Downregulation of the Glo1 Gene Is Associated with Reduced Adiposity and Ectopic Fat Accumulation in Spontaneously Hypertensive Rats.

Jan Šilhavý,Martina Hüttl,Hana Malínská,Michal Pravenec,František Liška,Olena Oliyarnyk,Irena Marková,Petr Mlejnek,Miroslava Šimáková,Radka Moravcová,Ludmila Kazdová,Jiří Novotný

doi:10.3390/antiox9121179

Abstract

Methylglyoxal (MG), a potent precursor of advanced glycation end-products (AGE), is increased in metabolic disorders such as diabetes and obesity. MG and other dicarbonyl metabolites are detoxified by the glyoxalase system in which glyoxalase 1, coded by the Glo1 gene, serves as the rate-limiting enzyme. In this study, we analyzed the effects of Glo1 downregulation on glucose and lipid metabolism parameters in spontaneously hypertensive rats (SHR) by targeting the Glo1 gene (SHR-Glo1+/− heterozygotes). Compared to SHR wild-type animals, SHR-Glo1+/− rats showed significantly reduced Glo1 expression and lower GLO1 activity in tissues associated with increased MG levels. In contrast to SHR controls, SHR-Glo1+/− rats exhibited lower relative weight of epididymal fat, reduced ectopic fat accumulation in the liver and heart, and decreased serum triglycerides. In addition, compared to controls, SHR-Glo1+/− rats showed reduced serum insulin and increased basal and insulin stimulated incorporation of glucose into white adipose tissue lipids (lipogenesis). Reduced ectopic fat accumulation in the heart was associated with significantly increased pAMPK/AMPK ratio and GLUT4 activity. These results provide evidence that Glo1 downregulation in SHR is associated with reduced adiposity and ectopic fat accumulation, most likely mediated by AMPK activation in the heart.

Highlights

Metabolic disorders such as diabetes and obesity are associated with increased dicarbonyl stress, with increased levels of dicarbonyl toxic metabolites, primarily methylglyoxal (MG), a potent precursor of advanced glycation end-products (AGE)
Expression of the Glo1 gene in the liver, heart, renal cortex and white adipose tissue (WAT) of spontaneously hypertensive rats (SHR)-Glo1+/−rats was approximately 30–40% lower compared to SHR wild-type controls (Figure 1A)
MG and GL concentrations significantly increased in the blood and heart, but no significant differences were observed in the kidney, liver or epididymal adipose tissue (Table 1)

Summary

Introduction

Metabolic disorders such as diabetes and obesity are associated with increased dicarbonyl stress, with increased levels of dicarbonyl toxic metabolites, primarily methylglyoxal (MG), a potent precursor of advanced glycation end-products (AGE). MG and other dicarbonyl metabolites are detoxified by the glyoxalase system, an enzymatic pathway found in the cytosol of cells This system consists of two enzymes—glyoxalase 1 (GLO1), which is dependent on reduced glutathione (GSH), and glyoxalase 2 (GLO2)—coded by the Glo and Glo genes, respectively. Since GLO1 is subject to the regulatory influence of these transcription factors, it potentially affects dicarbonyl and oxidative stress, and lipid and glucose metabolism. To test this theory, we analyzed the metabolic effects of the genetically downregulated Glo gene on dicarbonyl and oxidative stress and on parameters of glucose and lipid metabolism in spontaneously hypertensive rats (SHR). The same is true when the SHR is genetically modified, for instance by transgenic expression of resistin [8] or human gene for C-reactive protein (CRP) [9]

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Conclusion