Drosophila insulin release is triggered by adipose Stunted ligand to brain Methuselah receptor

Abstract

Animals adapt their growth rate and body size to available nutrients by a general modulation of insulin-insulin-like growth factor signaling. In Drosophila, dietary amino acids promote the release in the hemolymph of brain insulin-like peptides (Dilps), which in turn activate systemic organ growth. Dilp secretion by insulin-producing cells involves a relay through unknown cytokines produced by fat cells. Here, we identify Methuselah (Mth) as a secretin-incretin receptor subfamily member required in the insulin-producing cells for proper nutrient coupling. We further show, using genetic and ex vivo organ culture experiments, that the Mth ligand Stunted (Sun) is a circulating insulinotropic peptide produced by fat cells. Therefore, Sun and Mth define a new cross-organ circuitry that modulates physiological insulin levels in response to nutrients.

Torso-Like Is a Component of the Hemolymph and Regulates the Insulin Signaling Pathway in Drosophila

“…One is the fat body, which produces and releases important regulators of dILP secretion in response to intracellular nutrient levels ( Fig. 6B; Geminard et al 2009;Rajan & Perrimon, 2012;Sano et al 2015;Delanoue et al 2016;Koyama & Mirth 2016). Interestingly, a recent study found that knocking down tor specifically in the fat body led to a decreased body size, leading the authors to suggest that Tor acts in the fat body to influence insulin signalling via an unknown mechanism (Jun et al 2016).…”

Drosophila neprilysins control insulin signaling and food intake via cleavage of regulatory peptides

“…On the other hand, fat body-IPC feedback may be affected as well. However, the only factors known to mediate this process, Unpaired 2 (Rajan and Perrimon, 2012), DILP6 (Bai et al, 2012), and Stunted (Delanoue et al, 2016) have molecular masses of more than 5 kDa, and thus exceed the maximum mass of a putative neprilysin substrate (Oefner et al, 2000). Consequently, a direct regulatory influence of Nep4 on Unpaired 2, DILP6, or Stunted activity appears unlikely.…”

Drosophila FIT is a protein-specific satiety hormone essential for feeding control

“…Two recent studies identified growth-blocking peptides (GBP1 and GBP2) and Stunted (Sun) as AA-responding peptides secreted from the FB. These peptides also control the systemic growth of larvae by promoting the secretion of Drosophila insulin-like peptides (DILPs)1819. Nevertheless, AA-specific factors responsible for eliciting a behavioural change in feeding have so far eluded identification.…”