Pilot: Serum Amyloid A - a Novel Mediator of Adipose-Tissue Inflammation and Rnsulin Resistance

The acute phase protein, Serum amyloid A (SAA) has been implicated as a mediator of cardiovascular disease. This project investigates the role of SAA in the development of obesity associated inflammation and insulin resistance in mice. The rationale for the study stems from the observation that 1. Serum SAA levels are increased in obesity and are associated with insulin resistance 2. SAA acts as a chemoattractant and shows proinflammatory properties 3. SAA is a danger associated molecule capable of triggering NLRP3-inflammasome activation in cells, inflammasome is an important regulator of adipocyte function and insulin sensitivity. However, circulating SAA is associated with high density lipoprotein (HDL) which is known to mask the inflammatory properties of SAA. HDL-bound SAA is predominantly produced by the liver. Adipose tissue (AT) is a major site for SAA production in obesity and our preliminary results suggest that AT may not contribute to circulating SAA as much as that of the liver. We hypothesize that SAA plays a regulatory role in obesity]associated AT inflammation and insulin resistance and majority of AT-derived SAA remains lipid]free and contributes to AT-inflammation and insulin resistance in contrast to HDL-bound liver-derived SAA which would require being lipid-free before exerting its effect. We have developed unique mouse models, including mice deficient in all the isoforms of SAA (TKO), mice that express SAA only in liver (SAA1.1-TGliver) or only in adipose tissues (SAA1.1-TGfat) on a TKO background. We are hopeful that the results of the study would further enhance our understanding on the mechanisms of obesity associated AT-inflammation and insulin resistance. Future studies will include understanding the mechanisms involved in the regulation and developing strategies to target SAA in AT of obesity individuals.