Insulin signaling couples growth and early maturation to cholesterol intake

Nutrition is one of the most important influences on growth and the timing of developmental maturation 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, 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, 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 Niemann-Pick-type-C (Npc) cholesterol sensors/transporters 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 accelerated attainment of a nutritional checkpoint that ensures that animals do not initiate maturation prematurely. These findings couple sensing of the lipid cholesterol to growth control and maturational timing, which may help explain both the link between cholesterol and cancer as well as the critical connection between body fat (obesity) and early puberty. HIGHLIGHTSO_LIDietary cholesterol promotes developmental growth and leads to early maturation C_LIO_LIInsulin signaling couples cholesterol intake with systemic growth C_LIO_LICholesterol promotes insulin signaling and growth via glial and fat-tissue relays C_LIO_LICholesterol sensing affects a nutritional checkpoint that prevents early maturation C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/447368v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@14e786borg.highwire.dtl.DTLVardef@c3eab5org.highwire.dtl.DTLVardef@6645c8org.highwire.dtl.DTLVardef@6f729a_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG