1910-P: SOCS3 Deficiency on a High-Fat Diet Accelerates Systemic Inflammation and Results in Lethal Myeloid Hematopoiesis without Obesity and Adiposity

Introduction: Suppressors of cytokine signaling (SOCS) are negative regulators of cytokine signaling; SOCS3 controls myeloid hematopoiesis by suppressing G-CSF. SOCS3 haploinsufficiency attenuates diet-induced obesity by enhanced leptin sensitivity while improving insulin resistance. We established SOCS3 conditional knock-out (KO) mice to elucidate how high fat diets (HFD) affect inflammation and obesity in complete SOCS3 deficiency.

Methods: Embryonic lethality of complete SOCS3 deficiency was overcome using a conditional Socs3 allele inactivated by tamoxifen (TAM)-inducible cre-recombinase with SOCS3^fl/flRosa26-CreERT2^T/+ mice. They were fed HFD (60 kcal% fat) or control chaw (10 kcal% fat) starting at 4 weeks of age and TAM or vehicle administration was done at 8 weeks.

Results: Although insulin resistance improved and obesity and fatty liver were not confirmed in SOCS3-KO with HFD (S3HFD), the S3HFD group looked moribund around day 30 post-TAM by systemic inflammation; their mean survival was 62.5 days after TAM. Other groups did not look moribund. Significant granulopoiesis was also observed in S3HFD (peripheral blood neutrophil counts 29301 ± 20581/mm³). This myeloid hematopoiesis occurred in the spleen and not the bone marrow. S3HFD exhibited the progression of various granulocytes from progenitor cells (c-kit^int∼highLy6G^-) to mature granulocytes (c-kit^-Ly6G⁺).Hematopoietic infiltration was confirmed in the liver in S3HFD with granulocytes, monocytes, and macrophages. Inflammasome-associated genes (IL-1β and Caspase1) were elevated in the liver at day 65 post-TAM in S3HFD.

Conclusion: SOCS3 deficiency showed myeloid proliferation under HFD without obesity and adiposity. SOCS3-KO may help in the clarification of the specific mechanism of myeloid proliferation and invasion in HFD-induced inflammation.