases, intolerance to colchicine or its erratic intake may lead to long-term recurrent inflammation, which usually precedes the development of the tumor, while pre-existing leukopenia, as in our patient, could also be a factor promoting or accelerating the tumor progression. In conclusion, we suggest that in the presence of intolerance or resistance to colchicine, interleukin (IL)-1 inhibition could suppress peritoneal inflammation and prevent MSTs.

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. In addition to its well-established role in maintaining vascular homeostasis, the endothelium has been increasingly recognized as a key player in modulating healthy adipose tissue expansion in response to excess calories by providing adipocyte precursors and driving angiogenesis. When this increased storage need is unmet, excessive deposition of fat occurs at ectopic locations, including perivascular adipose tissue (PVAT). PVAT is in intimate contact with the vessel wall, hence affecting vascular function and structure. In lean individuals, PVAT exerts anticontractile and anti-inflammatory activities to protect the vasculature. In obesity, instead, these beneficial properties are lost and PVAT releases inflammatory mediators, promotes oxidative stress, and contributes to vascular dysfunction. The underlying mechanisms elicited by these outside-in signals include resistance to the vasodilator actions of insulin and activation of endothelin (ET)-1-mediated vasoconstriction. A number of adipokines and gut hormones, which are important modulators of food intake, energy balance, glucose and lipid metabolism, insulin sensitivity, and inflammation, have also positive vascular actions. This feature makes them promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant benefits. There is, therefore, real hope that unleashing the power of fat- and gut-derived substances might provide effective dual-action therapies for obesity and its complications.

Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to 'synthetic' determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low-level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well-established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing-related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed.

Activation of fractalkine and other chemokines plays an important role in atherogenesis and, in conjunction with endothelial dysfunction, promotes premature vascular damage in obesity and diabetes. We hypothesized that increased circulating fractalkine coexists with impaired vasomotor function in metabolically healthy or unhealthy obesity, and that treatment with antidiabetic drugs may impact these abnormalities in type 2 diabetes. Compared to lean subjects, in both obese groups the vasodilator responses to acetylcholine and sodium nitroprusside were impaired (both P .05). Our findings indicate that insulin resistant states are associated with elevated atherogenic chemokines and impaired vascular reactivity. Antidiabetic treatment results in lower circulating fractalkine, which may provide cardiovascular benefits.

Background The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs. Objectives To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin. Patients/methods Otherwise healthy, obese (BMI > 30 kg/m2 ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB2 data from obese subjects. At baseline, the major urinary TXA2 and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured. Results In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m2 ), residual serum TXB2 values between 4 and 48 hours after aspirin intake were increased 3- to 5-fold as compared with controls. At 24 hours, the residual serum TXB2 level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA2 metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects. Conclusions Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.

Metabolic diseases are chronic disorders correlated to a greater risk of cardiovascular event and death. Recently, many data have sustained the biological link between microvascular dysfunction, oxidative stress, vascular inflammation, and metabolic diseases. The determination of new and specific blood biomarkers of vascular inflammation associated with obesity-related metabolic syndrome (MetS) and diabetes such as lipoprotein-associated phospholipase A2 (Lp-PLA2) could be useful to identify subject with high risk of cardiovascular events. Lp-PLA2 participates by a crucial role in microvascular dysfunction and oxidative stress showing positive association with metabolic disorders. In this review, we will argue the evolving role of Lp-PLA2 in predicting cardiovascular events in metabolic disease patients.

Vascular aging in obesity and type 2 diabetes (T2D) is associated with progressive vascular calcification, an independent predictor of morbidity and mortality. Pathways for vascular calcification modulate bone matrix deposition, thus regulating calcium deposits. We investigated the association between biomarkers of vascular calcification and vasodilator function in obesity or T2D, and whether antidiabetic therapies favorably impact those markers. Circulating levels of proteins involved in vascular calcification, such as osteopontin (OPN), osteoprotegerin (OPG), regulated on activation, normal T cell expressed and secreted (RANTES), and fetuin-A were measured in lean subjects, individuals with metabolically healthy obesity (MHO), and patients with metabolically unhealthy obesity (MUO) or T2D. Vasodilator function was assessed by infusion of ACh and sodium nitroprusside (SNP). Circulating levels of OPN were higher in the MUO/T2D group than in lean subjects ( P < 0.05); OPG and RANTES were higher in MUO/T2D group than in the other groups (both P < 0.001); fetuin-A was not different between groups ( P > 0.05); vasodilator responses to either ACh or SNP were impaired in both MUO/T2D and MHO compared with lean subjects (all P < 0.001). In patients with T2D who were enrolled in the intervention trial, antidiabetic treatment with glyburide, metformin, or pioglitazone resulted in a significant reduction of circulating OPG ( P = 0.001), without changes in the other biomarkers and vasodilator responses (all P > 0.05). In conclusion, obese patients with MUO/T2D have elevated circulating OPN, OPG, and RANTES; in these patients, antidiabetic treatment reduces only circulating OPG. Further study is needed to better understand the mechanisms of vascular calcifications in obesity and diabetes.

The heavy impact of obesity on the development and progression of cardiovascular disease has sparked sustained efforts to uncover the mechanisms linking excess adiposity to vascular dysfunction. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality in obese patients, but also increased vasoconstrictor tone importantly contributes to their vascular damage. In particular, upregulation of the endothelin (ET)-1 system, consistently reported in these patients, might accelerate atherosclerosis and its complication, given the pro-inflammatory and mitogenic properties of ET-1. In recent years, a number of gut hormones, in addition to their role as modulators of food intake, energy balance, glucose and lipid metabolism, and insulin secretion and action, have demonstrated favorable vascular actions. They increase the bioavailability of vasodilator mediators like nitric oxide, but they have also been shown to inhibit the ET-1 system. These features make gut hormones promising tools for targeting both the metabolic and cardiovascular complications of obesity, a view supported by recent large-scale clinical trials indicating that novel drugs for type 2 diabetes with cardiovascular potential may translate into clinically significant advantages. Therefore, there is real hope that better understanding of the properties of gut-derived substances might provide more effective therapies for the obesity-related cardiometabolic syndrome.

Obesity represents one of the most complex public health challenges and has recently reached epidemic proportions. Obesity is also considered to be primarily responsible for the rising prevalence of metabolic syndrome, defined as the coexistence in the same individual of several risk factors for atherosclerosis, including dyslipidemia, hypertension and hyperglycemia, as well as for cancer. Additionally, the presence of three of the five risk factors (abdominal obesity, low high-density lipoprotein cholesterol, high triglycerides, high fasting glucose and high blood pressure) characterizes metabolic syndrome, which has serious clinical consequences. The current study was conducted in order to identify metabolic differences in visceral adipose tissue (VAT) collected from obese (body mass index 43–48) human subjects who were diagnosed with metabolic syndrome, obese individuals who were metabolically healthy and nonobese healthy controls. Extensive gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS/MS) analyses were used to obtain the untargeted VAT metabolomic profiles of 481 metabolites belonging to all biochemical pathways. Our results indicated consistent increases in oxidative stress markers from the pathologically obese samples in addition to subtle markers of elevated glucose levels that may be consistent with metabolic syndrome. In the tissue derived from the pathologically obese subjects, there were significantly elevated levels of plasmalogens, which may be increased in response to oxidative changes in addition to changes in glycerolphosphorylcholine, glycerolphosphorylethanolamine glycerolphosphorylserine, ceramides and sphingolipids. These data could be potentially helpful for recognizing new pathways that underlie the metabolic–vascular complications of obesity and may lead to the development of innovative targeted therapies.

Obese patients have vascular dysfunction related to impaired insulin-stimulated vasodilation and increased endothelin-1–mediated vasoconstriction. In contrast to the harmful vascular actions of angiotensin (Ang) II, the angiotensin-converting enzyme 2 product Ang-(1–7) has shown to exert cardiovascular and metabolic benefits in experimental models through stimulation of the Mas receptor. We, therefore, examined the effects of exogenous Ang-(1–7) on vasodilator tone and endothelin-1–dependent vasoconstriction in obese patients. Intra-arterial infusion of Ang-(1–7) (10 nmol/min) resulted in significant increase in unstimulated forearm flow ( P =0.03), an effect that was not affected by the Mas receptor antagonist A779 (10 nmol/min; P >0.05). In the absence of hyperinsulinemia, however, forearm flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during Ang-(1–7) administration compared with saline (both P >0.05). During infusion of regular insulin (0.15 mU/kg per minute), by contrast, endothelium-dependent vasodilator response to acetylcholine was significantly enhanced by Ang-(1–7) ( P =0.04 versus saline), whereas endothelium-independent response to sodium nitroprusside was not modified ( P =0.91). Finally, Ang-(1–7) decreased the vasodilator response to endothelin A receptor blockade (BQ-123; 10 nmol/min) compared with saline (6±1% versus 93±17%; P l - N -monomethylarginine (4 µmol/min) during concurrent endothelin A antagonism resulted in similar vasoconstriction in the absence or presence of Ang-(1–7 Ang-(1–7) ( P =0.69). Our findings indicate that in obese patients Ang-(1–7) has favorable effects not only to improve insulin-stimulated endothelium-dependent vasodilation but also to blunt endothelin-1–dependent vasoconstrictor tone. These findings provide support for targeting Ang-(1–7) to counteract the hemodynamic abnormalities of human obesity.

Patients with central obesity have impaired insulin-stimulated vasodilation and increased ET-1 (endothelin 1) vasoconstriction, which may contribute to insulin resistance and vascular damage. Apelin enhances insulin sensitivity and glucose disposal but also acts as a nitric oxide (NO)–dependent vasodilator and a counter-regulator of AT 1 (angiotensin [Ang] II type 1) receptor–induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr 1 )apelin on NO-mediated vasodilation and Ang II– or ET-1–dependent vasoconstrictor tone in obese patients. In the absence of hyperinsulinemia, forearm blood flow responses to graded doses of acetylcholine and sodium nitroprusside were not different during saline or apelin administration (both P >0.05). During intra-arterial infusion of regular insulin, however, apelin enhanced the vasodilation induced by both acetylcholine and nitroprusside (both P 1 (telmisartan) and AT 2 (PD 123,319) receptors was blunted by apelin (3±5% versus 32±9%; P A receptors (BQ-123) resulted in lower vasodilator response than during saline (23±10% versus 65±12%; P l - N -monometylarginine) during the concurrent blockade of either Ang II or ET A receptors resulted in similar vasoconstriction in the absence or presence of apelin ( P >0.05). In conclusion, in patients with central obesity, apelin has favorable effects not only to improve insulin-stimulated endothelium-dependent and endothelium-independent vasodilator responses but also to blunt Ang II– and ET-1–dependent vasoconstriction by a mechanism not involving NO. Taken together, our results suggest that targeting the apelin system might favorably impact some hemodynamic abnormalities of insulin-resistant states like obesity.

Obesity, the metabolic syndrome (MetS), and type 2 diabetes (T2DM) are associated with heightened cardiovascular risk. Given the vasoconstrictor and proatherogenic properties of endothelin (ET)-1, increased ET-1 activity has been postulated to participate in the derangement of adiposity-related vascular homeostasis. This concept is supported by human studies using receptor antagonists to show that the activity of endogenous ET-1 is indeed enhanced in overweight and obesity, the MetS, and T2DM. Also, increased ET-1 contributes to endothelial dysfunction related to obesity, the MetS, and T2DM, whereas decreasing ET-1 vasoconstrictor tone in these patients corrects the defective endothelium-dependent vasodilation. In addition, in patients with central adiposity and the MetS, enhanced intravascular ET-1 activity coexists with decreased nitric oxide (NO)-dependent vasodilator capacity, suggesting a prevalence of vasoconstrictor mediators in vessels of obese individuals. One mechanism evoked to explain the development of vascular abnormalities in obesity deals with the derangement of the physiological vascular effects of insulin in insulin-resistant states. Thus, in conditions of adiposity, defective insulin-mediated vasodilation leads to impaired ability of the hormone to enhance its delivery and that of substrates to peripheral tissues. An important role of ET-1 in this abnormality is supported by studies showing that upregulation of the ET-1 system impairs NO-mediated vasodilation in insulin-resistant patients, whereas NO bioactivity is restored following ET-1 antagonism. In conclusion, considerable evidence supports a mechanistic role of ET-1 in the pathophysiology of adiposity-related vascular dysfunction. Targeting the ET-1 system, therefore, might have the potential for effective cardiovascular prevention in obesity, the MetS, and T2DM.

This study tested the hypothesis that pioglitazone reduces endothelin-1 activity in the forearm vasculature in non-diabetic patients with hypertension or hypercholesterolemia and variable degrees of insulin resistance.We conducted a single center, randomized, double-blind, placebo controlled, cross-over trial in 80 patients with either hypertension or hypercholesterolemia and further classified as insulin-sensitive or insulin-resistant based on a published insulin sensitivity index. Participants received pioglitazone 45 mg daily or matching placebo for eight weeks. The main endpoint was the change in forearm vascular endothelin-1 activity, as assessed by intra-arterial infusion of the endothelin type A receptor blocker BQ-123, measured at the end of each 8-week treatment period.Pioglitazone lowered plasma insulin (P0.001), improved insulin sensitivity (P0.001), increased HDL (P0.001), and reduced triglycerides (P = 0.003), free fatty acids (P = 0.005), and C-reactive protein (P = 0.001). However, pioglitazone did not affect the vasodilator response to BQ-123 in the whole group (P = 0.618) and in the diagnosis or insulin sensitivity subgroups. Hence, in non-diabetic patients with hypertension or hypercholesterolemia, PPARγ activation with pioglitazone does not affect endothelin-1 activity, despite enhancing insulin sensitivity and reducing plasma insulin and C-reactive protein levels.In non-diabetic patients with hypertension or hypercholesterolemia, pioglitazone improves insulin sensitivity, lipid profile, and inflammation but does not affect endothelin activity. Our data suggest that the determinants of endothelin-1 vascular activity in vivo may differ and/or be more complex than those suggested by the results of previous in vitro studies.

Metabolic diseases are chronic disorders correlated to a greater risk of cardiovascular event and death. Recently, many data have sustained the biological link between microvascular dysfunction, oxidative stress, vascular inflammation, and metabolic diseases. The determination of new and specific blood biomarkers of vascular inflammation associated with obesity-related metabolic syndrome (MetS) and diabetes such as lipoprotein-associated phospholipase A2 (Lp-PLA2) could be useful to identify subject with high risk of cardiovascular events. Lp-PLA2 participates by a crucial role in microvascular dysfunction and oxidative stress showing positive association with metabolic disorders. In this review, we will argue the evolving role of Lp-PLA2 in predicting cardiovascular events in metabolic disease patients.

Over the last decades, an escalating rate of type 2 diabetes has paralleled an epidemic rise in the prevalence of obesity. Both diabetes and obesity confer an increased risk of cardiovascular comorbidities, including hypertension, coronary artery disease and stroke. Vascular dysfunction, represented by impaired endothelial release of vasodilator substances or defective smooth muscle vasodilator reactivity, is the early stage of the process leading to atherosclerosis and a common finding in patients with diabesity. It is understandable, therefore, that effective treatments for diabesity should restore vascular function to prevent the development of cardiovascular disease. Recent evidence from clinical studies supports the efficacy of incretin-based antidiabetic therapies for vascular protection. Thus, glucose control with either DDP-4 inhibitor or GLP-1 receptor therapies seems associated with favorable effects on vascular function in diabetes and the metabolic syndrome. Another mechanism to counter excess plasma glucose and reduce body weight in these patients may rely on drug therapies targeting gut hormones, as suggested by the efficacy of bariatric surgery to produce both sustained weight loss and high diabetes remission rates. Also, as knowledge of the multifaceted vascular actions of adipokines and their dysregulation in patients with diabesity increases, these substances become attractive targets for treatments aimed at cardiovascular prevention. The increasing coexistence of diabetes and obesity presents complex treatment challenges owing to the elevated risk of developing cardiovascular complications. Hence, therapeutic strategies integrating glycemic control, weight loss and vascular protection are of the greatest importance to successfully counteract the health and economic burden posed by diabesity.

In industrialized countries, overweight and obesity account for approximately 13.8% and 24.9% of the kidney disease observed in men and women, respectively. Moreover, obesity-associated glomerulopathy is now considered as “an emerging epidemic.” Kidney function can be negatively impacted by obesity through several mechanisms, either direct or indirect. While it is well established that obesity represents the leading risk factor for type 2 diabetes and hypertension, awareness that obesity is associated with direct kidney damage independently of hypertension and diabetes is still not widespread. In this paper we will discuss the emerging role of adipose tissue, particularly in the visceral depot, in obesity-induced chronic kidney damage.

Context: Hesperidin, a citrus flavonoid, and its metabolite hesperetin may have vascular actions relevant to their health benefits. Molecular and physiological mechanisms of hesperetin actions are unknown. Objective: We tested whether hesperetin stimulates production of nitric oxide (NO) from vascular endothelium and evaluated endothelial function in subjects with metabolic syndrome on oral hesperidin therapy. Design, Setting, and Interventions: Cellular mechanisms of action of hesperetin were evaluated in bovine aortic endothelial cells (BAEC) in primary culture. A randomized, placebo-controlled, double-blind, crossover trial examined whether oral hesperidin administration (500 mg once daily for 3 wk) improves endothelial function in individuals with metabolic syndrome (n = 24). Main Outcome Measure: We measured the difference in brachial artery flow-mediated dilation between placebo and hesperidin treatment periods. Results: Treatment of BAEC with hesperetin acutely stimulated phosphorylation of Src, Akt, AMP kinase, and endothelial NO synthase to produce NO; this required generation of H2O2. Increased adhesion of monocytes to BAEC and expression of vascular cell adhesion molecule-1 in response to TNF-α treatment was reduced by pretreatment with hesperetin. In the clinical study, when compared with placebo, hesperidin treatment increased flow-mediated dilation (10.26 ± 1.19 vs. 7.78 ± 0.76%; P = 0.02) and reduced concentrations of circulating inflammatory biomarkers (high-sensitivity C-reactive protein, serum amyloid A protein, soluble E-selectin). Conclusions: Novel mechanisms for hesperetin action in endothelial cells inform effects of oral hesperidin treatment to improve endothelial dysfunction and reduce circulating markers of inflammation in our exploratory clinical trial. Hesperetin has vasculoprotective actions that may explain beneficial cardiovascular effects of citrus consumption.

Obesity is rising worldwide at an alarming rate and so is the incidence of obesity-related disorders, such as the metabolic syndrome, type 2 diabetes and cardiovascular diseases. The obesity-dependent vascular damage appears to be derived from a variety of changes in the adipose tissue, leading to a chronic inflammatory state and dysregulation of adipocyte-derived factors. This, in turn, impairs vascular homeostasis by determining an unbalance between the protective effect of the nitric oxide pathway and the unfavourable action of the endothelin-1 system. In addition, hyperinsulinemia and insulin resistance contribute to vascular dysfunction because the opposing endothelium-dependent vasodilating and vasoconstrictor effects of insulin are shifted towards a predominant vasoconstriction in patients with obesity. Importantly, emerging evidence suggests that the vascular dysfunction of obesity is not only limited to the endothelium but also involves the other layers of the vessel wall. In particular, obesity-related changes in vascular smooth muscle seem to disrupt the physiological facilitatory action of insulin on the responsiveness to vasodilator stimuli, whereas the adventitia and the perivascular fat appear to be a source of proinflammatory and vasoactive factors that may contribute to endothelial and smooth muscle cell dysfunction and to the pathogenesis of vascular disease.