SAT-784 A Trained Immunity Phenotype In Adipocytes

Abstract J. Brown: None. J. Cancino: None. V. Fong: None. Abstract: Chronic inflammation of adipose tissue is strongly linked to metabolic dysfunction and its associated diseases but the underlying mechanisms are not well understood. Improved understanding of this pathway would allow creation of therapeutic strategies to mitigate adverse events associated with obesity. Trained immunity is an innate immune function that allows immune cells to respond differently after having had prior exposure to a stimulus. For these experiments, we hypothesized that adipocytes can acquire a trained immunity phenotype after exposure to exogenous immunogenic stimulus or endogenous metabolic stimulus. To test this, we used adipocytes derived from 3T3-L1 cells and adipose tissue derived mesenchymal stem cells (AdMSCs). The cells were differentiated into adipocytes and stimulated with lipopolysaccharides (LPS) on day 6 and 13. The levels of proinflammatory cytokine, IL-6, were measured 24hr after stimulation. We found significantly increased levels of IL-6 after second exposure to LPS when compared to the initial exposure in both adipocytes differentiated from 3T3-L1 cells and AdMSCs. In comparison, undifferentiated control cells secreted IL-6 in response to LPS stimulation but did not show any significant difference between exposures. To study the effect of obesity and metabolic dysfunction, adipocytes were differentiated from AdMSCs isolated from diet induced obese (DIO) mice fed a high fat diet (HFD) compared to a control where mice were fed chow. The mice were on the diet starting from 8 weeks of age and were fed for at least 36 weeks. Results showed that adipocytes differentiated from AdMSCs from mice fed HDF secreted more IL-6 on initial LPS exposure when compared to adipocytes from mice fed chow diet, but did not increase further with second exposure. Moreover, IL-6 secretion from HFD adipocytes on both days were not significant different when compared to the IL-6 secretion from the chow group on day 14. This suggests that AdMSCs from the DIO mice adipocytes were already trained from the effects of obesity. In addition to an altered cytokine profile, trained monocytes exhibit characteristic epigenetic and metabolic changes that maintain its trained phenotype. Accordingly, we examined the metabolic profiles of adipocytes that were stimulated with LPS versus not stimulated and found distinct profiles, suggesting a dramatic change in cell metabolism. Altogether, our data support the idea that adipocytes can display a proinflammatory trained immunity phenotype. Future work still needs to be done to demonstrate the epigenetic changes and molecular reprogramming that are responsible for these changes. Overall, our data indicates a larger role of adipocytes in adipose inflammation, suggesting a relationship between trained adipocytes and dysregulated metabolic signals that create a reinforcing feedback loop leading to chronic adipose tissue inflammation. Saturday, June 1, 2024