Journal
DISEASE MODELS & MECHANISMS
Volume 12, Issue 2, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.036186
Keywords
Glucose metabolism; Insulin receptor isoforms; Adeno-associated viruses; Gene therapy; Non-alcoholic fatty liver disease; Insulin resistance
Categories
Funding
- Ministerio de Ciencia e Innovacion [SAF2011/22555, SAF2014/51795-R, SAF2017-82133-R]
- Instituto de Salud Carlos III [PIE14/00061, CB07/08/0001]
- Comunidad de Madrid [CT1/18-CT2/18/PEJD-2017-PRE/BMD-4111]
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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.
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