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Abstract
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 (mϕRIP140KD), which induced browning of white adipose tissue (WAT). In vitro, conditioned medium from cultured adipose tissue macrophages (ATMs) of mϕRIP140KD 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 mϕRIP140KD 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.
Abbreviations:
- ATM(s), adipose tissue macrophage(s)
- BAT, brown adipose tissue
- FFA, free fatty acid
- GTT, glucose tolerance test
- HFD, high-fat diet
- IL4, Interleukin 4
- IR, insulin resistance
- ITT, insulin tolerance test
- KD, knockdown mice
- mϕRIP140KD, macrophage-specific RIP140 knockdown mutation
- ND, normal diet
- PBS, phosphate-buffered saline
- RIP140, Receptor Interacting Protein 140
- SVF, stromal vascular fraction
- TG, triglyceride
- (v)WAT, (visceral) white adipose tissue
- WT, wild-type mice
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Funding
This work was supported by NIH grants DK54733, DK60521, DK54733–11S, NIH 3 R01 DK60521–12S1, the Dean's Commitment and the Distinguished McKnight Professorship of University of Minnesota (LNW).