Platelet hyper-reactivity is a crucial cause of accelerated atherosclerosis increasing risk of thrombotic vascular events in diabetic patients.The mechanisms leading to abnormal platelet activity during diabetes are complex and not fully defined.The current study attempted to clarify the role of CTRP9,a novel adiponectin paralog,in enhanced platelet activity and determined whether CTRP9 may inhibit platelet activity.Adult male C57BL/6J mice were randomized to receive high-fat diet (HFD) or normal diet (ND).8 weeks after HFD,animals were sacrificed,and both plasma CTRP9 and platelet aggregation were determined.HFD-fed animals increased weight gain significantly,and became hyperglycemic and hyperinsulinemic 8 weeks post-HFD.Compared to ND animals,HFD animals exhibited significantly decreased plasma CTRP9 concentration and increased platelet response to ADP,evidenced by augmented aggregation amplitude,steeper aggregation slope,larger area under the curve,and shorter lag time (P<0.01).A significant negative correlation between plasma CTRP9 concentration and platelet aggregation amplitude was observed.More importantly,in vitro pre-treatment with CTRP9 significantly inhibited ADP-stimulated platelet activation in platelet samples from both ND and HFD animals.Taken together,our results suggest reduced plasma CTRP9 concentration during diabetes plays a causative role in platelet hyper-activity,contributing to platelet-induced cardiovascular damage during this pathologic condition.Enhancing CTRP9 production and/or exogenous supplementation of CTRP9 may protect against diabetic cardiovascular injury via inhibition of abnormal platelet activity.