Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice

Abstract

Adipose tissue (AT) inflammation and infiltration by macrophages is associated with insulin resistance and type 2 diabetes in obese humans, offering a potential target for therapeutics. However, whether AT macrophages (ATMs) directly contribute to systemic glucose intolerance has not been determined. The reason is the lack ofmethods to ablate inflammatory genes expressed inmacrophages specifically localized within AT depots, leavingmacrophages in other tissues unaffected. Here we report that i.p. administration of siRNA encapsulated by glucan shells in obese mice selectively silences genes in epididymal ATMs, whereas macrophages within lung, spleen, kidney, heart, skeletalmuscle, subcutaneous (SubQ) adipose, and liver are not targeted. Such administration of GeRPs to silence the inflammatory cytokines TNF-a or osteopontin in epididymal ATMs of obese mice caused significant improvement in glucose tolerance. These data are consistentwith the hypothesis that cytokines produced by ATMs can exacerbate whole-body glucose intolerance.