Date Published: December , 2012
Publisher: Blackwell Publishing Ltd
Author(s): Hua Bai, Ping Kang, Marc Tatar.
Reduced insulin/IGF signaling extends lifespan in diverse species, including Drosophila melanogaster where the genome encodes seven insulin-like peptides (dilp1-7). Of these, reduced dilp2 expressed in the brain has been associated with longevity assurance when over-expression of dfoxo in fat bodies extends lifespan. Here, we show that the insulin-regulated transcription factor dFOXO positively modulates dilp6 mRNA in adult fat body. Over-expression of dilp6 in adult fat body extends lifespan and increases longevity-associated metabolic phenotypes. Adult fat body dilp6 expression represses dilp2 and dilp5 mRNA in the brain, and the secretion of DILP2 into the hemolymph. The longevity benefit of expressing dfoxo in fat body, and the nonautonomous effect of fat body dfoxo upon brain dilp expression, is blocked by simultaneously repressing dilp6 by RNAi in fat body. dilp6 thus appears to bridge dFOXO, adipose tissue and brain endocrine function to regulate Drosophila longevity.
Insulin-like peptides are evolutionary conserved proteins that regulate growth, metabolism, reproduction, and longevity. Invertebrate genomes are notable for their many insulin-like peptide paralogs. The nematode Caenorhabditis elegans has some 40 insulin-like peptides (Pierce et al., 2001). Seven insulin-like peptides are encoded in Drosophila melanogaster (Drosophila insulin-like peptides, dilp1-7), and these are conserved across the genomes of 11 related Drosophilids (Brogiolo et al., 2001; Gronke et al., 2010). Genes encoding insulin-like peptides have likewise been identified from the silkworm Bombyx mori (Bombyxin) and subsequently in orders spanning Orthoptera, Diptera, Lepidoptera, Coleoptera and Hymenoptera (reviewed in (Wu & Brown, 2006)).
The Drosophila genome contains one insulin-receptor gene with several isoforms, and seven dilp loci (Brogiolo et al., 2001). Among these dilps, reduced dilp2 has been consistently associated with increased lifespan. Homologous recombination to knockout dilp2 increased longevity (Gronke et al., 2010), and mRNA levels of dilp2 were reduced and longevity was increased in genotypes that misexpressed JNK (Wang et al., 2005), sNPF (Lee et al., 2008), and dfoxo (Hwangbo et al., 2004; Giannakou et al., 2005) where dfoxo misexpression from fat body alone was sufficient to slow aging. The targets of dFOXO responsible for its non-autonomous control of aging are unknown, and there are potentially many candidates. dFOXO can bind to at least 700 promoter regions (Alic et al., 2011), and this factor has been associated with the transcriptional control of more than 1000 genes (Zinke et al., 2002; Gershman et al., 2007). At least in larvae, dilp6 is a target of dFOXO and through its expression in fat body dilp6 modulates growth during post-feeding development (Okamoto et al., 2009; Slaidina et al., 2009).