Insulin mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by Rosiglitazone

Background: Obesity associated hypertension is likely to be due to multiple mechanisms. Identification of the renin-angiotensin system (RAS) within adipose tissue does, however, suggest a potential causal role for it in obesity-associated hypertension. Obese patients are often hyperinsulinaemic, but mechanisms underlying insulin upregulation of the RAS in adipose tissue are unclear. TNFα, an inducer of angiotensinogen in hepatocytes, is elevated in hyperinsulinaemic, obese individuals, and may provide a link in mediating insulin upregulation of the RAS in adipose tissue. Further, thiazolidinediones lower blood pressure in vivo and downregulation of the RAS in adipose tissue may contribute to this effect. We therefore examined the effect of rosiglitazone (RSG), on the insulin mediated upregulation of the RAS. Methods and Results: Sera were obtained from the arterial circulation and from venous blood draining subcutaneous abdominal adipose tissue. Isolated human abdominal subcutaneous adipocytes (n=12) were treated with insulin (1-1000nM) and insulin in combination with RSG (10nM), and RSG (10nM) alone to determine angiotensinogen expression, angiotensin II, bradykinin and TNFα secretion. Subcutaneous adipocytes were also treated with TNFα (10-100ng/mL) to examine the direct effect on angiotensinogen expression and angiotensin II secretion. The findings showed that the arterio-venous difference in angiotensin II levels was significant (↑23%; p<0.001). Insulin increased TNFα secretion in a concentration-dependent manner (p<0.01) whilst RSG (10nM) significantly reduced the insulin mediated rise in TNFα (p<0.001), as well as AGT and angiotensin II. TNFα also increased angiotensinogen and angiotensin II in isolated adipocytes. Conclusions: Our in vivo data suggest that human subcutaneous adipose tissue is a significant source of angiotensin II. This study also demonstrates a potential TNFα mediated mechanism through which insulin may stimulate the RAS and may contribute to explain obesity associated hypertension. RSG downregulates the RAS in subcutaneous adipose tissue and this effect may contribute to the long-term effect of RSG on blood pressure

Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease

Introduction: Inflammation contributes to cardiovascular disease and is exacerbated with increased adiposity, particularly omental adiposity; however, the role of epicardial fat is poorly understood. Methods: For these studies the expression of inflammatory markers was assessed in epicardial fat biopsies from coronary artery bypass grafting (CABG) patients using quantitative RT-PCR. Further, the effects of chronic medications, including statins, as well as peri-operative glucose, insulin and potassium infusion, on gene expression were also assessed. Circulating resistin, CRP, adiponectin and leptin levels were determined to assess inflammation. Results: The expression of adiponectin, resistin and other adipocytokine mRNAs were comparable to that in omental fat. Epicardial CD45 expression was significantly higher than control depots (p < 0.01) indicating significant infiltration of macrophages. Statin treated patients showed significantly lower epicardial expression of IL-6 mRNA, in comparison with the control abdominal depots (p < 0.001). The serum profile of CABG patients showed significantly higher levels of both CRP (control: 1.28 ± 1.57 μg/mL vs CABG: 9.11 ± 15.7 μg/mL; p < 0.001) and resistin (control: 10.53 ± 0.81 ng/mL vs CABG: 16.8 ± 1.69 ng/mL; p < 0.01) and significantly lower levels of adiponectin (control: 29.1 ± 14.8 μg/mL vs CABG: 11.9 ± 6.0 μg/mL; p < 0.05) when compared to BMI matched controls. Conclusion: Epicardial and omental fat exhibit a broadly comparable pathogenic mRNA profile, this may arise in part from macrophage infiltration into the epicardial fat. This study highlights that chronic inflammation occurs locally as well as systemically potentially contributing further to the pathogenesis of coronary artery disease

Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies

Introduction Chronic low-grade inflammation is a significant factor in the development of obesity associated diabetes. This is supported by recent studies suggesting endotoxin, derived from gut flora, may be key to the development of inflammation by stimulating the secretion of an adverse cytokine profile from adipose tissue. Aims The study investigated the relationship between endotoxin and various metabolic parameters of diabetic patients to determine if anti-diabetic therapies exerted a significant effect on endotoxin levels and adipocytokine profiles. Methods Fasting blood samples were collected from consenting Saudi Arabian patients (BMI: 30.2 ± (SD)5.6 kg/m2, n = 413), consisting of non-diabetics (ND: n = 67) and T2DM subjects (n = 346). The diabetics were divided into 5 subgroups based on their 1 year treatment regimes: diet-controlled (n = 36), metformin (n = 141), rosiglitazone (RSG: n = 22), a combined fixed dose of metformin/rosiglitazone (met/RSG n = 100) and insulin (n = 47). Lipid profiles, fasting plasma glucose, insulin, adiponectin, resistin, TNF-α, leptin, C-reactive protein (CRP) and endotoxin concentrations were determined. Results Regression analyses revealed significant correlations between endotoxin levels and triglycerides (R2 = 0.42; p < 0.0001); total cholesterol (R2 = 0.10; p < 0.001), glucose (R2 = 0.076; p < 0.001) and insulin (R2 = 0.032; p < 0.001) in T2DM subjects. Endotoxin showed a strong inverse correlation with HDL-cholesterol (R2 = 0.055; p < 0.001). Further, endotoxin levels were elevated in all of the treated diabetic subgroups compared with ND, with the RSG treated diabetics showing significantly lower endotoxin levels than all of the other treatment groups (ND: 4.2 ± 1.7 EU/ml, RSG: 5.6 ± 2.2 EU/ml). Both the met/RSG and RSG treated groups had significantly higher adiponectin levels than all the other groups, with the RSG group expressing the highest levels overall. Conclusion We conclude that sub-clinical inflammation in T2DM may, in part, be mediated by circulating endotoxin. Furthermore, that whilst the endotoxin and adipocytokine profiles of diabetic patients treated with different therapies were comparable, the RSG group demonstrated significant differences in both adiponectin and endotoxin levels. We confirm an association between endotoxin and serum insulin and triglycerides and an inverse relationship with HDL. Lower endotoxin and higher adiponectin in the groups treated with RSG may be related and indicate another mechanism for the effect of RSG on insulin sensitivity

The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes

Context: Obesity-associated inflammation is a contributory factor in the pathogenesis of type 2 diabetes mellitus (T2DM); the mechanisms underlying the progression to T2DM are unclear. The adipokine resistin has demonstrated pro-inflammatory properties in relation to obesity and T2DM. Objective: To characterize resistin expression in human obesity and address the role of resistin in the innate immune pathway. Furthermore, examine the influence of lipopolysaccharide, recombinant human resistin (rhResistin), insulin and rosiglitazone in human adipocytes. Finally, analyze the effect of rhResistin on the expression of components of the NF-κB pathway and insulin signaling cascade. Methods: Abdominal subcutaneous adipose tissue was obtained from patients undergoing elective liposuction surgery (n = 35, aged: 36-49 yr; BMI: 26.5 ± 5.9 kg/m2). Isolated adipocytes were cultured with rhResistin (10-50 ng/ml). The level of cytokine secretion from isolated adipocytes was examined by ELISA. The effect of rhResistin on protein expression of components of the innate immune pathway was examined by Western blot. Results: In-vitro studies demonstrated that antigenic stimuli increase resistin secretion (P < 0.001) from isolated adipocytes. Pro-inflammatory cytokine levels were increased in response to rhResistin (P < 0.001); this was attenuated by rosiglitazone (P < 0.01). When examining components of the innate immune pathway, rhResistin stimulated Toll-like receptor-2 protein expression. Similarly, mediators of the insulin signaling pathway, phosphospecific JNK1 and JNK2, were upregulated in response to rhResistin. Conclusion: Resistin may participate in more than one mechanism to influence pro-inflammatory cytokine release from human adipocytes; potentially via the integration of NF-κB and JNK signaling pathways

Increased circulating ANG II and TNF-α represents important risk factors in obese Saudi adults with hypertension irrespective of diabetic status and BMI

Central adiposity is a significant determinant of obesity-related hypertension risk, which may arise due to the pathogenic inflammatory nature of the abdominal fat depot. However, the influence of pro-inflammatory adipokines on blood pressure in the obese hypertensive phenotype has not been well established in Saudi subjects. As such, our study investigated whether inflammatory factors may represent useful biomarkers to delineate hypertension risk in a Saudi cohort with and without hypertension and/or diabetes mellitus type 2 (DMT2). Subjects were subdivided into four groups: healthy lean controls (age: 47.9±5.1 yr; BMI: 22.9±2.1 Kg/m2), non-hypertensive obese (age: 46.1±5.0 yr; BMI: 33.7±4.2 Kg/m2), hypertensive obese (age: 48.6±6.1 yr; BMI: 36.5±7.7 Kg/m2) and hypertensive obese with DMT2 (age: 50.8±6.0 yr; BMI: 35.3±6.7 Kg/m2). Anthropometric data were collected from all subjects and fasting blood samples were utilized for biochemical analysis. Serum angiotensin II (ANG II) levels were elevated in hypertensive obese (p<0.05) and hypertensive obese with DMT2 (p<0.001) compared with normotensive controls. Systolic blood pressure was positively associated with BMI (p<0.001), glucose (p<0.001), insulin (p<0.05), HOMA-IR (p<0.001), leptin (p<0.01), TNF-α (p<0.001) and ANG II (p<0.05). Associations between ANG II and TNF-α with systolic blood pressure remained significant after controlling for BMI. Additionally CRP (p<0.05), leptin (p<0.001) and leptin/adiponectin ratio (p<0.001) were also significantly associated with the hypertension phenotype. In conclusion our data suggests that circulating pro-inflammatory adipokines, particularly ANG II and, TNF-α, represent important factors associated with a hypertension phenotype and may directly contribute to predicting and exacerbating hypertension risk

Virological failure and development of new resistance mutations according to CD4 count at combination antiretroviral therapy initiation

Objectives: No randomized controlled trials have yet reported an individual patient benefit of initiating combination antiretroviral therapy (cART) at CD4 counts > 350 cells/μL. It is hypothesized that earlier initiation of cART in asymptomatic and otherwise healthy individuals may lead to poorer adherence and subsequently higher rates of resistance development. Methods: In a large cohort of HIV-positive individuals, we investigated the emergence of new resistance mutations upon virological treatment failure according to the CD4 count at the initiation of cART. Results: Of 7918 included individuals, 6514 (82.3%), 996 (12.6%) and 408 (5.2%) started cART with a CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Virological rebound occurred while on cART in 488 (7.5%), 46 (4.6%) and 30 (7.4%) with a baseline CD4 count ≤ 350, 351-499 and ≥ 500 cells/μL, respectively. Only four (13.0%) individuals with a baseline CD4 count > 350 cells/μL in receipt of a resistance test at viral load rebound were found to have developed new resistance mutations. This compared to 107 (41.2%) of those with virological failure who had initiated cART with a CD4 count < 350 cells/μL. Conclusions: We found no evidence of increased rates of resistance development when cART was initiated at CD4 counts above 350 cells/μL. HIV Medicin

Search for heavy neutral leptons in final states with electrons, muons, and hadronically decaying tau leptons in proton-proton collisions at s \sqrt{s} = 13 TeV

A search for heavy neutral leptons (HNLs) of Majorana or Dirac type using proton-proton collision data at = 13 TeV is presented. The data were collected by the CMS experiment at the CERN LHC and correspond to an integrated luminosity of 138 fb−1. Events with three charged leptons (electrons, muons, and hadronically decaying tau leptons) are selected, corresponding to HNL production in association with a charged lepton and decay of the HNL to two charged leptons and a standard model (SM) neutrino. The search is performed for HNL masses between 10 GeV and 1.5 TeV. No evidence for an HNL signal is observed in data. Upper limits at 95% confidence level are found for the squared coupling strength of the HNL to SM neutrinos, considering exclusive coupling of the HNL to a single SM neutrino generation, for both Majorana and Dirac HNLs. The limits exceed previously achieved experimental constraints for a wide range of HNL masses, and the limits on tau neutrino coupling scenarios with HNL masses above the W boson mass are presented for the first time

Measurement of the polarizations of prompt and non-prompt J/ψ and ψ (2S) mesons produced in pp collisions at s\sqrt{s} = 13 TeV

The polarizations of prompt and non-prompt J∕ψ and ψ(2S) mesons are measured in proton-proton collisions at √ = 13 TeV, using data samples collected by the CMS experiment in 2017 and 2018, corresponding to a total integrated luminosity of 103.3 fb$^{−1}$. Based on the analysis of the dimuon decay angular distributions in the helicity frame, the polar anisotropy, , is measured as a function of the transverse momentum, $_T$, of the charmonium states, in the 25–120 and 20–100 GeV ranges for the J∕ψ and ψ(2S), respectively. The non-prompt polarizations agree with predictions based on the hypothesis that, for T ≳ 25 GeV, the non-prompt J∕ψ and ψ(2S) are predominantly produced in two-body B meson decays. The prompt results clearly exclude strong transverse polarizations, even for $_T$ exceeding 30 times the J∕ψ mass, where tends to an asymptotic value around 0.3. Taken together with previous measurements, by CMS and LHCb at √ = 7 TeV, the prompt polarizations show a significant variation with $_T$, at low $_T$

Search for new physics in high-mass diphoton events from proton-proton collisions at √s = 13 TeV

Results are presented from a search for new physics in high-mass diphoton events from proton-proton collisions at sqrt(s) = 13 TeV. The data set was collected in 2016–2018 with the CMS detector at the LHC and corresponds to an integrated luminosity of 138 fb−1 . Events with a diphoton invariant mass greater than 500 GeV are considered. Two diferent techniques are used to predict the standard model backgrounds: parametric fts to the smoothly-falling background and a frst-principles calculation of the standard model diphoton spectrum at next-to-next-to-leading order in perturbative quantum chromodynamics calculations. The frst technique is sensitive to resonant excesses while the second technique can identify broad diferences in the invariant mass shape. The data are used to constrain the production of heavy Higgs bosons, Randall-Sundrum gravitons, the large extra dimensions model of Arkani-Hamed, Dimopoulos, and Dvali (ADD), and the continuum clockwork mechanism. No statistically signifcant excess is observed. The present results are the strongest limits to date on ADD extra dimensions and RS gravitons with a coupling parameter greater than 0.1