Injecting engineered anti-inflammatory macrophages therapeutically induces white adipose tissue browning and improves diet-induced insulin resistance

We recently exploited a transgenic approach to coerce macrophage anti-inflammatory M2 polarization in vivo by lowering Receptor Interacting Protein 140 (RIP140) level in macrophages (mwRIP140KD), which induced browning of white adipose tissue (WAT). In vitro, conditioned medium from cultured adipose tissue macrophages (ATMs) of mwRIP140KD mice could trigger preadipocytes’ differentiation into beige cells. Here we describe a cell therapy for treating high fat diet (HFD)-induced insulin resistance (IR). Injecting M2 ATMs retrieved from the WAT of mwRIP140KD mice into HFD-fed obese adult wild-type mice effectively triggers their WAT browning, reduces their pro-inflammatory responses, and improves their insulin sensitivity. These data provide a proof-of-concept that delivering engineered anti- inflammatory macrophages can trigger white fat browning, stimulate whole-body thermogenesis, and reduce obesity- associated IR.