Ablation of insulin-producing cells prevents obesity but not premature mortality caused by a high-sugar diet in Drosophila

Abstract

Ageing can be modulated by genetic as well as nutritional interventions. In female Drosophila melanogaster, lifespan is maximized at intermediate concentrations of sucrose as the carbohydrate source, and yeast as the protein source. Dampening the signal through the insulin/IGF signalling (IIS) pathway, by genetic ablation of median neurosecretory cells (mNSCs) that produce insulin-like peptides, extends lifespan and counteracts the detrimental effects of excess yeast. However, how IIS reduction impacts health on a high-sugar diet remains unclear. We find that, while the ablation of the mNSCs can extend lifespan and delay the age-related decline in the health of the neuromuscular system irrespective of the amount of dietary sugar, it cannot rescue the lifespan-shortening effects of excess sugar. On the other hand, ablation of mNSCs can prevent adult obesity resulting from excess sugar, and this effect appears independent from the canonical effector of IIS, dfoxo. Our study indicates that while treatments that reduce IIS have anti-ageing effects irrespective of dietary sugar, additional interventions may be required to achieve full benefits in humans, where excessive sugar consumption is a growing problem. At the same time, pathways regulated by IIS may be suitable targets for treatment of obesity.

Keywords: Drosophila melanogaster; ageing; high-sugar diet; insulin/IGF-like signalling; obesity.

Figure 1.

Ablation of mNSCs extends lifespan in the presence of excess sugar without alleviating the detrimental effect of the diet. (a) Lifespans of female flies ablated for the mNSCs (dilp3GAL4>rpr) or the two genetic controls (dilp3GAL4 or UAS-rpr alone) on the food containing a healthy amount of sucrose (1×) or excess sucrose (8×). Statistical analysis of the data is shown in table 1. (b) Lifespans of wild-type or dfoxoΔ/dfoxoΔ female flies on food containing 1× or 8× sucrose. Statistical analysis of the data is shown in table 2.

Figure 2.

Beneficial effects of the mNSC ablation on climbing ability are observed irrespective of sugar content. Proportion of high climbers (climbing over 22 cm, (a,b)) or combined high and medium climbers (climbing over 4 cm, (c,d)) on the food containing a healthy amount of sucrose (1×, (a,c)) or excess sucrose (8×, (b,d)) in three cohorts of females flies with mNSC ablation (dilp3GAL4>rpr) or the two genetic controls (dilp3GAL4 or UAS-rpr alone). The data from the three cohorts are combined, and the error bars show the standard error of the proportion. Statistical analysis of the data is shown in table 3.

Figure 3.

Ablation of the mNSCs prevents high-sugar-induced TAG accumulation independently of dfoxo. (a) Boxplots showing the levels of TAG measured in individual female flies with mNSC ablation (dilp3GAL4>rpr) or the two genetic controls (dilp3GAL4 or UAS-rpr alone) on days 7, 14, 21, 28 and 42, on the food containing a healthy amount of sucrose (1×) or excess sucrose (8×). Statistical analysis of the data is shown in table 4. (b) Boxplots showing the levels of TAG measured in individual female flies with mNSC ablation (dilp3GAL4>rpr) or the two genetic controls (dilp3GAL4 or UAS-rpr alone) that were wild-type or deleted for dfoxo, on days 7, 14 and 21 on the food containing excess sucrose (8×). The same colour code is used as in (a) and (b), and is given in (a). Statistical analysis of the data is shown in table 5. (c) Lifespans of female flies with mNSC ablation (dilp3GAL4>rpr) or the two genetic controls (dilp3GAL4 or UAS-rpr alone) that were wild-type or deleted for dfoxo on the food containing excess sucrose (8×). Statistical analysis of the data is shown in table 6.