Cell Metabolism
Volume 31, Issue 4, 7 April 2020, Pages 710-725.e7
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Article
Sugar-Induced Obesity and Insulin Resistance Are Uncoupled from Shortened Survival in Drosophila

https://doi.org/10.1016/j.cmet.2020.02.016Get rights and content
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Highlights

  • Sugar-induced lifespan shortening can be uncoupled from obesity and insulin resistance

  • A high-sugar diet induces water imbalance in adult Drosophila

  • High-sugar feeding shortens fly lifespan through dysregulation of purine catabolism

  • Dietary sugar intake in humans is associated with circulating purine levels

Summary

High-sugar diets cause thirst, obesity, and metabolic dysregulation, leading to diseases including type 2 diabetes and shortened lifespan. However, the impact of obesity and water imbalance on health and survival is complex and difficult to disentangle. Here, we show that high sugar induces dehydration in adult Drosophila, and water supplementation fully rescues their lifespan. Conversely, the metabolic defects are water-independent, showing uncoupling between sugar-induced obesity and insulin resistance with reduced survival in vivo. High-sugar diets promote accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones, a process aggravated by dehydration and physiological acidification. Importantly, regulating uric acid production impacts on lifespan in a water-dependent manner. Furthermore, metabolomics analysis in a human cohort reveals that dietary sugar intake strongly predicts circulating purine levels. Our model explains the pathophysiology of high-sugar diets independently of obesity and insulin resistance and highlights purine metabolism as a pro-longevity target.

Keywords

aging
high-sugar diet
obesity
diabetes
water imbalance
purine catabolism
uric acid
Drosophila

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These authors contributed equally

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