Obesity-driven Immunometabolic Activation of Myeloid Cells

Background/Rationale: Obesity is a chronic inflammatory disorder and a strong predictor of tissue insulin resistance and Type 2 Diabetes. Accumulation of pro-inflammatory adipose tissue macrophages (ATM) are culprits to tissue insulin resistance. Tissue infiltration and the subsequent differentiation of Ly6Chigh monocytes largely contribute to ATM accumulation during obesity. Interestingly, Ly6Chigh monocytes are elevated in the circulation and in the bone marrow (BM) during obesity. However, the temporal relation of the obesity-driven increase in ATM and BM Ly6Chigh monocytes are unknown. Furthermore, it is also unknown what obesity-induced changes drive the increased production of Ly6Chigh monocytes in the BM. Moreover, it is unknown how monocytes are affected with obesity and whether the metabolic skewing, as observed in ATM, are also induced in BM monocytes. Hypotheses: I hypothesized, that increased BM Ly6Chigh monocytosis occur prior to ATM accumulation with high fat diet (HFD). Additionally, I hypothesized, that local BM adipocyte (BMA) expansion favour increased Ly6Chigh monocyte development. Lastly, I hypothesized, that a glycolytic shift would be induced in BM monocytes with HFD. Methods: A murine HFD feeding model with the durations of 3, 8 and 18 weeks were adopted. Using flow cytometry analysis, the accumulated ATM and BM monocytes were quantified. Furthermore, in vivo correlative analysis between BMA and monocytes were assessed. In vitro models were adopted to assess the direct influence of adipocytes on monocyte development. Lastly, the metabolic status of monocytes were studied using the Seahorse assay, MitoTrackerTM staining and expression analysis of mitochondrial genes via RT qPCR. Results/conclusion: An earlier elevation of the BM monocytes compared to the ATM were detected with HFD. Furthermore, BMA whitening temporally correlated with Ly6Chigh monocyte expansion in the BM during HFD. White adipocytes and HFD-derived BMA directly favoured Ly6Chigh monocytes, in vitro. Interestingly, white adipocytes induced conversion of Ly6Clow to Ly6Chigh monocytes. We further discovered that Ly6Chigh monocytes prefer glycolytic and Ly6Clow monocytes prefer oxidative metabolism. During HFD, the metabolism of Ly6Clow monocytes are skewed to resemble that of Ly6Chigh monocytes. The findings reported here place the BM as a key site for the origin of cellular and metabolic disruptions with obesity.Ph.D.2021-12-29 00:00:0