An intestinal zinc sensor regulates food intake and developmental growth

Abstract

In cells, organs and bodies, nutrient sensing is key to maintaining homeostasis and adapting to a fluctuating environment1. In the digestive system of many animals, enteroendocrine cells harbour nutrient sensors; less is known about nutrient sensing in their cellular siblings – the absorptive enterocytes1. A genetic screen in Drosophila melanogaster identified Hodor: an enterocyte ionotropic receptor that sustains larval development particularly in nutrient-scarce conditions. Experiments in Xenopus oocytes and flies indicate that Hodor is a pH-sensitive zinc-gated chloride channel that mediates a previously unrecognised dietary preference for zinc. Hodor controls systemic growth from a small subset of midgut enterocytes (interstitial cells) by promoting food intake and insulin/IGF signalling. Although Hodor sustains gut luminal acidity and restrains microbial loads, its effect on systemic growth can be uncoupled from these functions and results from its modulation of Tor signalling and lysosomal homeostasis within interstitial cells. Hodor-like genes are only present in insects, and may represent specific targets for disease vector control. Indeed, CRISPR/Cas9 genome editing revealed that the single Anopheles gambiae hodor orthologue is an essential gene. Our findings underscore the need to consider instructive contributions of metals and, more generally, micronutrients to energy homeostasis.