Heterozygous GAA knockout is nonconsequential on metabolism and the spatial liver transcriptome in high-fat diet-induced obese and prediabetic mice.

Abstract

Glycophagy is the autophagic degradation of glycogen by the enzyme acid alpha-glucosidase (GAA). Although GAA inhibitors improve metabolic health by inhibiting GAA in the intestine, it is not clear if GAA inhibition in peripheral tissues such as the liver is metabolically beneficial. This study tested if the heterozygous knockout of GAA (HetKO-GAA) alters liver metabolism and metabolic health in mice fed a low-fat diet or a high-fat diet to induce obesity. HetKO-GAA mice fed either diet did not have altered body weight, glucose tolerance, insulin action, energy expenditure, substrate metabolism, liver glucose output, or liver triglycerides compared to control wildtype mice. A liver spatial transcriptomics analysis revealed that high-fat diet feeding reduced the gene abundance of predominantly metabolic pathways in both periportal and perivenous hepatocytes, and uniquely reduced ribosome gene abundance in perivenous hepatocytes. HetKO-GAA mice did not have significantly altered transcriptomes in periportal or perivenous hepatocytes compared to wildtype mice. In conclusion, heterozygous GAA knockout is nonconsequential on metabolism and metabolic health in high-fat diet induced obesity. Spatial transcriptomics revealed alterations in the transcriptome of periportal and perivenous hepatocytes from high-fat diet induced obese mice, highlighting novel targets that could be exploited to improve metabolic health in obesity.