Abstract
ABSTRACTAmong 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.This article has an associated First Person interview with the first author of the paper.
Highlights
Obesity is widely considered the epidemic of the 21st century (NCD Risk Factor Collaboration, 2016; Gonzalez-Muniesa et al, 2017; Reilly and Saltiel, 2017), and is characterized by a huge body weight for height, with increased accumulation of adipose tissue
Given that obesity and type 2 diabetes mellitus (T2DM) are closely related, we wanted to expand these studies to a murine model of high-fat diet (HFD)-induced insulin resistance, and to explore whether isoform A (IRA) could work as a therapeutic tool in these conditions
We wanted to establish whether this increase in liver glucose uptake could ameliorate the glucose uptake in muscle, and our results show that the gastrocnemius glucose uptake in HFDIRA mice is higher than that in the other groups, the difference was only statistically significant when compared with the HFD-green fluorescent protein (GFP) group, suggesting that hepatic IRA expression induces a global glucose uptake improvement (Fig. 3B)
Summary
Obesity is widely considered the epidemic of the 21st century (NCD Risk Factor Collaboration, 2016; Gonzalez-Muniesa et al, 2017; Reilly and Saltiel, 2017), and is characterized by a huge body weight for height, with increased accumulation of adipose tissue It is usually accompanied by mild, chronic and systemic inflammation. Insulin resistance affects many tissues, including muscle and adipose tissue, the liver – involved in the regulation of blood glucose homeostasis by glucose uptake and storage in the postprandial state – is one of the main organs affected (von Wilamowitz-Moellendorff et al, 2013). Hepatic insulin resistance becomes a hallmark of T2DM development (Cook et al, 2015), and precise regulation of glucose homeostasis is essential for proper diabetes management (Callejas et al, 2013)
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