Journal
PLOS GENETICS
Volume 9, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003175
Keywords
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Categories
Funding
- American Diabetes Association [7-09-IN-07]
- NIGMS [T32GM062754]
- American Heart Association [0835243N]
- NIH [T32 GM007464, 5K12HD001459-12]
- Children's Discovery Institute [MD-II-2010-41]
- NHLBI [NIH/NHLBI RO1 HL54732-16, R01 HL085481-04, P01 HL0980539-02]
- NIA [P01 AG033561-02]
- NIDDK of the National Institutes of Health [R24 DK098053]
- Ellison Medical Foundation [AG-SS-2135-08]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [K12HD001459] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL085481, R01HL054732] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020579, F32DK098053] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM062754, T32GM007464] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG033561] Funding Source: NIH RePORTER
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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.
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