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

Abstract

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-1α (HIF-1α) 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-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α 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-1α may contribute to this process.

Incretins

“…Thus, the net glycaemic effect of GIP is largely dependent on the balance of actions on both pancreatic α-and β-cells. Furthermore, evidence from rodent studies has linked GIP signalling to fat accumulation, adipose inflammation and weight gain, which may exacerbate insulin resistance (Chen et al 2014).…”

Nuclear translocation of HIF-1α induced by influenza A (H1N1) infection is critical to the production of proinflammatory cytokines

“…HIF-1α is involved in the transcriptional regulation of cytokines, such as IL-6 and TNF-α, during inflammation. 20, 21, 22 In addition, data suggest that HIF-1α expression can be induced by virus infection. 23, 24, 25, 26 However, the role of HIF-1α in H1N1 infection is still unknown.…”

Gastric inhibitory polypeptide/glucose‐dependent insulinotropic polypeptide signaling in adipose tissue

“…Previous in vitro studies have shown that GIP increases IL‐6 expression levels in adipose tissue. In astrocytes, CREB activated by β‐adrenergic receptor enhances IL‐6 expression induced by tumor necrosis factor (TNF)‐α receptor signaling.…”