Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes

Timper K, Grisouard J, Sauter NS, Herzog-Radimerski T, Dembinski K, Peterli R, Frey DM, Zulewski H, Keller U, Muller B, Christ-Crain M. Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes. Am J Physiol Endocrinol Metab 304: E1-E13, 2013. First published October 23, 2012; doi:10.1152/ajpendo.00100.2012.-Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1 beta, and the IL-1 receptor antagonist IL-1Ra, whereas TNF alpha, IL-8, and monocyte chemotactic protein (MCP)-1 remained unchanged. Cytokine induction involved PKA and the NF-kappa B pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1 beta, and TNF alpha. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-kappa B activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-kappa B-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes.