IEX-1 deficiency in hematopoietic cells mitigates high fat diet-induced obesity and glucose intolerance

Abstract

Abstract We previously showed that IEX-1 paucity in mice inhibited high fat diet (HFD)-induced obesity and insulin resistance. IEX-1 deficiency induced browning of white adipose tissue (WAT) by promoting alternative activation of macrophages (AAMs), increasing energy expenditure. We now hypothesize that IEX-1 deficiency in macrophages promotes alternative activation of adipose tissue macrophages (ATM) and induces browning to inhibit obesity. We performed reciprocal bone marrow (BM) transplantation between IEX-1 knockout (KO) and wild-type (WT) mice to generate four types of chimeras. We fed these mice with HFD for 20 weeks and monitored their body weight, glucose disposal, and determined ATM phenotype using flow cytometry. While WT+WT-BM control mice (WT mice received WT bone marrow) gained ~80% body weight on HFD, WT+KO-BM mice (WT mice received KO bone marrow) increased their body weight only by 50% (p<0.01). Conversely, KO+WT-BM mice (KO mice received WT bone marrow) exhibited increased weight gain on HFD as compared to KO+KO-BM control mice that remained lean (p<0.05). Likewise, WT+KO-BM mice displayed greater glucose disposal as compared to WT control, and KO+WT-BM mice became glucose intolerant as compared to KO control as determined by glucose tolerance test. Analysis of ATM phenotype in mice fed with HFD for 5 weeks showed that HFD increased the percentage of classically activated macrophages (CAMs) by 3–4-folds (p<0.01), and decreased AAMs by ~30% (P<0.05) in epidydmal and inguinal WAT of WT+WT-BM mice. However, these effects were markedly suppressed in WT+KO-BM mice. Collectively, these data suggest that IEX-1 in hematopoietic cells contributes to HFD-induced obesity and glucose intolerance via inhibiting AAMs polarization.