Abstract

White adipose tissue (WAT) expands with angiogenesis. We have demonstrated that adipose-tissue-macrophages (ATMs) highly express platelet-derived growth factor (PDGF)-B in obesity, and exposure of PDGF-B stimulates detachment of pericytes (PCs) from vessels. Since vessel-attached PCs inhibit endothelial cell growth, the detachment restarts angiogenesis. In the present study, we aimed to clarify the significance of ATMs on adipose angiogenesis. Intraperitoneal injection of liposome-encapsulated clodronate (Clod) for 6 weeks achieved depletion of macrophages and decreased expression of Pdgfb mRNA in WAT of HFD-fed mice. Clod-treated mice showed smaller WAT with vessels well covered with PCs compared to control mice. We next investigated underlying mechanism of Pdgfb induction. LPS but not IL-4 stimulated Pdgfb expression in peritoneal macrophages. In RAW 264.7 macrophages, Pdgfb expression induced by high glucose plus LPS stimulation was completely blocked by pretreatment with 2-deoxyglucose (2-DG), a hexokinase inhibitor or heptelidic acid, a GAPDH inhibitor, whereas it was not affected by treatment with 6-aminonicotinamide, an inhibitor of glucose-6-phosphate dehydrogenase acting as the rate-limiting enzyme of the pentose phosphate pathway. In addition, high glucose plus LPS induced phosphorylations of S6 kinase, ERK, and JNK but not p38 MAP kinase. These phosphorylations were significantly attenuated by treatment with 2DG. Importantly, enhanced expression of Pdgfb by high glucose plus LPS was effectively suppressed by inhibitor or knockdown of Erk but not by rapamycin. The expression was also attenuated by inhibition of NFκb pathway. In conclusion, hyperglycemia and chronic inflammation reprogram metabolic pathways toward glycolysis, and subsequent activation of NFκB plays a pivotal role in the production of PDGF-B in ATMs during obesity development. Disclosure T. Wada: None. Y. Onogi: None. A. Okekawa: None. T. Matsuzawa: None. E. Watanabe: None. G. Komatsu: None. H. Tsuneki: None. T. Sasaoka: None. Funding Japan Society for the Promotion of Science (JP18K08469)

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