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Serum amyloid A (SAA) increases in response to acute inflammatory stimuli and is modestly and chronically elevated in obesity. SAA3, an inducible form of SAA, is highly expressed in adipose tissue in obese mice where it promotes monocyte chemotaxis, providing a mechanism for the macrophage accumulation that occurs with adipose tissue expansion in obesity. Humans do not express functional SAA3 protein, but instead express SAA1 and SAA2 in hepatic as well as extrahepatic tissues, making it difficult to distinguish between liver and adipose tissue-specific SAA effects. SAA3 does not circulate in plasma, but may exert local effects that impact systemic inflammation. We tested the hypothesis that SAA3 contributes to chronic systemic inflammation and adipose tissue macrophage accumulation in obesity using mice deficient for Saa3 (Saa3(-/-)). Mice were rendered obese by feeding a pro-inflammatory high fat, high sucrose diet with added cholesterol (HFHSC). Both male and female Saa3(-/-) mice gained less weight on the HFHSC diet compared to Saa3(+/+) littermate controls, with no differences in body composition or resting metabolism. Female Saa3(-/-) mice, but not males, had reduced HFHSC diet-induced adipose tissue inflammation and macrophage content. Both male and female Saa3(-/-) mice had reduced liver Saa1 and Saa2 expression in association with reduced plasma SAA. Additionally, female Saa3(-/-) mice, but not males, showed improved plasma cholesterol, triglycerides, and lipoprotein profiles, with no changes in glucose metabolism. Taken together, these results suggest that the absence of Saa3 attenuates liver-specific SAA (i.e., SAA1/2) secretion into plasma and blunts weight gain induced by an obesogenic diet. Furthermore, adipose tissue-specific inflammation and macrophage accumulation are attenuated in female Saa3(-/-) mice, suggesting a novel sexually dimorphic role for this protein. These results also suggest that Saa3 influences liver-specific SAA1/2 expression, and that SAA3 could play a larger role in the acute phase response than previously thought.
Pubmed ID: 25251243
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Founded on the principle that strong science would lead to important new medicines, Regeneron has become an integrated biopharmaceutical company that discovers, develops, and commercializes medicines for the treatment of serious medical conditions. Regeneron currently markets ARCALYST (rilonacept) Injection for Subcutaneous Use for the treatment of a rare, inherited, inflammatory condition. Regeneron has therapeutic candidates in Phase 3 clinical trials for the potential treatment of gout, age-related macular degeneration, central retinal vein occlusion, and certain cancers. Additional therapeutic candidates are in earlier stage development programs in rheumatoid arthritis and other inflammatory conditions, pain, cholesterol reduction, allergic conditions, and cancer. The Company''s ability to develop product candidates is enhanced by the application of several proprietary technologies that Regeneron has incorporated into a comprehensive drug discovery and development process. This process is designed to thoroughly understand the biology of specific diseases, discover potential therapeutic candidates, and evaluate these candidates in clinical trials. One specific area of Regeneron expertise is the rapid development of fully-human monoclonal antibodies. In November 2007, Regeneron and sanofi-aventis entered into a global, strategic collaboration to discover, develop, and commercialize fully-human therapeutic antibodies utilizing Regeneron''s proprietary VelociSuite of technologies, and we expanded the collaboration in November 2009. Five human antibodies developed under the sanofi-aventis collaboration are in clinical development today, with a goal of advancing an average of four to five new antibodies into clinical development each year through 2017. In addition to the Company''s corporate headquarters and research laboratories in Tarrytown, New York, Regeneron has a large-scale biologics manufacturing facility in Rensselaer, New York, where it produces commercial and investigational products for its clinical trials, and a satellite office in Bridgewater, New Jersey.
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View all literature mentionsCenter that produces knockout mice and carries out high-throughput phenotyping of each line in order to determine function of every gene in mouse genome. These mice will be preserved in repositories and made available to scientific community representing valuable resource for basic scientific research as well as generating new models for human diseases.
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