Disruption of macrophage polarization promote adipocyte disfunction via APOE-APP Intercellular communication

Human exposure to endocrine disrupting chemicals (EDCs) such as plasticizers contributes to part of metabolic disorders especially in children and adolescents. Immune cells especially macrophages were essential targets of plasticizers, however their roles on plasticizers induced metabolic disorders and the underlying mechanism were poorly elucidated. Here we reported that dicyclohexyl phthalate (DCHP), one substitute for di-2-ethylhexyl phthalate (DEHP), prepubertal exposure decreased adipose tissue mass and increased plasma triglycerides in mice. Mechanistically, adipose tissue macrophages, particularly lipid associated macrophages (LAM), played key role in this systemic metabolic disorder. Phthalates facilitated the formation of LAMs. And LAMs communicated with adipocyte precursors, especially adipose progenitor cells, via APOE-APP interaction, leading to abnormal adipogenesis. Blocking LAMs formation via macrophage-specific PPAR? knockout enabled adaptive adipogenesis, ameliorating DCHP-induced metabolic disorder. Our data highlights the essential role of LAMs in inhibiting adaptive adipogenesis, supplying a scientific basis for EDCs associated metabolic disorder, especially environmental related lipodystrophy. Overall design: Human APP conditional knockout preadipocytes and adipogenesis assays were conducted using hTERT A41hWAT-SVF cells. An APP knockout cell line was established employing the CRISPR-Cas9 system to investigate the role of APP in regulating adipogenesis. Total RNA was extracted using TRIzol for transcriptome sequencing, with three biological replicates set for both hTERT A41hWAT-SVF and APP knockout cell lines.