Abstract 18901: Metabolic Regulation of Adipose Tissue Inflammation and Systemic Insulin Sensitivity: A Role for PFKFB3 in Macrophage Polarization

Abstract

Much evidence demonstrates that macrophages play a pivotal role in the development of overnutrition-associated metabolic diseases, such as cardiovascular disease and type II diabetes. Macrophage inflammatory status (polarization) is a key determinant of systemic insulin resistance, which is under the control of bi-directional regulation: macrophage proinflammatory activation and macrophage alternative activation (anti-inflammatory). It has been previously shown that PFKFB3, a gene that encodes for a key regulatory enzyme of glycolysis, is crucial for the control of systemic insulin sensitivity. In the present study, if and how PFKFB3 alters macrophage polarization in relation to adipose tissue inflammation and systemic insulin sensitivity were examined. Bone marrow cells were isolated from wild-type mice and PFKFB3-disrupted mice and differentiated into macrophages which were referred to as bone marrow-derived macrophages (BMDM). Compared with control cells, the phosphorylation of NF-kB p65 and JNK1/2 is in PFKFB3-disrupted BMDM. Additionally, the expression of proinflammatory cytokines, such as TNF-α and IL-6, was increased in PFKFB3-disrupted BMDM under the stimulation of lipopolysaccharides (LPS, 100 ng/ml). Upon adoptive transfer of bone marrow cells to lethally irradiated wild-type mice, the recipients with PFKFB3-disrupted bone marrow cells displayed a decrease in systemic insulin sensitivity, which was accompanied by an increase in adipose tissue inflammatory responses. The later were evidenced by increases in adipose tissue macrophage infiltration, the phosphorylation of NF-kB p65, and mRNA levels of proinflammatory cytokines. Taken together, PFKFB3 is a metabolic regulator of macrophage polarization, which accounts for the effects of PFKFB3 on protecting against diet-induced adipose tissue inflammation and systemic insulin resistance.