Resolution of NASH and hepatic fibrosis by the GLP-1R and GCGR dual-agonist cotadutide via modulating mitochondrial function and lipogenesis

Abstract

Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a GLP-1R/GcgR agonist, was shown to reduce blood glycemia, body weight and hepatic steatosis in patients with T2DM. Here, we demonstrate that the effects of Cotadutide to reduce body weight, food intake and improve glucose control are predominantly mediated through the GLP-1 signaling, while, its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signaling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism enzymes in liver of mice treated with Cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, which are consistent with a unique therapeutic contribution of GcgR agonism by Cotadutide in vivo . Significantly, Cotadutide also alleviated fibrosis to a greater extent than Liraglutide or Obeticholic acid (OCA), despite adjusting dose to achieve similar weight loss in 2 preclinical mouse models of NASH. Thus Cotadutide, via direct hepatic (GcgR) and extra-hepatic (GLP-1R) effects, exerts multi-factorial improvement in liver function and is a promising therapeutic option for the treatment of steatohepatitis.

OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes

“…Peptide therapy Synthetic OXM-104, cotadutide, and semaglutide (Synpeptide, Shanghai China) were dissolved in Phosphatebuffered Saline or 0.9 % NaCl for subcutaneous administration. The dose chosen for OXM-104 was based on in-house acute testing (Supplementary Figure S 2), while cotadutide and semaglutide doses were based on published studies 12,[18][19][20] . Aliquots were kept at -20 and thawed immediately before use.…”

“…Dual GLP-1 and glucagon (GCG) receptor agonists are other types of candidates showing great potential as NASH treatment. Interestingly, a combination of these two peptide hormones not only reduces the hyperglycemic risk linked to GCG agonism but also provides promising hepatospecific effects 11,12 .…”

Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

“…In rodent models, acute activation of GCGR improves whole-body glucose metabolism [105]. Additionally, hepatic GCGR stimulation also drives glycogen flux and improves mitochondrial turnover (Table 1) [106]. Thus, drugs that can enhance hepatic glucagon signaling may be potentially beneficial in treating NAFLD/NASH.…”

Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD

“…These data suggest that hepatic GCGR activation improves glucose tolerance by enhancing the action of insulin. It has also been reported that hepatic GCGR stimulation reduces lipid content, drives glycogen flux, and improves mitochondrial turnover and function [ 33 ]. This glucagon signaling pointing mechanism has high potential applications in new drugs for NAFLD/NASH.…”