Abstract 271: Id3 Promotes Obesity-Induced Inflammatory Macrophage Accumulation Through Proliferation of MCP-1-Producing Adipocyte Progenitor Cells

Abstract

High fat diet (HFD)-induced increases in MCP-1 are a hallmark feature of adipose tissue inflammation during obesity. Macrophages are the main producers of MCP-1 in established obesity; however, early increases in obesity-induced production of MCP-1 precede migration of M1 macrophages to adipose tissue. Global deletion of transcription factor Inhibitor of Differentiation 3 (Id3) attenuates HFD-induced obesity and adipose tissue inflammation. Specifically, Id3-/- mice have less visceral adipose tissue (VAT), fewer M1 adipose tissue macrophages, and attenuated HFD-induced MCP-1 production. The source of initial obesity-induced MCP-1 in vivo, as well as the role that Id3 plays in regulation of MCP-1, is currently unknown. Flow cytometry demonstrated that committed CD45-CD31-Ter119-CD29+CD34+Sca-1+CD24- adipocyte progenitor cells (AdPCs) express high levels of MCP-1. HFD increased the number of AdPCs in an Id3-dependent manner. Loss of Id3 increased levels of p21Cip1 and attenuated HFD-induced proliferation of AdPCs, resulting in lower levels of MCP-1 and reduced M1 macrophage numbers in VAT, compared to Id3+/+ littermate controls. Adoptive transfer of 50,000 Id3+/+ AdPCs into Id3-/- recipient mice restored adipose tissue inflammation via increased MCP-1 levels and M1 macrophage accumulation in VAT. Notably, the M1:M2 macrophage ratio significantly increased due to injection of AdPCs. Additionally, flow cytometry identified MCP-1-producing CD45-CD31-CD34+CD44+CD90+ AdPCs in human omental and subcutaneous adipose tissue. The percentage of AdPCs expressing MCP-1 was higher in omental adipose compared to subcutaneous adipose. Furthermore, high surface expression of CD44 marked abundant MCP-1 producers, only in omental adipose tissue. The present study provides the first in vivo evidence that committed AdPCs are the source of early obesity-induced MCP-1. Id3 is a critical regulator of p21Cip1 expression and proliferation in AdPCs, and in this manner, promotes overall MCP-1 expression and M1 macrophage accumulation in VAT. Inhibition of Id3 and AdPC expansion, as well as CD44 expression in human AdPCs, may serve as unique therapeutic targets for the regulation of adipose tissue inflammation.