Figure 3.

Model of Wnt signalling in energy balance regulation. (a) Leptin activates lipoprotein receptor‐related protein (LRP)‐6, which results in inactivation of glycogen synthase kinase 3β (GSK3β). This might trigger a positive‐feedback loop in which the phosphorylation by GSK3β on inhibitory phosphorylation sites of insulin receptor substrate 1 (IRS‐1) is reduced. The modification of IRS‐1 might result in an activation of the IRS‐phosphoinositide 3‐kinase (PI3K) pathway by insulin increasing phospho‐AKT. Phospho‐AKT then might enhance this mechanism through inactivation of GSK3β. (b) By contrast, in genetically obese leptin‐deficient mice, there is no inactivation of LRP‐6 by leptin. Therefore, increased GSK‐3β activity inhibits IRS‐1 through phosphorylation of inhibitory sites. This inhibition can potentially lead to hypothalamic insulin resistance and subsequently to the development of type‐2 diabetes. Axin‐2, Axin inhibition protein 2; DKK1, Dickkopf 1; LepR, leptin receptor; IR, insulin receptor; JAK, Janus kinase. Reprinted with permission 20.