Complement C3: an emerging risk factor in cardiometabolic disease.

C3 is the central component of the complement system and activation of C3 via any of the three major activation pathways-the classical, the lectin and the alternative pathways-results in initiation of the terminal complement pathway and release of the anaphylatoxin C3a. Both terminal pathway activation and signalling of C3a and its inactivation product C3a-desarg via the C3a receptor and C5a-like receptor 2, respectively, can induce inflammatory, immunomodulatory and metabolic responses. C3 has been implicated in metabolic disorders, notably adiposity, dyslipidaemia, insulin resistance, liver dysfunction and diabetes, and C3 is increasingly recognised as a cardiometabolic risk factor. C3 may play a role in the macrovascular, as well as microvascular, complications of diabetes. Moreover, C3 may interact with the coagulation system and as such also contribute to a procoagulant, hypofibrinolytic and, ultimately, prothrombotic state. Recent data suggest a diabetes-dependent incorporation of C3 into fibrin clots, with concomitant effects on clot characteristics. Taken together, epidemiological and experimental evidence concordantly point to a role of complement C3 in metabolic, atherosclerotic/atherothrombotic and microangiopathic processes and further research should be directed towards the elucidation of complement function and activation in cardiometabolic disorders.