Insulin signaling in metabolic diseases: the role of IGFBP7 in adipose tissue metabolic function

Abstract

Insulin and insulin-like growth factors (IGFs) are mitogenic and pro-survival factors to many different cell types. Circulating IGFs are bound by IGF binding proteins (IGFBPs) that regulate their action. IGFBP7 is a novel IGFBP-related protein (IGFBP-rP) that, in contrast to other IGFBPs/IGFBP-rPs, features higher affinity for insulin than for IGFs. We previously demonstrated that IGFBP7 exerts mitogenic and pro-survival autocrine effects in acute lymphoblast leukemia (ALL) cells that were dependent on insulin/IGF. IGFBP7 was shown to prolong the surface retention of the IGF1 receptor (IGF1R), under insulin/IGF1 stimulation, resulting in sustained IGF1R, IRS1, Akt and Erk phosphorylation. It's well known that defective insulin/IGF1 signaling is a key feature of metabolic diseases such as obesity and type 2 diabetes. In obesity, a series of factors contribute to development of insulin resistance and hyperinsulinemia, however one of the main factors is the dysfunction of the adipose tissue. Insulin/IGF1, acting through their cognate receptors, are essential for adipocyte differentiation, development and metabolic function. Given that IGFBP7 is shown to prolong the effect of insulin/IGF1 in the leukemia cells, we hypothesize that this molecule may exert positive effects on adipocyte function and metabolic homeostasis in conditions of metabolic disease. Therefore, the main goal of this project is to characterize the role of IGFBP7 in adipocyte's metabolic function in the context of metabolic diseases such as obesity and type 2 diabetes. (AU)