Endocrine Abstracts

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 (Axokine^TM), 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, 63–68, (2019).

2 Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab 2, 1034–1045, (2020).