Cell Metab. 2020; 31(4):710725.e7. doi: 10.1016/j.cmet.2020.02.016. PMID: 32197072.
In brief: High-sugar diets cause thirst, obesity and metabolic dysregulation, leading to insulin resistance, the MetS, T2DM and shortened lifespan. This study shows that high sugar diets induce dehydration in adult Drosophila. Water supplementation fully rescued the shortened lifespan, but not the metabolic defects, indicating that these are water-independent. High-sugar diets promote the accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones. These findings were confirmed in a human cohort with metabolomics and dietary data. Thus, the purine pathway is strongly involved in survival.
Comment: High-sugar diets promote the development of obesity, insulin resistance and T2DM, and also shorten survival, which was assumed to be a consequence of these metabolic derangements.
In a series of elegant studies in Drosophila, a chronic high-sugar diet was shown to induce thirst and dehydration, insulin resistance, obesity and decreased lifespan. Water supplementation fully rescued their shortened lifespan; however, the metabolic traits (hyperglycaemia, insulin resistance, increased triglycerides and glycation damage) persisted. Therefore, it was concluded that these metabolic defects are not the direct cause of the shortened lifespan, but that water imbalance is involved. Although gut function is critical to nutritional physiology, the experiments were unable to show a link to the high-sugar shortened lifespan.
The authors further explored the effects of high-sugar diet on renal physiology. Flies fed on high-sugar showed changes in renal morphology, including uric acid deposits in their tubules, and this was fully rescued by water supplementation. High-sugar diets were suggested to provide precursors for purine biosynthesis, thus fuelling the accumulation of uric acid, a waste product of purine catabolism. Administration of allopurinol, an inhibitor that blocks uric acid formation, abolished the increase in uric acid levels and tubule uric acid deposits.
Finally, to assess whether dietary habits are linked to purine metabolism in humans, serum metabolomics data were correlated to dietary records in a cohort of 650 healthy participants. Indeed, the consumption of sugar-rich foods was strongly associated with higher levels of circulating purines and renal dysfunction. Interestingly, metabolomics data showed significant interactions of circulating levels of purines with the consumption of fruits, soft drinks and cereals, but not with the consumption of purine-rich food groups such as fish and meat.
The authors conclude that these findings may explain the fat but fit paradox, and provide a novel approach for the discovery of new therapeutic strategies.