Insulin signaling couples growth and early maturation to cholesterol intake in Drosophila

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Nutrition is one of the most important influences on growth and the timing of maturational transitions including mammalian puberty and insect metamorphosis. Childhood obesity is associated with precocious puberty, but the assessment mechanism that links body fat to early maturation is unknown. During development, the intake of nutrients promotes signaling through insulin-like systems that govern the growth of cells and tissues and also regulates the timely production of the steroid hormones that initiate the juvenile-adult transition. We show here that the dietary lipid cholesterol, which is required as a component of cell membranes and as a substrate for steroid biosynthesis, also governs body growth and maturation in Drosophila via promoting the expression and release of insulin-like peptides. This nutritional input acts via the nutrient sensor TOR, which is regulated by the Niemann-Pick-type-C 1 (Npc1) cholesterol transporter, in the glia of the blood-brain barrier and cells of the adipose tissue to remotely drive systemic insulin signaling and body growth. Furthermore, increasing intracellular cholesterol levels in the steroid-producing prothoracic gland strongly promotes endoreduplication, leading to an accelerated attainment of a nutritional checkpoint that normally ensures that animals do not initiate maturation prematurely. These findings, therefore, show that a Npc1-TOR signaling system couples the sensing of the lipid cholesterol with cellular and systemic growth control and maturational timing, which may help explain both the link between cholesterol and cancer as well as the connection between body fat (obesity) and early puberty.

OriginalsprogEngelsk
TidsskriftCurrent Biology
Vol/bind32
Udgave nummer7
Sider (fra-til)1548-1562.e6
ISSN0960-9822
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We warmly thank our colleagues who have contributed materials, the use of equipment, and expertise to this effort: Ernst Hafen, Pierre Léopold, Ryusuke Niwa, Michael O’Connor, Mike Pankratz, Nuria Romero, Gedske Thygesen, Luisa Vasconcelos, and Jan Veenstra, as well as three anonymous reviewers; and the Bloomington, Kyoto, and Vienna Drosophila stock centers. This work was supported by grant #8021-00055B from the Independent Research Fund Denmark (Natural Sciences) to K.R.

Publisher Copyright:
© 2022 The Author(s)

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