Loss of Antigen Presentation in Adipose Tissue Macrophages or in Adipocytes, but Not Both, Improves Glucose Metabolism

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Macrophages, B cells, and adipocytes are among the adipose tissue (AT) APCs that differentiate and activate naive CD4 + T cells. Mice with adipocyte loss of MHC class II (MHC II) are more insulin sensitive. Because macrophages are professional APCs, mice with genetic myeloid MHC II depletion (myeloid MHC II knockout [mMHCII -/- ]) were created and metabolically characterized. FITC + glucan-coated particles (glucan-encapsulated small interfering RNA [siRNA] particles [GeRPs]) were also used to target MHC II knockout specifically in AT macrophages (ATMs). Mice with total body mMHCII -/- were generated by crossing LyzMCre with H2Ab1 floxed mice. For specific ATM depletion of H2Ab1, GeRPs containing H2Ab1 siRNA were administered to high-fat diet-fed C57BL/6 mice. Unexpectedly, mMHCII -/- mice had loss of both macrophage and adipocyte H2Ab1, one of only two Ag-presenting arms; thus, neither cell could present Ag and activate CD4 + T cells. This inability led to a reduction in AT immunosuppressive regulatory T cells, increased AT CD8 + T cells, and no improvement in systemic metabolism. Thus, with combined systemic myeloid and adipocyte MHC II loss, the impact of ATM-specific alterations in APC activity could not be delineated. Therefore, GeRPs containing H2Ab1 siRNA were administered to specifically reduce ATM H2Ab1 which, in contrast, revealed improved glucose tolerance. In conclus

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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