Liver-specific insulin receptor isoform A expression enhances hepatic glucose uptake and ameliorates liver steatosis in a mouse model of diet-induced obesity

Abstract

Among the main complications associated with obesity are insulin resistance and altered glucose and lipid metabolism within the liver. It has previously been described that insulin receptor isoform A (IRA) favors glucose uptake and glycogen storage in hepatocytes compared with isoform B (IRB), improving glucose homeostasis in mice lacking liver insulin receptor. Thus, we hypothesized that IRA could also improve glucose and lipid metabolism in a mouse model of high-fat-diet-induced obesity. We addressed the role of insulin receptor isoforms in glucose and lipid metabolism in vivo . We expressed IRA or IRB specifically in the liver by using adeno-associated viruses (AAVs) in a mouse model of diet-induced insulin resistance and obesity. IRA, but not IRB, expression induced increased glucose uptake in the liver and muscle, improving insulin tolerance. Regarding lipid metabolism, we found that AAV-mediated IRA expression also ameliorated hepatic steatosis by decreasing the expression of Fasn , Pgc1a , Acaca and Dgat2 and increasing Scd-1 expression. Taken together, our results further unravel the role of insulin receptor isoforms in hepatic glucose and lipid metabolism in an insulin-resistant scenario. Our data strongly suggest that IRA is more efficient than IRB at favoring hepatic glucose uptake, improving insulin tolerance and ameliorating hepatic steatosis. Therefore, we conclude that a gene therapy approach for hepatic IRA expression could be a safe and promising tool for the regulation of hepatic glucose consumption and lipid metabolism, two key processes in the development of non-alcoholic fatty liver disease associated with obesity.

Concerted regulation of non-alcoholic fatty liver disease progression by microRNAs in apolipoprotein E-deficient mice

“…In our mouse model, the ApoE -/-HFD group showed a dramatically reduced ACC expression. Many reports have demonstrated that a decrease in Acaca expression indicated a steatosis amelioration (Donnelly et al, 2005;Li et al, 2018;Lopez-Pastor et al, 2019).…”

Alternative RNA Splicing in Fatty Liver Disease

“…Kumar et al (81) have reported that the splicing of the INSR is altered in patients with NAFLD, NASH, and cirrhosis and in mice on highfat diet or NASH diets, with increased expression of INSR-A. In pre-clinical studies, Lopez-Pastor et al reported that AAV expression of INSR-A or INSR-B significantly reduced the NAFLD activity score (NAS) and improved insulin secretion, but did not affect body weight or glucose tolerance in mice on a high fat diet (131). Interestingly, INSR-A improved insulin sensitivity and increased glucose uptake into liver and muscle.…”

Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model

“…In recent studies, to elucidate the role of IR isoforms in glucose and lipid metabolism, we took advantage of the capacity of adeno-associated vectors serotype 8 (AAV8) to specifically transfer recombinant genes to the liver [15]. In our hands, the hepatic expression of IRA through gene therapy approaches with AAV8 resulted in an improvement in glucose tolerance, even with a regression in beta cell hyperplasia [16], as well as in hepatic steatosis [17].…”