Ab1159 High Fat Diet and the Adipocyte to Myofibroblast Transition: Implications for Systemic Sclerosis Cutaneous Fibrosis

Background: Systemic sclerosis (SSc) is an autoimmune fibrosing disease that affects 24.4 out of every 100,000 people in the United States and is associated with significant morbidity and mortality.1 Previous studies have shown that activated fibroblasts termed myofibroblasts drive fibrosis in SSc through the overproduction of extracellular matrix.2 Lineage tracing studies focused on identifying the cellular origin of myofibroblasts have shown, in a mouse model of SSc, that myofibroblasts were derived from dermal adipocytes.3 Targeting the adipocyte to myofibroblast transition (AMT) may be a novel approach to reversing fibrosis in patients with SSc, however, the mechanisms that drive this transition are currently poorly understood. One factor that may influence AMT is expansion of dermal white adipose tissue (DWAT). High fat diet has been shown to increase DWAT and reduce dermal thickness in mice.4 Additionally, fat transplantation into fibrotic tissue of bleomycin-treated mice reverses skin fibrosis through increased adipogenesis.5 Objectives: Determine if high fat diet decreases fibrosis and increases DWAT in a mouse model of systemic sclerosis. Methods: Three-week-old female C57BL/6 mice were started on either a chow diet, a high fat lard diet (high in palmitic, oleic, linoleic and stearic acids) or a high fat coconut oil diet (high in lauric acid) (5 mice per diet). High fat lard diet and high fat coconut oil diet were isocaloric. After five weeks, two mice were sacrificed from each group and skin was collected for histology. The remaining 3 mice in each diet group were started on every other day subcutaneous injections with bleomcyin to induce skin fibrosis. Injections were continued for a total of 21 days, at which point the remaining three mice in each diet group were sacrificed and skin was collected for histology. Results: High fat lard diet increased dermal white adipose tissue (DWAT) and appeared to protect mice from a bleomycin-induced decrease in DWAT compared to chow and high fat coconut oil diets (although the differences were not statistically significant, likely due to low n). High fat lard diet also affected the hair follicle cycle. Mice on high fat lard diet were in anagen at day 0 and at day 21 of bleomycin injections while mice on chow and high fat coconut oil diets appeared to be in telogen on day 0 and day 21 of bleomycin injections. Conclusion: High fat lard diet may protect against fibrosis in a mouse model of systemic sclerosis in this pilot study. Additionally, high fat lard diet appeared to have an effect on the hair follicle cycle. Interestingly, high fat coconut oil diet was not associated with either of these effects, suggesting that the chemical composition of the fat may affect its function. Future studies are needed to determine how high fat diets that differ in their composition of fatty acids exert different effects on dermal white adipose tissue, fibrosis and the hair follicle cycle. REFERENCES: 1 Fan, Y. et al. Journal of Managed Care and Specialty Pharmacy (2020); 26(12), 1539–1547. 2 Hinchcliff, M. et al. Current Rheumatology Reports (2020); 22(8). 3 Marangoni, R. G. et al. Arthritis Rheumatology (2015); 67(4), 1062–1073. 4 Zhang, Z., et al. Experimental Dermatology (2021); 30(1), 102–111. 5 Wang, J. et al. Stem Cell Research and Therapy (2022); 13(1), 1–13. Acknowledgements: NIL. Disclosure of Interests: Arissa Young: None declared, Stephanie Hernandez: None declared, Elizabeth Volkmann Boehringer Ingelheim, GSK, Boehringer Ingelheim, Promethus, Horizon, Heather Christofk Pelage pharmaceuticals, Faeth therapeutics, Pelage pharmaceuticals.