A Glyoxalase-1 Knockdown Does Not Have Major Short Term Effects on Energy Expenditure and Atherosclerosis in Mice

Abstract

Objective. Glyoxalase-1 is an enzyme detoxifying methylglyoxal (MG). MG is a potent precursor of advanced glycation endproducts which are regarded to be a key player in micro- and macrovascular damage. Yet, the role of Glo1 in atherosclerosis remains unclear. In this study, the effect of Glo1 on mouse metabolism and atherosclerosis is evaluated. Methods. Glo1 knockdown mice were fed a high fat or a standard diet for 10 weeks. Body weight and composition were investigated by Echo MRI. The PhenoMaster system was used to measure the energy expenditure. To evaluate the impact of Glo1 on atherosclerosis, Glo1KD mice were crossed with ApoE-knockout mice and fed a high fat diet for 14 weeks. Results. Glo1 activity was significantly reduced in heart, liver, and kidney lysates derived from Glo1KD mice. Yet, there was no increase in methylglyoxal-derived AGEs in all organs analyzed. The Glo1 knockdown did not affect body weight or body composition. Metabolic studies via indirect calorimetry did not show significant effects on energy expenditure. Glo1KD mice crossed to ApoE−/− mice did not show enhanced formation of atherosclerosis. Conclusion. A Glo1 knockdown does not have major short term effects on the energy expenditure or the formation of atherosclerotic plaques.

Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes

“…The loss of AKR1b3 in apoE-knock-out mice not only increased AGE accumulation but also the formation of atherosclerotic lesions. However, Glo1 knock-down mice on the apoE background did not show any differences in either MG-derived AGEs or enhanced formation of atherosclerosis [49]. These studies would suggest that the loss of Glo1 alone is insufficient to trigger the development of complications in diabetes.…”

Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism – What We Know in Mammals and What We Can Learn From Yeast

“…Glo1-knockout mice showed reduced anxiety-like, but increased depression-like behavior [49]. Interestingly, there were no changes in body fat composition, body weight, plasma glucose levels as well as plasma triglycerides and cholesterol concentrations compared to wildtype littermates [50]. This applied for both, mice fed a standard or high fat diet.…”

Cellular mechanisms and consequences of glycation in atherosclerosis and obesity

“…Critically, in that study, levels of vascular AGEs were not reduced by overexpression of GLO1. Others showed similar findings in atherosclerosis and demonstrated that in Glo1 -knockdown mice, methylglyoxal-derived AGE levels were not increased and atherosclerosis did not differ when compared to wild-type animals [38]. Hence, the specific AGEs biologically active in diabetes and atherosclerosis may not all be modulated through the actions of GLO1.…”

“…CD36 was shown to mediate uptake and degradation of AGEs by adipocytes [63] and through CD36 actions, leptin is downregulated in these cells [64, 65]. Intriguingly, in vivo studies in GLO1 knockdown mice fed high fat diet did not reveal altered body mass, composition or energy expenditure versus the wild-type controls [38]. Such findings, analogous to those in atherosclerosis considered above, suggest that perhaps non-GLO1-dependent AGEs also contribute importantly to obesity and energy balance.…”