Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.

Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.

Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell.

BACKGROUND: Vascular smooth muscle cell proliferation plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the human injured artery and suppressed endothelial inflammatory response as well as macrophage-to-foam cell transformation. The present study investigated the effects of adiponectin on proliferation and migration of human aortic smooth muscle cells (HASMCs). Methods and Results- HASMC proliferation was estimated by [(3)H] thymidine uptake and cell number. Cell migration assay was performed using a Boyden chamber. Physiological concentrations of adiponectin significantly suppressed both proliferation and migration of HASMCs stimulated with platelet-derived growth factor (PDGF)-BB. Adiponectin specifically bound to (125)I-PDGF-BB and significantly inhibited the association of (125)I-PDGF-BB with HASMCs, but no effects were observed on the binding of (125)I-PDGF-AA or (125)I-heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) to HASMCs. Adiponectin strongly and dose-dependently suppressed PDGF-BB-induced p42/44 extracellular signal-related kinase (ERK) phosphorylation and PDGF beta-receptor autophosphorylation analyzed by immunoblot. Adiponectin also reduced PDGF-AA-stimulated or HB-EGF-stimulated ERK phosphorylation in a dose-dependent manner without affecting autophosphorylation of PDGF alpha-receptor or EGF receptor. CONCLUSIONS: The adipocyte-derived plasma protein adiponectin strongly suppressed HASMC proliferation and migration through direct binding with PDGF-BB and generally inhibited growth factor-stimulated ERK signal in HASMCs, suggesting that adiponectin acts as a modulator for vascular remodeling.

Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Dysregulation of adipocyte-derived bioactive molecules plays an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipocyte-specific plasma protein, accumulated in the injured artery from the plasma and suppressed endothelial inflammatory response and vascular smooth muscle cell proliferation, as well as macrophage-to-foam cell transformation in vitro. The current study investigated whether the increased plasma adiponectin could actually reduce atherosclerosis in vivo. METHODS AND RESULTS: Apolipoprotein E-deficient mice were treated with recombinant adenovirus expressing human adiponectin (Ad-APN) or beta-galactosidase (Ad-betagal). The plasma adiponectin levels in Ad-APN-treated mice increased 48 times as much as those in Ad-betagal treated mice. On the 14th day after injection, the lesion formation in aortic sinus was inhibited in Ad-APN-treated mice by 30% compared with Ad-betagal-treated mice (P<0.05). In the lesions of Ad-APN-treated mice, the lipid droplets became smaller compared with Ad-betagal-treated mice (P<0.01). Immunohistochemical analyses demonstrated that the adenovirus-mediated adiponectin migrate to foam cells in the fatty streak lesions. The real-time quantitative polymerase chain reaction revealed that Ad-APN treatment significantly suppressed the mRNA levels of vascular cell adhesion molecule-1 by 29% and class A scavenger receptor by 34%, and tended to reduce levels of tumor necrosis factor-alpha without affecting those of CD36 in the aortic tissue. CONCLUSIONS: These findings documented for the first time that elevated plasma adiponectin suppresses the development of atherosclerosis in vivo.

Association of hypoadiponectinemia with coronary artery disease in men.

BACKGROUND: Adiponectin is an adipocyte-derived plasma protein that accumulates in the injured artery and has potential antiatherogenic properties. This study was designed to determine whether a decreased plasma adiponectin level (hypoadiponectinemia) can be independently associated with the prevalence of coronary artery disease (CAD). METHODS AND RESULTS: The consecutive 225 male patients were enrolled from inpatients who underwent coronary angiography. Voluntary blood donors (n=225) matched for age served as controls. Plasma adiponectin levels in the CAD patients were significantly lower than those in the control subjects. Multiple logistic regression analysis including plasma adiponectin level, diabetes mellitus, dyslipidemia, hypertension, smoking habits, and body mass index revealed that hypoadiponectinemia was significantly and independently correlated with CAD (P<0.0088). The entire study population was categorized in quartiles based on the distribution of plasma adiponectin levels. The interquartile cutoff points were 4.0, 5.5, and 7.0 microg/mL. The multivariate-adjusted odds ratios for CAD in the first, second, and third quartiles were 2.051 (95% confidence interval [CI], 1.288 to 4.951), 1.221 (95% CI, 0.684 to 2.186), and 0.749 (95%CI, 0.392 to 1.418), respectively. CONCLUSIONS: Male patients with hypoadiponectinemia (<4.0 microg/mL) had a significant 2-fold increase in CAD prevalence, independent of well-known CAD risk factors.

Clinical significance of high-molecular weight form of adiponectin in male patients with coronary artery disease.

BACKGROUND: It has been reported previously that the measurement of plasma total adiponectin level is clinically useful to estimate the risk of coronary artery disease (CAD). Here, the relevance of high molecular weight (HMW) adiponectin with risk factors for atherosclerosis is investigated METHODS AND RESULTS: A total of 186 consecutive male CAD patients participated in the study and were categorized into quartiles based on their total adiponectin level. The interquartile cut-off points were 4.0, 5.5 and 7.0 microg/ml. The HMW adiponectin levels were significantly lower in the quartile of lower total adiponectin levels both in non-diabetic and diabetic patients. In contrast, low molecular weight adiponectin levels (which were calculated as the Total - HMW) were constant. In univariate analysis, total adiponectin correlated negatively with body mass index and hemoglobin (Hb) A1c, and HMW adiponectin correlated negatively with HbA1c in non-diabetic patients. On the other hand, total and HMW adiponectin correlated positively with high-density lipoprotein-cholesterol (HDL-C) in diabetic patients. Multiple regression analysis revealed that HMW adiponectin correlated negatively with HbA1c in non-diabetic patients, and total and HMW adiponectin correlated positively with HDL-C in diabetic patients. CONCLUSIONS: Change in the HMW isoform reflects a change in total adiponectin level. Measurement of total and HMW adiponectin were equally useful in assessing metabolic risk in CAD patients.

Ultrasound attenuated coronary plaque as a risk factor for slow flow or no-reflow during percutaneous coronary intervention: a case report.

Slow flow or no-reflow is a serious complication during percutaneous coronary intervention (PCI), but little is known about the risk factors. A 64-year-old man underwent coronary angiography and PCI for stable angina. Pre-interventional intravascular ultrasound demonstrated an ultrasound attenuated coronary plaque, as a long eccentric bulky plaque with a marked decrease of the back echo without calcification. Since the lesion was highly eccentric in the large left anterior descending artery, directional coronary atherectomy (DCA) and subsequent stent implantation were planned. Serious no-reflow occurred after DCA. The DCA specimen suggested that the lipid-laden atheromatous gruel could attenuate the ultrasound reflection and cause distal embolization, resulting in no-reflow during PCI. The presence of ultrasound attenuated coronary plaque is a predictor of slow flow or no-reflow in PCI, indicating that distal protection devices may be required during the procedure.

Gadopentetate dimeglumine as a potential alternative contrast medium during percutaneous coronary intervention: a case report.

BACKGROUND: There have not been previous reports of patients undergoing percutaneous coronary intervention (PCI) using a gadolinium chelate. METHODS AND RESULTS: A 74-year-old woman, who had a history of anaphylactic shock 4 times in response to iodinated contrast media despite preprocedural intravenous administration of hydrocortisone, was hospitalized because of unstable angina refractory to intensive medical treatment. Fully considering the risks of iodinated agents, digital subtraction coronary angiography and PCI were performed using gadopentetate dimeglumine without any side effects or complications. CONCLUSIONS: Gadolinium chelates can be an alternative contrast media during PCI in particular patients with contraindications to iodinated media.

Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis.

Obesity is more linked to vascular disease, including atherosclerosis and restenotic change, after balloon angioplasty. The precise mechanism linking obesity and vascular disease is still unclear. Previously we have demonstrated that the plasma levels of adiponectin, an adipose-derived hormone, decreases in obese subjects, and that hypoadiponectinemia is associated to ischemic heart disease. In current the study, we investigated the in vivo role of adiponectin on the neointimal thickening after artery injury using adiponectin-deficient mice and adiponectin-producing adenovirus. Adiponectin-deficient mice showed severe neointimal thickening and increased proliferation of vascular smooth muscle cells in mechanically injured arteries. Adenovirus-mediated supplement of adiponectin attenuated neointimal proliferation. In cultured smooth muscle cells, adiponectin attenuated DNA synthesis induced by growth factors including platelet-derived growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), basic fibroblast growth factor, and EGF and cell proliferation and migration induced by HB-EGF. In cultured endothelial cells, adiponectin attenuated HB-EGF expression stimulated by tumor necrosis factor alpha. The current study suggests an adipo-vascular axis, a direct link between fat and artery. A therapeutic strategy to increase plasma adiponectin should be useful in preventing vascular restenosis after angioplasty.