Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1 alpha, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1 alpha gene silencing diminished both macrophage-and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1 alpha may contribute to this process.