Background: An intricate network of reciprocal interactions between adipose tissue and
immune system have been largely demonstrated, leading to the well-accepted concept of insulin resistance
as a low grade inflammatory state and, conversely, chronic high-grade inflammation as a dysmetabolic
condition. Immune homeostasis is regulated by several players including the complement system,
a complex protein network at the crossroad between the innate and adaptive arms of the human
defences against pathogens.
Objective: Complement C3 represents the nodal point of the complement cascade independently of the
pathway recruited. Aim of this review is to collect the evidence supporting the role of complement C3
as a candidate biomarker of insulin resistance and other metabolic disorders.
Methods: We reviewed the available evidence pointing to a role of complement system, and in particular
complement C3, in insulin resistance and other cardiometabolic diseases including diabetes
(T2D), hypertension, non-alcoholic fatty liver disease (NAFLD) and atherosclerosis.
Results: Compelling preclinical evidence demonstrated a role of adipose-tissue C3 and its cleavage
products C3a and acylation stimulating protein (ASP) in adipose tissue inflammation and insulin
resistance. To further support this hypothesis, several clinical studies, both cross-sectional and
longitudinal, confirmed this association in independent cohorts. Moreover, preliminary evidence
support a role of complement C3 in other cardiometabolic diseases such as hypertension, NAFLD and
Conclusion: Future studies are needed to fully confirm the usefulness of C3 as a clinical biomarker
and to establish accurate cut-off values. Moreover, the therapeutic potential of C3 modulation in either
cardiometabolic and inflammatory diseases need to be investigated.