Effects of Methylglyoxal on Adipocyte Metabolism: Cellular Adaptations to a High Glycemic Environment
Abstract
Diets high in added sugar are associated with obesity. However, it is not known if sugar directly contributes to metabolic changes in adipose tissue that underlie chronic diseases. Acute postprandial hyperglycemia followed by enhanced insulin secretion may be a mechanism by which high sugar intake disrupts metabolism. Insulin increases the rate of glycolysis and the formation of the highly reactive by-product, methylglyoxal. Methylglyoxal is higher in serum and tissues during diabetes and plays a direct role in diabetic complications. Under normal conditions, the level of methylglyoxal is extremely low. However, in studies using animal models and high-fructose feeding, methylglyoxal has been shown to accumulate in adipose tissue. To determine whether a low concentration of methylglyoxal induces changes to the normal metabolism of adipocytes, we first used a differential proteomics approach to analyze the changes in protein expression in 3T3-L1 adipocytes treated with 100 uM methylglyoxal for 48 hours. We also assessed the effects of methylglyoxal on cell viability, oxidative stress, lactate secretion and gene expression, using real-time PCR. We found that though methylglyoxal did not affect cell viability or induce oxidative stress, it lowered the expression of genes involved in adipogenesis and de novo lipogenesis while increasing the gene expression of pro-inflammatory cytokines. Our proteomics analysis revealed that methylglyoxal lowered the expression of many mitochondrial proteins, including enzymes involved in oxidative phosphorylation, the TCA cycle and beta-oxidation, while significantly increasing protein expression of the glycolytic enzymes lactate dehydrogenase and GAPDH. Further analysis confirmed that the gene expression of 4 glycolytic enzymes were significantly up-regulated. We conclude that a low concentration of methylglyoxal induces changes in adipocytes that result in a shift to glycolytic metabolism, similar to that seen in hypoxia. We propose that methylglyoxal induces the activation of hypoxia inducible factor 1a (HIF1a) in adipocytes cultured under normal oxygen conditions. These findings suggest that methylglyoxal may be a contributing factor to the dysregulated metabolism of adipocytes associated with chronic diseases and the consumption of diets high in sugar.^
Degree
Ph.D.
Advisors
Kee H. Kim, Purdue University.
Subject Area
Molecular biology|Nutrition
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