Disruption of the Gys2 gene that encodes the liver isoform of glycogen synthase generates a mouse (LGSKO mouse) with an almost complete lack of hepatic glycogen, impaired glucose disposal and a pre-disposition to enter the fasted state. This study explores how the lack of liver glycogen increases fat accumulation and the development of liver insulin resistance. Insulin signaling in LGSKO mice is reduced in liver, but not in muscle, suggesting an organ specific defect. Phosphorylation of several components of the hepatic insulin signaling pathway, IRS1, Akt, and GSK3, were decreased in LGSKO mice and, after insulin stimulation, their responses were significantly suppressed, both temporally and in an insulin dose response. FoxO1 phosphorylation was somewhat reduced and the protein was still in the nucleus after insulin treatment. Fat over-accumulated in LGSKO livers, showing an aberrant distribution in the acinus. The increase was not explained by a reduction in hepatic triglyceride export. Rather, when fasted mice were challenged orally with glucose, glucose was directed towards lipogenesis as judged by the activity, protein levels and expression of several genes relevant to fatty acid synthesis, namely acetyl CoA carboxylase, fatty acid synthase, SREBP1c, chREBP, glucokinase and pyruvate kinase. Moreover, using cultured primary hepatocytes, lipogenesis was increased by 40% in LGSKO cells as compared to control. The hepatic insulin resistance was not associated with increased levels of pro-inflammatory markers. Our results suggest that the inability to synthesize liver glycogen diverts glucose towards fat synthesis, correlating with impaired hepatic insulin signaling and glucose disposal.
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Publication date: Available online 4 January 2018 Source: European Journal of Radiology Author(s): Peiyao Zhang, Jing Wang, Qin Xu, Zhen...
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