Serum amyloid A3 is required for normal weight and immunometabolic function in mice

Serum amyloid A (SAA) is an apolipoprotein that is robustly upregulated in numerous inflammatory diseases and has been implicated as a candidate pro-inflammatory mediator. However, studies comparing endogenous SAAs and recombinant forms of the acute phase protein have generated conflicting data on the function of SAA in immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to immune-mediated disease, and found that mice lacking SAA3 develop adult-onset obesity and metabolic dysfunction along with defects in innate immune development. Mice that lack SAA3 gain more weight, exhibit increased visceral adipose deposition, and develop hepatic steatosis compared to wild-type littermates. Leukocytes from the adipose tissue of SAA3-/- mice express a pro-inflammatory phenotype, and bone marrow derived dendritic cells from mice lacking SAA3 secrete increased levels of IL-1β, IL-6, IL-23, and TNFα in response to LPS compared to cells from wild-type mice. Finally, BMDC lacking SAA3 demonstrate an impaired endotoxin tolerance response and inhibited responses to retinoic acid. Our findings indicate that endogenous SAA3 modulates metabolic and immune homeostasis.