Abstract 20010: Diet-induced Obesity Stimulates Inflammatory Monopoiesis From Hematopoietic Stem Progenitor Cells Through Activating Histone Methylation

Abstract

Obesity-induced monopoiesis has been implicated in the development of obesity-related complications. Monopoiesis is largely dependent on hematopoietic stem progenitor cells (HSPCs) in the bone marrow (BM). However, little is known about hematopoietic control mechanisms in diet-induced obesity. In a mouse model of diet-induced obesity (DIO), we found leukocytosis (9.465 ± 0.7350 K/ul versus 7.277 ± 0.3450 K/ul in healthy controls, n=7 each? , p=0.023) and increased inflammatory Ly6Chi monocytes in circulation (377.2 ± 40.94/ul vs. 224.8 ± 39.18/ul in lean control; n=7; p=0.023), associated with increased myeloid progenitor cells (60% increase in granulocyte-monocyte progenitor cells, n=4) in the BM. By flow cytometry based profiling, we found that active marks for transcription, histone 3 lysine 4 trimethylation (H3K4me3), are upregulated (1.82-fold increase in mean fluorescent intensity (MFI) vs. lean mice, n=5, p<0.05) in Ly6Chi inflammatory monocytes in DIO mice, along with increased inflammatory gene expression in response to TLR (toll-like receptor) 4 stimulation. In the BM, HSPCs but not myeloid progenitor cells have enriched H3K4me3 in DIO mice (2.84-fold in MFI in cKit+Sca1+Lin- cells, n=5, p<0.05). This activated mark in HSPCs is associated with increased monopoiesis from HSPCs (1.55-fold increase in output CD11b+Ly6Chi monocytes from cultured HSPCs, n=3-5, p<0.01) in response to TLR2 and TLR4 stimulations. Of note, HSPCs produce inflammatory cytokines to promote differentiation into inflammatory monocytes. Moreover, HIF-1a, a potential upstream of H3K4me3, is upregulated (2.29-fold in MFI, n=5, p<0.05) in HSPCs in DIO mice. These results suggest that obesity increases HIF-1a-mediated H3K4me3 enrichment in HSPCs, which in turn contributes to inflammatory cytokine expression and to increased inflammatory monopoiesis. Thus, epigenetic marks in HSPCs could be a target for obesity-related complications.