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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. Intestinal nutrient-sensing is important in metabolic control. Here the authors show that the gut-derived hormone Allatostatin C, a somatostatin homolog in fruit flies, links enteric nutrient sensing to behavioral and metabolic adaptations that maintain energetic homeostasis in Drosophila melanogaster.

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. The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the D rosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.

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. Malita, Kubrak et al. show that the gut-derived hormone neuropeptide F suppresses sugar intake and increases the consumption of protein-rich food in Drosophila . This gives insight into the regulation of nutrient-specific appetite that ensures appropriate food choices to meet nutritional demands.

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.

Sickness-induced sleep is a behavior conserved across species that promotes recovery from illness, yet the underlying mechanisms are poorly understood. Here, we show that interleukin-6-like cytokine signaling from the Drosophila gut to brain glial cells regulates sleep. Under healthy conditions, this pathway promotes wakefulness. However, elevated gut cytokine signaling in response to oxidative stress – triggered by immune and inflammatory responses in the intestine – induces sleep. The cytokines Unpaired 2 and –3 are upregulated by oxidative stress in enteroendocrine cells and activate JAK–STAT signaling in glial cells, including those of the blood–brain barrier (BBB). This activity maintains elevated sleep during oxidative-stress-induced intestinal disturbances, suggesting that the JAK–STAT pathway in glia inhibits wake-promoting signaling to facilitate sleep-dependent restoration under these conditions. We find that the enteric peptide Allatostatin A (AstA) enhances wakefulness, and during intestinal oxidative stress, gut-derived Unpaired 2/3 inhibits AstA receptor expression in BBB glia, thereby sustaining an elevated sleep state during gut inflammation or illness. Taken together, our work identifies a gut-to-glial communication pathway that couples sleep with intestinal homeostasis and disease, enhancing sleep during intestinal sickness, and contributing to our understanding of how sleep disturbances arise from gastrointestinal disturbances. When we are sick, we often feel tired or sleepy. This sickness-induced sleep is a deeply conserved response across species that helps the body recover. While the immune system and the brain must somehow communicate to make this happen, we still know little about how signals from a sick body reach the brain to change sleep behavior. The gut, for instance, plays an important role in health and illness, and inflammation in the gut is known to affect mental health and sleep. However, we do not fully understand how this inflammation might influence brain activity. To find out more, Malita et al. used the fruit fly Drosophila as a model to investigate how stress and inflammation in the gut might affect sleep, focusing on hormone-like signaling molecules called cytokines, which are involved in immune response and inflammation. The researchers genetically engineered flies to eliminate the release of specific cytokines from the endocrine cells of the gut and tracked the animals’ sleep and activity patterns. They next exposed flies to a chemical that triggers oxidative stress and inflammatory responses in the gut and monitored how this affected sleep. The flies were then dissected and stained for further immunohistochemical studies and confocal microscopy imaging. The results revealed that oxidative stress triggers the release of specific cytokines from endocrine cells in the lining of the gut as part of an immune and inflammatory response. These cytokines travel through the body’s circulatory system and activate a signaling pathway in glial cells that form the blood-brain barrier – the protective layer surrounding the brain. This pathway promotes sleep during intestinal stress and inflammation, likely to support recovery. Under healthy conditions, however, the same cytokine signals help keep the animal awake. Malita et al. reveal a connection between the gut and the brain through which the intestine communicates its health status to the brain, enabling the animal to adjust its behaviors, such as sleep, in response to internal signals like inflammation or oxidative stress. These findings help us understand how gut health influences sleep and mental well-being, and they may shed light on the sleep disturbances that often afflict people with gut disorders. While this work was done in fruit flies, the cytokine signaling pathways involved in disease exist in a similar form in humans. Further research is needed to determine whether similar gut-to-brain communication pathways that regulate sleep under conditions of intestinal illness exist in humans, which could eventually inform new strategies for managing sleep or mood disorders linked to gut inflammation.

Sickness-induced sleep is a behavior conserved across species that promotes recovery from illness, yet the underlying mechanisms are poorly understood. Here, we show that interleukin-6-like cytokine signaling from the Drosophila gut to brain glial cells regulates sleep. Under healthy conditions, this pathway promotes wakefulness. However, elevated gut cytokine signaling in response to oxidative stress – triggered by immune and inflammatory responses in the intestine – induces sleep. The cytokines Unpaired 2 and –3 are upregulated by oxidative stress in enteroendocrine cells and activate JAK–STAT signaling in glial cells, including those of the blood–brain barrier (BBB). This activity maintains elevated sleep during oxidative-stress-induced intestinal disturbances, suggesting that the JAK–STAT pathway in glia inhibits wake-promoting signaling to facilitate sleep-dependent restoration under these conditions. We find that the enteric peptide Allatostatin A (AstA) enhances wakefulness, and during intestinal oxidative stress, gut-derived Unpaired 2/3 inhibits AstA receptor expression in BBB glia, thereby sustaining an elevated sleep state during gut inflammation or illness. Taken together, our work identifies a gut-to-glial communication pathway that couples sleep with intestinal homeostasis and disease, enhancing sleep during intestinal sickness, and contributing to our understanding of how sleep disturbances arise from gastrointestinal disturbances. When we are sick, we often feel tired or sleepy. This sickness-induced sleep is a deeply conserved response across species that helps the body recover. While the immune system and the brain must somehow communicate to make this happen, we still know little about how signals from a sick body reach the brain to change sleep behavior. The gut, for instance, plays an important role in health and illness, and inflammation in the gut is known to affect mental health and sleep. However, we do not fully understand how this inflammation might influence brain activity. To find out more, Malita et al. used the fruit fly Drosophila as a model to investigate how stress and inflammation in the gut might affect sleep, focusing on hormone-like signaling molecules called cytokines, which are involved in immune response and inflammation. The researchers genetically engineered flies to eliminate the release of specific cytokines from the endocrine cells of the gut and tracked the animals’ sleep and activity patterns. They next exposed flies to a chemical that triggers oxidative stress and inflammatory responses in the gut and monitored how this affected sleep. The flies were then dissected and stained for further immunohistochemical studies and confocal microscopy imaging. The results revealed that oxidative stress triggers the release of specific cytokines from endocrine cells in the lining of the gut as part of an immune and inflammatory response. These cytokines travel through the body’s circulatory system and activate a signaling pathway in glial cells that form the blood-brain barrier – the protective layer surrounding the brain. This pathway promotes sleep during intestinal stress and inflammation, likely to support recovery. Under healthy conditions, however, the same cytokine signals help keep the animal awake. Malita et al. reveal a connection between the gut and the brain through which the intestine communicates its health status to the brain, enabling the animal to adjust its behaviors, such as sleep, in response to internal signals like inflammation or oxidative stress. These findings help us understand how gut health influences sleep and mental well-being, and they may shed light on the sleep disturbances that often afflict people with gut disorders. While this work was done in fruit flies, the cytokine signaling pathways involved in disease exist in a similar form in humans. Further research is needed to determine whether similar gut-to-brain communication pathways that regulate sleep under conditions of intestinal illness exist in humans, which could eventually inform new strategies for managing sleep or mood disorders linked to gut inflammation.

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 behaviors is poorly defined. Here, we show that the enteroendocrine cells (EECs) of the adult female Drosophila midgut sense nutrients and in response release neuropeptide F (NPF), an ortholog of mammalian NPY-family gut-brain hormones. Gut-derived NPF acts via effects on glucagon-like adipokinetic hormone (AKH) signaling to induce sugar satiety and to drive hunger for protein-rich food, and on adipose tissue to promote storage of ingested nutrients. Suppression of gut NPF leads to overconsumption of dietary sugar while decreasing intake of protein-rich yeast. Furthermore, we show a female-specific function of gut-derived NPF in the suppression of AKH signaling after mating. This induces a dietary switch that promotes preference for protein-containing food to support reproduction. Together, our findings suggest that the gut NPF-AKH axis regulates appetite that drives specific food choices to ensure homeostatic consumption of nutrients, providing insight into the hormonal mechanisms that underlie nutrient-specific hungers. Competing Interest Statement The authors have declared no competing interest.

Abstract 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 specific gut hormones that communicate energy availability to target organs to induce appropriate metabolic and behavioral responses are poorly defined. Here we show that the enteroendocrine cells (EECs) of the Drosophila gut sense nutrient stress via the intracellular TOR pathway, and in response secrete the peptide hormone allatostatin C (AstC). Gut-derived AstC induces secretion of glucagon-like adipokinetic hormone (AKH) via its receptor AstC-R2, a homolog of mammalian somatostatin receptors, to coordinate food intake and energy mobilization. Loss of gut AstC or its receptor in the AKH-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. Competing Interest Statement The authors have declared no competing interest.

Males and females have different physiological and reproductive demands, and consequently exhibit widespread differences in metabolism and behavior. One of the most consistent differences across animals is that females store more body fat than males, a metabolic trait conserved from flies to humans. Given the central role of gut hormones in energy balance, we asked whether gut endocrine signaling underlies these sex differences. We therefore performed a multidimensional screen of enteroendocrine cell (EEC)-derived signaling across a broad panel of metabolic and behavioral traits in male and female Drosophila. This screen uncovered extensive sex-biased roles for EEC-derived signals – many of which are conserved in mammals – in energy storage, stress resistance, feeding, and sleep. We found that EEC-derived amidated peptide hormones sustain female-typical states, including elevated fat reserves, enhanced stress resilience, and protein-biased food choice. In contrast, the non-amidated peptide Allatostatin C (AstC) promoted male-like traits by stimulating energy mobilization, thereby antagonizing amidated-peptide function. Female guts contained more AstC-positive EECs. Disruption of peptide amidation by eliminating peptidylglycine α-hydroxylating monooxygenase – the enzyme required for maturation of most gut peptide hormones – abolished female-typical physiology and behavior, shifting females toward a male-like state. Among individual amidated peptides, Diuretic hormone 31 (DH31) and Neuropeptide F (NPF) emerged as key mediators of female physiology. These findings establish gut hormone signaling as a determinant of sex-specific metabolic and behavioral states.

Sickness-induced sleep is a behavior conserved across species that promotes recovery from illness, yet the underlying mechanisms are poorly understood. Here, we show that interleukin-6-like cytokine signaling from the Drosophila gut to brain glial cells regulates sleep. Under healthy conditions, this pathway promotes wakefulness. However, elevated gut cytokine signaling in response to oxidative stress – triggered by immune and inflammatory responses in the intestine – induces sleep. The cytokines Unpaired 2 and -3 are upregulated by oxidative stress in enteroendocrine cells and activate JAK-STAT signaling in glial cells, including those of the blood-brain barrier (BBB). This activity maintains elevated sleep during oxidative-stress-induced intestinal disturbances, suggesting that the JAK-STAT pathway in glia inhibits wake-promoting signaling to facilitate sleep-dependent restoration under these conditions. We find that the enteric peptide Allatostatin A (AstA) enhances wakefulness, and during intestinal oxidative stress, gut-derived Unpaired 2/3 inhibits AstA receptor expression in BBB glia, thereby sustaining an elevated sleep state during gut inflammation or illness. Taken together, our work identifies a gut-to-glial communication pathway that couples sleep with intestinal homeostasis and disease, enhancing sleep during intestinal sickness, and contributes to our understanding of how sleep disturbances arise from gastrointestinal disturbances.