Abstract
SummaryHigh-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.
Highlights
An exogenous water source was provided to the flies in the form of an agar gel (Figure 1A), a strategy previously used to rescue salt toxicity and explore mechanisms of dietary restriction in adult Drosophila (Ja et al, 2009; Piper et al, 2010)
We assayed thirst by two additional independent methods: first, we exposed flies to agar containing blue dye and quantified the amount of water ingested colorimetrically (Figure S1A); and second, we performed an adaptation of the liquid Capillary Feeder (CAFE) system (Ja et al, 2007) to supply drinking water to the vials and measured the volume of water consumed by the flies (Figure S1B)
By both of these approaches, flies pre-treated with the 20%S diet were significantly thirstier, which disappeared upon water supplementation
Summary
Fly Media and Agar Tips Flies were raised on standard sugar-yeast-agar medium (5%S) consisting of: 5% w/v sucrose (granulated sugar, Tate & Lyle), 10% w/v Brewer’s yeast (#903312, MP Biomedicals), 1.5% w/v agar (Sigma A7002), supplemented with nipagin (Sigma H5501; 30 mL/L of 10% w/v nipagin in 95% EtOH) and propionic acid (0.3% v/v; Sigma P1386) as preservatives, added once the food had cooled down to < 60C (Grandison et al, 2009b). For high-sugar food, the sugar content was increased 4-fold to 20% w/v sucrose (20%S). For low-sugar food, the sugar content was deceased to 0%, 1% and 2.5% w/v sucrose (0%S, 1%S and 2.5%S respectively). The 5%S diet was supplemented with a 15% w/v excess of D-fructose (Sigma F0127) or D-glucose (Sigma G8270). For the high-purine diet, the 5%S food was supplemented with 10 mM purine, consisting of 5 mM adenine (Sigma A8626) and 5 mM guanine (Sigma G11950).
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