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In this study, we revealed that periostin (<jats:italic>Postn<\/jats:italic>) is produced at extraordinary levels by adipose tissue after feeding with a high-fat diet (HFD). <jats:italic>Postn<\/jats:italic> was secreted at least from macrophages in visceral adipose tissue during the development of obesity, possibly due to hypoxia. <jats:italic>Postn<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice had lower levels of crown-like structure formation and fibrosis in adipose tissue and were protected from liver steatosis. These mice also showed amelioration in systemic insulin resistance compared with HFD-fed WT littermates. Mice deficient in <jats:italic>Postn<\/jats:italic> in their hematopoietic compartment also had lower levels of inflammation in adipose tissue, in parallel with a reduction in ectopic lipid accumulation compared with the controls. 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