Obesity-associated
inflammation in white adipose tissue (WAT) is a causal factor of systemic
insulin resistance; however, precisely how immune cells regulate WAT
inflammation in relation to systemic
insulin resistance remains to be elucidated. The present study examined a role for 6-phosphofructo-2-
kinase/
fructose-2,6-bisphosphatase 3 (PFKFB3) in hematopoietic cells in regulating WAT
inflammation and systemic
insulin sensitivity. Male C57BL/6J mice were fed a high-fat diet (HFD) or
low-fat diet (LFD) for 12 weeks and examined for WAT inducible
6-phosphofructo-2-kinase (iPFK2) content, while additional HFD-fed mice were treated with
rosiglitazone and examined for PFKFB3 mRNAs in WAT stromal vascular cells (SVC). Also, chimeric mice in which PFKFB3 was disrupted only in hematopoietic cells and control chimeric mice were also fed an HFD and examined for HFD-induced WAT
inflammation and systemic
insulin resistance. In vitro, adipocytes were co-cultured with bone marrow-derived macrophages and examined for adipocyte proinflammatory responses and
insulin signaling. Compared with their respective levels in controls, WAT iPFK2 amount in HFD-fed mice and WAT SVC PFKFB3 mRNAs in
rosiglitazone-treated mice were significantly increased. When the inflammatory responses were analyzed, peritoneal macrophages from PFKFB3-disrputed mice revealed increased proinflammatory activation and decreased anti-inflammatory activation compared with control macrophages. At the whole animal level, hematopoietic cell-specific PFKFB3 disruption enhanced the effects of HFD feeding on promoting WAT
inflammation, impairing WAT
insulin signaling, and increasing systemic
insulin resistance. In vitro, adipocytes co-cultured with PFKFB3-disrupted macrophages revealed increased proinflammatory responses and decreased
insulin signaling compared with adipocytes co-cultured with control macrophages. These results suggest that PFKFB3 disruption in hematopoietic cells only exacerbates HFD-induced WAT
inflammation and systemic
insulin resistance.