Production of systemically circulating Hedgehog by the intestine couples nutrition to growth and development

Abstract

In Drosophila larvae, growth and developmental timing are regulated by nutrition in a tightly coordinated fashion. The networks that couple these processes are far from understood. Here, we show that the intestine responds to nutrient availability by regulating production of a circulating lipoprotein-associated form of the signaling protein Hedgehog (Hh). Levels of circulating Hh tune the rates of growth and developmental timing in a coordinated fashion. Circulating Hh signals to the fat body to control larval growth. It regulates developmental timing by controlling ecdysteroid production in the prothoracic gland. Circulating Hh is especially important during starvation, when it is also required for mobilization of fat body triacylglycerol (TAG) stores. Thus, we demonstrate that Hh, previously known only for its local morphogenetic functions, also acts as a lipoprotein-associated endocrine hormone, coordinating the response of multiple tissues to nutrient availability.

Conditional Deletion of Indian Hedgehog in Limb Mesenchyme Results in Complete Loss of Growth Plate Formation but Allows Mature Osteoblast Differentiation

“…In addition, recent studies identified circulating hedgehog or osteoblast precursors that could possibly affect or be involved through vascularization in our osteoblast phenotype. (20)(21)(22)(23) In our study, we observe that the appearance of Col1a1-positive mutant osteoblasts was not always consistent with blood vessel invasions using E17.5 samples. The expression of Ihh and Gli1 was reduced even when tested using whole bones.…”

Drosophilaas a model to study obesity and metabolic disease

“…Lipoprotein complexes containing highly conserved apolipoproteins (called apolipophorins in Drosophila) carry sterols and diacylglycerols from the gut to other tissues (Palm et al, 2012). Fly lipoproteins also contain the signaling molecule Hedgehog, a cholesterol-linked, gutderived ligand that binds the transmembrane receptor Patched on fat body target cells to promote lipolysis during larval starvation (Palm et al, 2013;Rodenfels et al, 2014). Other gut-expressed factors also contribute to the control of systemic lipid homeostasis.…”

CREB non-autonomously regulates Reproductive Aging through Hedgehog/Patched Signalling

“…The Hedgehog signaling system is a dynamic, complex network that encompasses more than the canonical signaling pathway, and has regulatory roles beyond its well-known functions in controlling pattern formation and cell proliferation (Robbins et al, 2012). For instance, in Drosophila larvae, a circulating lipoprotein-associated form of the Hedgehog protein is involved in coordinating metabolic processes, growth, and other physiological changes in response to nutrient deprivation, acting in part through a noncanonical pathway (Rodenfels et al, 2014). In C. elegans , there is an expansive group of Hedgehog-related families that are believed to share a common ancestor with the Hedgehog molecules of other phyla (Aspöck et al, 1999).…”