Cell-intrinsic TLR4-dependent bone marrow lympho-myeloid distortions in obesity

Abstract

Abstract Obesity compromises bone marrow (BM) progenitor function and the mechanistic underpinnings are just beginning to be established. Here we show that following 16 weeks of high fat diet, mice exhibit poor emergency hematopoiesis in a toll-like receptor 4 (TLR4)-dependent manner, and that adoptive transfer of obese BM to lean recipients restores rebound capability. Genes associated with a myeloid signature (c-fms, pu.1, ikaros) are enhanced and lymphoid signature (flt3, meis1, e47) reduced. The skewed lympho-myeloid outgrowth of discrete BM subsets is apparent by 6 weeks of high fat diet, earlier than is commonly recognized. Using mixed BM chimeras we demonstrate that obesity-associated subversion of lineage-c-kit+Sca-1- (LKSneg) precursors to the myeloid lineage and common lymphoid progenitors (CLP) to the B lineage depends on BM cell subset-autonomous TLR4. The endogenous TLR4 ligands responsible for BM dysfunction in obesity are unclear. Here, we show that exposure of lean mice to lipopolysaccharide (LPS) at levels similar to that observed in obesity recapitulates key aspects of BM lympho-myeloid disruption. Together, our results establish a mechanistic role for BM cell-intrinsic TLR4 early in obesity-driven BM dysfunction, and demonstrate the biological importance of one obesity-associated TLR4 ligand.