An intestinal zinc sensor regulates food intake and developmental growth

Siamak Redhai, Clare Pilgrim, Pedro Gaspar, Lena van Giesen, Tatiana Lopes, Olena Riabinina, Théodore Grenier, Alexandra Milona, Bhavna Chanana, Jacob B. Swadling, Yi-Fang Wang, Farah Dahalan, Michaela Yuan, Michaela Wilsch-Brauninger, Wei-hsiang Lin, Nathan Dennison, Paolo Capriotti, Mara K. N. Lawniczak, Richard A. Baines, Tobias Warnecke, Nikolai Windbichler, Francois Leulier, Nicholas W. Bellono and Irene Miguel-Aliaga ()
Additional contact information
Siamak Redhai: MRC London Institute of Medical Sciences
Clare Pilgrim: MRC London Institute of Medical Sciences
Pedro Gaspar: MRC London Institute of Medical Sciences
Lena van Giesen: Harvard University
Tatiana Lopes: MRC London Institute of Medical Sciences
Olena Riabinina: MRC London Institute of Medical Sciences
Théodore Grenier: Université de Lyon, ENS de Lyon
Alexandra Milona: MRC London Institute of Medical Sciences
Bhavna Chanana: MRC London Institute of Medical Sciences
Jacob B. Swadling: MRC London Institute of Medical Sciences
Yi-Fang Wang: MRC London Institute of Medical Sciences
Farah Dahalan: Imperial College London
Michaela Yuan: Max Planck Institute of Molecular Cell Biology and Genetics
Michaela Wilsch-Brauninger: Max Planck Institute of Molecular Cell Biology and Genetics
Wei-hsiang Lin: University of Manchester, Manchester Academic Health Science Centre
Nathan Dennison: Imperial College London
Paolo Capriotti: Imperial College London
Mara K. N. Lawniczak: Wellcome Sanger Institute
Richard A. Baines: University of Manchester, Manchester Academic Health Science Centre
Tobias Warnecke: MRC London Institute of Medical Sciences
Nikolai Windbichler: Imperial College London
Francois Leulier: Université de Lyon, ENS de Lyon
Nicholas W. Bellono: Harvard University
Irene Miguel-Aliaga: MRC London Institute of Medical Sciences

Nature, 2020, vol. 580, issue 7802, 263-268

Abstract: Abstract In cells, organs and whole organisms, nutrient sensing is key to maintaining homeostasis and adapting to a fluctuating environment1. In many animals, nutrient sensors are found within the enteroendocrine cells of the digestive system; however, less is known about nutrient sensing in their cellular siblings, the absorptive enterocytes1. Here we use a genetic screen in Drosophila melanogaster to identify Hodor, an ionotropic receptor in enterocytes 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 unrecognized dietary preference for zinc. Hodor controls systemic growth from a subset of 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 results from the modulation of Tor signalling and lysosomal homeostasis within interstitial cells. Hodor-like genes are insect-specific, and may represent targets for the control of disease vectors. Indeed, CRISPR–Cas9 genome editing revealed that the single hodor orthologue in Anopheles gambiae is an essential gene. Our findings highlight the need to consider the instructive contributions of metals—and, more generally, micronutrients—to energy homeostasis.

Date: 2020
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DOI: 10.1038/s41586-020-2111-5

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