The gp130 receptor (gp130R) cytokines interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) can improve metabolic disease, but due to the known pro-inflammatory effects of IL-6 and the antigenic response to the clinically used form of CNTF (AxokineTM), both proteins have limited therapeutic utility. Accordingly, we recently engineered a chimeric gp130R ligand, termed IC7Fc, where one gp130 binding site has been removed from IL-6 and replaced with the leukemia inhibitory factor receptor (LIFR) binding site from CNTF and then fused with the fragment crystallizable (Fc) domain of immunoglobulin G (IgG), that shows promise for treating metabolic disease1. Moreover, in multiple models of insulin resistance and T2D, IC7Fc either increases, or prevents the loss, of skeletal muscle mass via increased abundance and activity of the Yes-associated protein (YAP)1. In parallel studies, we recently demonstrated that activation of the gp130R in the intestinal epithelium activates YAP and, in doing so, prevents fructose feeding-induced gut barrier deterioration, systemic endotoxemia, non-alcoholic steatohepatitis (NASH) and NASH driven liver cancer2. The concept that spg130R ligands could, therefore, have therapeutic utility for the treatment of several age-related diseases will be discussed.
References: 1 Findeisen, M. et al. Treatment of type 2 diabetes with the designer cytokine IC7Fc. Nature 574, 6368, (2019).
2 Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab 2, 10341045, (2020).
08 Nov 2021 - 10 Nov 2021