Adiponectin receptors in revascularization and metabolic dysfunction

Thesis (Ph.D.)--Boston UniversityAdipose-derived secreted factors termed adipokines affect both metabolic and cardiovascular function. Previous studies have shown that ablation of the adipokine adiponectin leads to endothelial and metabolic dysfunction, whereas its overexpression is protective. However, the receptor(s) mediating the protective effects of adiponectin on the vasculature are not known. The goal of this study was to elucidate the role of three adiponectin receptors: T-cadherin, AdipoR1, and AdipoR2, in the revascularization response to chronic ischemia and the metabolic adaptation to diet-induced obesity. T-cadherin is a membrane protein which localizes adiponectin to the vascular endothelium. In a model of peripheral artery disease, T-cadherin-deficient mice phenocopy adiponectin-deficient mice such that both strains display impaired blood flow recovery compared to wild-type controls. Adiponectin delivery rescued the impaired revascularization phenotype in adiponectin-deficient mice, but not in T-cadherin-deficient mice. In cultured endothelial cells, T-cadherin deficiency prevented the ability of adiponectin to promote cellular migration and proliferation. These data highlight a previously unrecognized role for T-cadherin in limb revascularization, and show that it is essential for mediating the vascular actions of adiponectin. AdipoR1- and AdipoR2-deficient mice were also subjected to hind limb ischemia surgery to determine their role in vascular function. Blood flow recovery in AdipoR1-deficient mice was similar to wild-type; however, revascularization in AdipoR2-deficient mice was severely attenuated. Adiponectin administration enhanced the recovery of wild-type but not AdipoR2-deficient mice. These data show for the first time that AdipoR2 is functionally important in an in vivo model of vascular disease and that its expression is essential for the revascularization actions of adiponectin. Since adiponectin also plays an important role in metabolic disease, T-cadherin, AdipoR1- and AdipoR2-deficient mice were evaluated in a model of diet-induced obesity. No differences in metabolic function were detected at baseline between wild-type and any of these knockout strains. On a high-calorie diet, T-cadherin-deficient mice developed glucose intolerance despite an attenuated weight gain. Strikingly, AdipoR1-deficiency resulted in severe metabolic dysfunction and increased body weight, whereas, AdipoR2-deficiency was protective against diet-induced weight gain and metabolic perturbations. These studies show that T-cadherin, AdipoR1 and AdipoR2 have important yet divergent roles in mouse models of vascular and metabolic disease

INSL6 Protective Effects in Heart Failure

Background The insulin/insulin‐like growth factor/relaxin family represents a group of structurally related but functionally diverse proteins. The family member relaxin‐2 has been evaluated in clinical trials for its efficacy in the treatment of acute heart failure. In this study, we assessed the role of insulin‐like peptide 6 (INSL6), another member of this protein family, in murine heart failure models using genetic loss‐of‐function and protein delivery methods. Methods and Results Insl6‐deficient and wild‐type (C57BL/6N) mice were administered angiotensin II or isoproterenol via continuous infusion with an osmotic pump or via intraperitoneal injection once a day, respectively, for 2 weeks. In both models, Insl6‐knockout mice exhibited greater cardiac systolic dysfunction and left ventricular dilatation. Cardiac dysfunction in the Insl6‐knockout mice was associated with more extensive cardiac fibrosis and greater expression of fibrosis‐associated genes. The continuous infusion of chemically synthesized INSL6 significantly attenuated left ventricular systolic dysfunction and cardiac fibrosis induced by isoproterenol infusion. Gene expression profiling suggests liver X receptor/retinoid X receptor signaling is activated in the isoproterenol‐challenged hearts treated with INSL6 protein. Conclusions Endogenous Insl6 protein inhibits cardiac systolic dysfunction and cardiac fibrosis in angiotensin II– and isoproterenol‐induced cardiac stress models. The administration of recombinant INSL6 protein could have utility for the treatment of heart failure and cardiac fibrosis

Association between serum adiponectin levels and muscular fitness in Portuguese adolescents: LabMed Physical Activity Study

Background and aim: Paradoxically, recent investigations have showed that adiponectin levels are inversely associated with muscle strength. However, to date, there is a lack of knowledge on the relationship between muscular fitness (MF) and adiponectin levels in adolescents. We aimed to examine the independent associations between MF and adiponectin levels in adolescents, controlling for several potential confounders.Methods and results: This is a cross-sectional analysis with 529 Portuguese adolescents aged 12-18 years. A MF score was computed as the mean of the handgrip strength and standing long jump standardized values by age and gender. We measured fasting glucose, insulin, HDL-cholesterol, C-reactive protein and adiponectin. Linear regression analysis showed a significant inverse association between adiponectin (Z-score by age and sex) and MF score, after adjustments for age, sex, pubertal stage, socioeconomic status, adherence to the Mediterranean diet, body mass index, HOMA-IR, HDL-cholesterol, C-reactive protein and cardiorespiratory fitness (unstandardized beta = -0.176; p < 0.005). Analysis of covariance showed a significant difference between the Low MF/Non-overweight group and the High MF/Non-overweight Group (p < 0.05) and between the Low MF/Non-overweight and High MF/Overweight Group (p < 0.05) (F ((5,) (523)) = 2.262, p = 0.047).Conclusion: Adiponectin circulating levels are inversely and independently associated with MF. In non-overweight adolescents, those with high levels of MF presented lower levels of adiponectin compared to those with Low MF. Likewise, overweight adolescents with High MF presented lower levels of serum adiponectin than non-overweight adolescents with Low MF. (C) 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.This study was supported by FCT grants: BPD/102381/2014 and BD88984/2012; The author Cesar Aparecido Agostinis Sobrinho was given Doctoral scholarship from Brazilian government by CAPES (Coordination of Improvement of Higher Education Personnel) (Proc: 9588-13-2). The Research Centre on Physical Activity Health and Leisure (CIAFEL) is supported by UID/DTP/00617/2013 (FCT). The author Rute Santos has a Discovery Early Career Research Award from the Australian Research Council (DE150101921).The authors gratefully acknowledged the participation of all adolescents and their parents, teachers and schools of the LabMed Study. They also acknowledge the cooperation of volunteer's subjects and the Research Centre in Physical Activity, Health and Leisure (University of Porto) for the sponsoring the LabMed Study.info:eu-repo/semantics/publishedVersio

Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to common and discrete local effects whilst AdipoR2 promotes additional systemic effects

Hypoadiponectinemia and adiponectin resistance are implicated in the aetiology of obesity-related cardiometabolic disorders, hence represent a potential therapeutic axis. Here we characterised the effects of in vivo electrotransfer-mediated overexpression of the adiponectin receptors, AdipoR1 or AdipoR2, into tibialis anterior muscle (TAM) of lean or obese mice. In lean mice, TAM-specific overexpression of AdipoR1 (TAMR1) or AdipoR2 (TAMR2) increased phosphorylation of AMPK, AKT and ERK and expression of the insulin responsive glucose transporter glut4. In contrast, only TAMR2 increased pparα and a target gene acox1. These effects were decreased in obese mice despite no reduction in circulating adiponectin levels. TAMR2 also increased expression of adipoQ in TAM of lean and obese mice. Furthermore, in obese mice TAMR2 promoted systemic effects including; decreased weight gain; reduced epididymal fat mass and inflammation; increased epididymal adipoQ expression; increased circulating adiponectin. Collectively, these results demonstrate that AdipoR1 and AdipoR2 exhibit overlapping and distinct effects in skeletal muscle consistent with enhanced adiponectin sensitivity but these appear insufficient to ameliorate established obesity-induced adiponectin resistance. We also identify systemic effects upon TAMR2 in obese mice and postulate these are mediated by altered myokine production. Further studies are warranted to investigate this possibility which may reveal novel therapeutic approaches

Adiponectin circulating levels and 10-year (2002–2012) cardiovascular disease incidence:the ATTICA Study

Purpose: Adiponectin is an adipokine with anti-inflammatory and cardiovascular-protective properties. Existing epidemiological evidence is conflicting on the exact relationship between adiponectin and long-term cardiovascular disease (CVD) risk. Our aim was to prospectively assess whether circulating adiponectin is associated with long-term incident CVD. Methods: A population-based, prospective study in adults (>18 years) without previous CVD history (ATTICA study). Circulating total adiponectin levels were measured at baseline (2001–2002) in a sub-sample (n = 531; women/men: 222/309; age: 40 ± 11 years) of the ATTICA cohort and complete 10-year follow-up data were available in 366 of these participants (women/men: 154/212; age: 40 ± 12 years). Results: After adjusting for multiple factors, including age, sex, body mass index, waist circumference, smoking, physical activity, Mediterranean diet adherence, hypertension, diabetes, and hypercholesterolemia, our logistic regression analysis indicates that an increase in circulating total adiponectin levels by 1 unit was associated with 36% lower CVD risk (relative risk [RR]: 0.64, 95% confidence interval [CI] 0.42–0.96; p = 0.03). Further adjusting for interleukin-6 plasma levels had no significant impact (RR: 0.60, 95% CI 0.38–0.94; p = 0.03), while additional adjustment for circulating C-reactive protein (CRP) modestly attenuated this association (RR: 0.63, 95% CI 0.40–0.99; p = 0.046). Conclusions: In our study, elevated circulating total adiponectin levels were associated with lower 10-year CVD risk in adults without previous CVD, independently of other established CVD risk factors. This association appeared to be modestly attenuated by CRP, yet was not mediated by interleukin-6 which is the main endocrine/circulating pro-inflammatory cytokine

Achieving Integrated Street Management in the City of Westminster

The purpose of "Achieving Integrated Street Management in the City of Westminster" was threefold: firstly to gain an understanding of the current street cleansing system; secondly to recommend improvements to that system; and thirdly to develop reporting specifications that would be useful for implementation in future handheld technology

T-cadherin is essential for adiponectin-mediated revascularization

Adipose tissue secretes protein factors that have systemic actions on cardiovascular tissues. Previous studies have shown that ablation of the adipocyte-secreted protein adiponectin leads to endothelial dysfunction, whereas its overexpression promotes wound healing. However, the receptor(s) mediating the protective effects of adiponectin on the vasculature is not known. Here we examined the role of membrane protein T-cadherin, which localizes adiponectin to the vascular endothelium, in the revascularization response to chronic ischemia. T-cadherin-deficient mice were analyzed in a model of hind limb ischemia where blood flow is surgically disrupted in one limb and recovery is monitored over 28 days by laser Doppler perfusion imaging. In this model, T-cadherin-deficient mice phenocopy adiponectin-deficient mice such that both strains display an impaired blood flow recovery compared with wild-type controls. Delivery of exogenous adiponectin rescued the impaired revascularization phenotype in adiponectin-deficient mice but not in T-cadherin-deficient mice. In cultured endothelial cells, T-cadherin deficiency by siRNA knockdown prevented the ability of adiponectin to promote cellular migration and proliferation. These data highlight a previously unrecognized role for T-cadherin in limb revascularization and show that it is essential for mediating the vascular actions of adiponectin

Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis

Abstract Background Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients. Methods We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro. Results Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity. Conclusions These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease