Abstract
Animals maintain metabolic homeostasis by modulating the activity of specialized organs that adjust internal metabolism to external conditions. However, the hormonal signals coordinating these functions are incompletely characterized. Here we show that six neurosecretory cells in the Drosophila central nervous system respond to circulating nutrient levels by releasing Capa hormones, homologs of mammalian neuromedin U, which activate the Capa receptor (CapaR) in peripheral tissues to control energy homeostasis. Loss of Capa/CapaR signaling causes intestinal hypomotility and impaired nutrient absorption, which gradually deplete internal nutrient stores and reduce organismal lifespan. Conversely, increased Capa/CapaR activity increases fluid and waste excretion. Furthermore, Capa/CapaR inhibits the release of glucagon-like adipokinetic hormone from the corpora cardiaca, which restricts energy mobilization from adipose tissue to avoid harmful hyperglycemia. Our results suggest that the Capa/CapaR circuit occupies a central node in a homeostatic program that facilitates the digestion and absorption of nutrients and regulates systemic energy balance.
Highlights
Animals maintain metabolic homeostasis by modulating the activity of specialized organs that adjust internal metabolism to external conditions
To unambiguously demonstrate a post-developmental role of Capa/Capa receptor (CapaR) signaling in sustaining adult survival, we adopted an alternative genetic strategy in which we designed a UAS-inducible tissue-specific CRISPR/Cas[9] construct for CapaR (Supplementary Fig. 1a, e), which we spatio-temporally restricted to the adult stage using the TARGET system[15]
Our work has identified a system in which Capa peptides released by six Va neuroendocrine cells of the ventral nerve cord activate their receptor CapaR localized to visceral muscles to control intestinal motility and food transit
Summary
Animals maintain metabolic homeostasis by modulating the activity of specialized organs that adjust internal metabolism to external conditions. In the fruit fly Drosophila melanogaster discrete populations of neurosecretory cells function as nutrient sensors, which upon activation secrete neurohormones that modulate food intake, energy mobilization, gut peristalsis or renal secretion[5,6,7] Both mammals and flies regulate organ activities in response to internal state, and in many instances accomplish this regulation by similar mechanisms. Loss of Capa/CapaR signaling reduces intestinal contractility, gut regionalization and nutrient absorption, which result in systemic metabolic defects characterized by pronounced hypoglycemia and lipodystrophy These metabolic effects cause a gradual loss of muscle function due to dysregulated Ca2+ homeostasis in skeletal muscles, which impairs feeding behavior and causes premature mortality. Our work uncovers an adult-specific inter-tissue program that is essential to maintain osmotic and metabolic homeostasis in Drosophila—a program that shows remarkable functional similarity with NmU signaling in mammals
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