High Sugar-Induced Insulin Resistance in Drosophila Relies on the Lipocalin Neural Lazarillo

Matthieu Y Pasco,Pierre Léopold,Alexander W Shingleton

doi:10.1371/journal.pone.0036583

Matthieu Y Pasco, Pierre Léopold + Show 1 more

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https://doi.org/10.1371/journal.pone.0036583

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Abstract

In multicellular organisms, insulin/IGF signaling (IIS) plays a central role in matching energy needs with uptake and storage, participating in functions as diverse as metabolic homeostasis, growth, reproduction and ageing. In mammals, this pleiotropy of action relies in part on a dichotomy of action of insulin, IGF-I and their respective membrane-bound receptors. In organisms with simpler IIS, this functional separation is questionable. In Drosophila IIS consists of several insulin-like peptides called Dilps, activating a unique membrane receptor and its downstream signaling cascade. During larval development, IIS is involved in metabolic homeostasis and growth. We have used feeding conditions (high sugar diet, HSD) that induce an important change in metabolic homeostasis to monitor possible effects on growth. Unexpectedly we observed that HSD-fed animals exhibited severe growth inhibition as a consequence of peripheral Dilp resistance. Dilp-resistant animals present several metabolic disorders similar to those observed in type II diabetes (T2D) patients. By exploring the molecular mechanisms involved in Drosophila Dilp resistance, we found a major role for the lipocalin Neural Lazarillo (NLaz), a target of JNK signaling. NLaz expression is strongly increased upon HSD and animals heterozygous for an NLaz null mutation are fully protected from HSD-induced Dilp resistance. NLaz is a secreted protein homologous to the Retinol-Binding Protein 4 involved in the onset of T2D in human and mice. These results indicate that insulin resistance shares common molecular mechanisms in flies and human and that Drosophila could emerge as a powerful genetic system to study some aspects of this complex syndrome.

Highlights

Complex organisms living in changing environment need to adapt their energy supply to energy-costing processes such as metabolism, growth and reproduction
Forced secretion of brain Dilps concomitant to high sugar diet (HSD) feeding was sufficient to prevent hyperglycemia, indicating that, as in the case of treatment of type II diabetes (T2D) by insulin secretagogues, promoting insulin release from insulin-producing cells can circumvent peripheral insulin resistance (Figure 2H). These results indicate that the growth deficit observed in HSD is caused by a general reduction of insulin/IGF signaling (IIS), itself a consequence of Dilp resistance in peripheral tissues
Drosophila IIS does not exert separate controls on metabolism and growth One particularity of the insect IIS is the presence of a unique receptor for multiple insulin-like peptides

Summary

Introduction

Complex organisms living in changing environment need to adapt their energy supply to energy-costing processes such as metabolism, growth and reproduction In many organisms, this adaptation relies on insulin/IGF signaling (IIS), as loss of components in IIS leads to important metabolic and growth defects. The dichotomy between fuel metabolism and growth control as seen in mammals is relying on the action of two distinct hormones, insulin and Insulin-like Growth Factor-I (IGF-I), exerting their cellular effects through the activation of distinct receptors. This is exemplified by the strikingly differences of the phenotypes observed upon genetically removing either the receptor for insulin (IR) or the receptor for IGF-I (IGFR-IR) [1,2]. Evolution-wise, this setup is restricted to the vertebrate phylum and most animal species make use of more primitive insulin/IGF systems (IIS), raising the issue of how independently these physiological regulations might be carried out in other phyla

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