Professor Mark Febbraio
Senior Principal Research Fellow Monash Institute of Pharmaceutical Science, Monash University
The gp130 receptor cytokines interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) can improve metabolic disease, but both proteins have limited therapeutic utility for treatment of type 2 diabetes (T2D). Accordingly, we engineered a chimeric gp130 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), creating a new cytokine with CNTF-like, but IL-6R- dependent, signaling. IC7Fc significantly improves glucose tolerance and hyperglycemia and prevents weight gain and liver steatosis in both obese mice and in non-human primates. 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) (Findeisen et al Nature, 2019). Non-alcoholic steatohepatitis (NASH) is a serious metabolic disease that can result in liver failure or hepatocellular carcinoma (HCC). We recently used an isocaloric model of NASH induction employing high fructose diet (HFrD) to probe a link between barrier disruption associated with downregulation of tight junction proteins and NASH plus HCC development. Since loss of intestinal epithelial cell (IEC) tight junctions caused compensatory YAP activation, we examined whether IL-6-induced and YAP-mediated barrier restoration can prevent NASH and HCC development. We show that IEC-specific expression of IL-6 signal transducer (IL6ST) abrogated loss of barrier integrity and prevented hepatic steatosis, NASH and HCC (Todoric et al. Cell Metabolism in press). These two studies demonstrate, therefore, that activation of the gp130 receptor complex is a useful target to treat metabolic diseases such as T2D and NASH driven HCC.
Professor Mark Febbraio is a Senior Principal Research Fellow of the NHMRC, and the Head of the Cellular and Molecular Metabolism Laboratory within the Drug Discovery Program at Monash Institute of Pharmaceutical Sciences, Monash University Australia. He is also the CSO of N-Gene Research Laboratories Inc., a USA based Biotechnology Company and the Founder and CSO of the recently incorporated company Kinomedica. His research is focussed on understanding mechanisms associated with exercise, obesity, type 2 diabetes and cancer and his aim is to develop novel drugs to treat lifestyle related diseases. He has authored over 250 peer reviewed papers in leading journals has over 33,000 career citations and an H Factor of 100.
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