Functional implications of Drosophila insulin-like peptides in metabolism, aging, and dietary restriction

Kavitha Kannan,Yih-Woei C Fridell

doi:10.3389/fphys.2013.00288

Abstract

The neuroendocrine architecture and insulin/insulin-like signaling (IIS) events in Drosophila are remarkably conserved. As IIS pathway governs growth and development, metabolism, reproduction, stress response, and longevity; temporal, spatial, and nutrient regulation of dilps encoding Drosophila insulin-like peptides (DILPs) provides potential mechanisms in modulating IIS. Of eight DILPs (DILP1–8) identified, recent studies have furthered our understanding of physiological roles of DILP2, DILP3, DILP5, and DILP6 in metabolism, aging, and responses to dietary restriction (DR), which will be the focus of this review. While the DILP producing IPCs of the brain secrete DILP2, 3, and 5, fat body produces DILP6. Identification of factors that influence dilp expression and DILP secretion has provided insight into the intricate regulatory mechanisms underlying transcriptional regulation of those genes and the activity of each peptide. Studies involving loss-of-function dilp mutations have defined the roles of DILP2 and DILP6 in carbohydrate and lipid metabolism, respectively. While DILP3 has been implicated to modulate lipid metabolism, a metabolic role for DILP5 is yet to be determined. Loss of dilp2 or adult fat body specific expression of dilp6 has been shown to extend lifespan, establishing their roles in longevity regulation. The exact role of DILP3 in aging awaits further clarification. While DILP5 has been shown associated with DR-mediated lifespan extension, contradictory evidence that precludes a direct involvement of DILP5 in DR exists. This review highlights recent findings on the importance of conserved DILPs in metabolic homeostasis, DR, and aging, providing strong evidence for the use of DILPs in modeling metabolic disorders such as diabetes and hyperinsulinemia in the fly that could further our understanding of the underlying processes and identify therapeutic strategies to treat them.

Highlights

Conserved insulin/insulin-like growth factor signaling (IIS) pathway governs growth and development, metabolism, reproduction, stress response, and longevity
This study has provided another important piece of evidence of how the abdominal fat body may influence systemic IIS by controlling DILP2 secretion from the insulin-like peptide producing cells (IPCs)
This review that has focused on DILPs 2, 3, 5, and 6 has highlighted some of the regulatory mechanisms governing their expression and secretion, and their functions pertaining to lifespan regulation as well as the controversy surrounding the role of DILPs in dietary restriction (DR)

Summary

INTRODUCTION

Conserved insulin/insulin-like growth factor signaling (IIS) pathway governs growth and development, metabolism, reproduction, stress response, and longevity. We will discuss the regulation, functional diversity, and redundancy of the DILPs as circulating peptides and the physiology of the tissues producing them. Recent discoveries of the involvement of the nutrient sensing fat body in controlling DILP secretion from insulin-like peptide producing cells (IPCs) in the brain has provided a physiological link between those two major tissues governing nutrient sensing, metabolism, and aging (Geminard et al, 2009; Bai et al, 2012; Rajan and Perrimon, 2012). NUTRIENT, TEMPORAL, AND SPATIAL REGULATION OF dilp EXPRESSION AND DILP SECRETION More than a decade ago, the search for the extracellular ligands for the DInR led to the identification of seven Drosophila insulin-like peptide genes (dilp1–7) with diverse temporal and spatial specific www.frontiersin.org

Kannan and Fridell

CONCLUSION AND OUTLOOK