We provide evidence of a role for hexosamine flux, a metabolic pathway accessed by glucose. Video S8. TDO is inactive in vermilion mutants of Drosophila melanogaster . Finally, we present evidence that dietary sucrose directs heart damage in part by its flux through the hexosamine biosynthetic pathway. The role of the hexosamine biosynthetic pathway on heart homeostasis is poorly understood in the context of the whole animal. In contrast, over-expressing the pathway inhibitor OGA reversed sugar-induced heart defects including calcium transients . In vermilion mutants high sucrose diet delayed pupae emergence from larvae by 1. Here we develop the Drosophila heart as a new model for the study of diet-induced heart dysfunction. We further validate our model by demonstrating that two pathways previously shown to mediate heart dysfunction in mammals— the insulin and P38 MAPK pathways— modulate HSD-induced heart defects in Drosophila as well. Overall, high fructose and high glucose diets produced similar negative effects on fly physiology.
Diets high in carbohydrates have long been linked to progressive heart dysfunction, yet the mechanisms by which chronic high sugar leads to heart failure remain poorly understood. Here we combine diet, genetics, and physiology to establish an adult Drosophila melanogaster model of chronic high sugar-induced heart disease. We demonstrate deterioration of heart function accompanied by fibrosis-like collagen accumulation, insulin signaling defects, and fat accumulation. The result was a shorter life span that was more severe in the presence of reduced insulin and P38 signaling. We provide evidence of a role for hexosamine flux, a metabolic pathway accessed by glucose. Increased hexosamine flux led to heart function defects and structural damage; conversely, cardiac-specific reduction of pathway activity prevented sugar-induced heart dysfunction. Our data establish Drosophila as a useful system for exploring specific aspects of diet-induced heart dysfunction and emphasize enzymes within the hexosamine biosynthetic pathway as candidate therapeutic targets. Heart disease remains the most common source of mortality in the American population.
The impaired contractile ability of the heart observed in glucosamine-fed flies was reminiscent of the heart dilation phenotype reported in mice with cardiomyocyte-restricted knockout of the insulin receptor . Yet high glucose preferentially reduced mitochondrial respiratory capacity, whereas high fructose increased peroxide production, suggesting that these sugars differentially regulate catabolism [ 36 ]. Characterization of the xanthurenic acid:UDP-glucosyltransferase activity. We aim to bring about a change in modern scholarly communications through the effective use of editorial and publishing polices. Similar effects of high-fructose and high-glucose feeding in a Drosophila model of obesity and diabetes. In our experimental paradigm P38 proved to be required for full protection from high dietary sugar. We regularly observe significant differences among various control genetic backgrounds, and our control flies were of a different genotype w outcrosses than those studied previously [the common Canton-S [ 34, 36 ], a wild-type IF line [ 35, 37 ], and another wild-type line derived from a single wild-caught female from the Vancouver area [ 38 ]]. Some features of the site may not work correctly. Phosphorylation of P38 was responsive to insulin stimulation in the retina but not the liver in a mouse model of diabetes . The relationship between immunity and metabolism in Drosophila diet-induced insulin resistance. B Dietary glucosamine significantly reduced life span: the average life span of flies fed 0.