Biology subjects

Malita, A.

Publications and source records attributed to Malita, A..

7 recordsLinked to original sources

bioRxiv2025

Gut hormone signaling drives sex differences in metabolism and behavior

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 -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.

physiology↗

bioRxiv2025

High-throughput assessment of exercise-induced adaptations and muscle function in health and ageing

Exercise improves metabolic health, enhances insulin sensitivity, and preserves muscle function, making it a core intervention to combat age-related decline and metabolic disorders. However, large-scale genetic and pharmacological screens to uncover exercise-induced adaptations remain challenging in mammalian models due to their complexity and cost. Here, we present the ClimbMaster, a fully automated, computer-controlled platform for assessing exercise-induced adaptations and physical performance in the fruit fly Drosophila. The system uses repeated climbing exercises to simulate endurance training, enabling precise measurements of climbing speed and endurance across different conditions and life stages. Using the ClimbMaster, we demonstrate that exercise improves endurance, promotes fat loss, and enhances insulin-mediated glucose uptake and modulates insulin sensitivity in muscle, highlighting key conserved features of exercise physiology between flies and mammals. We also show that rapamycin, a TOR inhibitor, mitigates age-related performance decline. This platform enables high-throughput screens to investigate genetic and environmental factors influencing muscle health, aging, and insulin resistance, providing a scalable and versatile tool for the identification of novel therapeutic targets to improve healthspan and physical performance.

physiology↗

bioRxiv2024

Glia-mediated gut-brain cytokine signaling couples sleep to intestinal 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 contributes to our understanding of how sleep disturbances arise from gastrointestinal disturbances.

animal behavior and cognition↗

bioRxiv2022

A gut-derived hormone switches dietary preference after mating 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 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.

animal behavior and cognition↗

bioRxiv2021

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

cell biology↗

bioRxiv2020

The gut hormone Allatostatin C 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 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.

physiology↗

bioRxiv2019

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 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 sleep in Drosophila. Neuronal loss of nowl causes short and fragmented sleep, especially during the night. 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. We also show that nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Furthermore, knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep-fragmentation phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl promotes sleep by decreasing the excitability of GABA-responsive wake-driving neurons. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling and sleep that contributes to the 22q11.2 DS.

animal behavior and cognition↗