A gut-derived hormone suppresses sugar appetite and regulates food choice in Drosophila.

Animals must adapt their dietary choices to meet their nutritional needs. How these needs are detected and translated into nutrient-specific appetites that drive food-choice behaviours is poorly understood. Here we show that enteroendocrine cells of the adult female Drosophila midgut sense nutrients and in response release neuropeptide F (NPF), which is an ortholog of mammalian neuropeptide Y-family gut-brain hormones. Gut-derived NPF acts on glucagon-like adipokinetic hormone (AKH) signalling to induce sugar satiety and increase consumption of protein-rich food, and on adipose tissue to promote storage of ingested nutrients. Suppression of NPF-mediated gut signalling leads to overconsumption of dietary sugar while simultaneously decreasing intake of protein-rich yeast. Furthermore, gut-derived NPF has a female-specific function in promoting consumption of protein-containing food in mated females. Together, our findings suggest that gut NPF-to-AKH signalling modulates specific appetites and regulates food choice to ensure homeostatic consumption of nutrients, providing insight into the hormonal mechanisms that underlie nutrient-specific hungers.

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

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.

The gut hormone Allatostatin C/Somatostatin regulates food intake and metabolic homeostasis under nutrient stress.

The intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal information to other organs to coordinate systemic energy balance. However, the gut-derived hormones affecting metabolic and behavioral responses are poorly defined. Here we show that the endocrine cells of the Drosophila gut sense nutrient stress through a mechanism that involves the TOR pathway and in response secrete the peptide hormone allatostatin C, a Drosophila somatostatin homolog. Gut-derived allatostatin C induces secretion of glucagon-like adipokinetic hormone to coordinate food intake and energy mobilization. Loss of gut Allatostatin C or its receptor in the adipokinetic-hormone-producing cells impairs lipid and sugar mobilization during fasting, leading to hypoglycemia. Our findings illustrate a nutrient-responsive endocrine mechanism that maintains energy homeostasis under nutrient-stress conditions, a function that is essential to health and whose failure can lead to metabolic disorders.

Interorgan communication in the control of metamorphosis.

Steroid hormones control major developmental transitions such as metamorphosis in insects and puberty in mammals. The juvenile must attain a sufficient size before it begins maturation in order to give rise to a properly sized and reproductively fit adult. Studies in the insect Drosophila have begun to reveal a remarkable example of the complex interplay between different organs and the neuroendocrine system that controls the production of the steroid ecdysone, which triggers metamorphosis. This review discusses the inter-organ signals mediating this crosstalk, which allows the neuroendocrine system to assess nutrient availability and growth status of internal organs, ensuring that maturation is initiated at the appropriate time. We discuss how the neuroendocrine system integrates signals from different tissues to coordinate growth and maturation. These studies are still unraveling the organ-to-organ signaling networks that control the timing of metamorphosis, defining important principles underlying the logic of growth and maturation coordination in animals.

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control.

The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of known genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 (night owl, nowl) as a regulator of night-time sleep in Drosophila. In humans, LZTR1 has been associated with Ras-dependent neurological diseases also caused by Neurofibromin-1 (Nf1) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. Furthermore, nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl regulates sleep through modulation of GABA signaling. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling important for normal sleep that contributes to the 22q11.2 DS.

Autophagy regulates steroid production by mediating cholesterol trafficking in endocrine cells.

Steroid hormones are made from cholesterol and are essential for many developmental processes and disease conditions. The production of these hormones is nutrient dependent and tightly controlled by mechanisms that involve delivery of the precursor molecule cholesterol stored in lipid droplets (LDs). Recent studies have implicated macroautophagy/autophagy, a process regulated by nutrition, in the degradation of LDs and the mobilization of stored lipids. We recently identified an autophagy-dependent mechanism that regulates steroid production via effects on cholesterol trafficking. Through gain- and loss-of-function studies in Drosophila, we found that essential autophagy-related (Atg) genes are required in steroidogenic cells for normal steroid production. Inhibition of autophagy in these cells by knockdown of Atg genes causes strong accumulation of cholesterol in LDs and reduces steroid production, resembling effects seen in some lipid-storage disorders and steroid-dependent cancer conditions. This autophagy-dependent steroid hormone regulation (ASHR) process is regulated by the wts-yki/Warts-Yorkie tumor-suppressor pathway downstream of nutrition, coupling nutrient intake with steroid-dependent developmental growth. This mechanism potentially contributes to the development of certain cancers and lipid-storage disorders and thus may be of great therapeutic relevance.

A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion.

Organisms adapt their metabolism and growth to the availability of nutrients and oxygen, which are essential for development, yet the mechanisms by which this adaptation occurs are not fully understood. Here we describe an RNAi-based body-size screen in Drosophila to identify such mechanisms. Among the strongest hits is the fibroblast growth factor receptor homolog breathless necessary for proper development of the tracheal airway system. Breathless deficiency results in tissue hypoxia, sensed primarily in this context by the fat tissue through HIF-1a prolyl hydroxylase (Hph). The fat relays its hypoxic status through release of one or more HIF-1a-dependent humoral factors that inhibit insulin secretion from the brain, thereby restricting systemic growth. Independently of HIF-1a, Hph is also required for nutrient-dependent Target-of-rapamycin (Tor) activation. Our findings show that the fat tissue acts as the primary sensor of nutrient and oxygen levels, directing adaptation of organismal metabolism and growth to environmental conditions.

Autophagy-Mediated Cholesterol Trafficking Controls Steroid Production.

Steroid hormones are important signaling molecules that regulate growth and drive the development of many cancers. These factors act as long-range signals that systemically regulate the growth of the entire organism, whereas the Hippo/Warts tumor-suppressor pathway acts locally to limit organ growth. We show here that autophagy, a pathway that mediates the degradation of cellular components, also controls steroid production. This process is regulated by Warts (in mammals, LATS1/2) signaling, via its effector microRNA bantam, in response to nutrients. Specifically, autophagy-mediated mobilization and trafficking of the steroid precursor cholesterol from intracellular stores controls the production of the Drosophila steroid ecdysone. Furthermore, we also show that bantam regulates this process via the ecdysone receptor and Tor signaling, identifying pathways through which bantam regulates autophagy and growth. The Warts pathway thus promotes nutrient-dependent systemic growth during development by autophagy-dependent steroid hormone regulation (ASHR). These findings uncover an autophagic trafficking mechanism that regulates steroid production.