A tumor-secreted protein utilizes glucagon release to cause host wasting

Cell Discovery, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 10, 2025

Abstract Tumor‒host interaction plays a critical role in malignant tumor-induced organ wasting across multiple species. Despite known regulation of regional individual peripheral organs by tumors, whether and how tumors utilize host catabolic hormone(s) to simultaneously induce systemic wasting, is largely unknown. Using the conserved yki 3SA -tumor model Drosophila , we discovered that increase production adipokinetic hormone (Akh), glucagon-like hormone, cause including muscle dysfunction, lipid loss, hyperglycemia, ovary atrophy. We next integrated RNAi screening Gal4-LexA dual expression system show -gut secrete Pvf1 remotely activate its receptor Pvr Akh-producing cells (APCs), ultimately promoting Akh production. The underlying molecular mechanisms involved Pvf1-Pvr axis triggers Mmp2-dependent ECM remodeling APCs enhances innervation from excitatory cholinergic neurons. Interestingly, also confirmed similar governing glucagon release mammals. Blockade either or PDGFR (homolog Pvr) action efficiently ameliorated presence tumors. Therefore, our results demonstrate promote neural-associated Akh/glucagon via wasting.

Язык: Английский

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

Nature Metabolism, Год журнала: 2022, Номер 4(11), С. 1532 - 1550

Опубликована: Ноя. 7, 2022

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

Язык: Английский

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

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Фев. 4, 2022

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 coordinate systemic energy balance. However, gut-derived hormones affecting behavioral responses poorly defined. Here we show that endocrine cells Drosophila gut sense nutrient stress mechanism involves TOR pathway in response secrete peptide hormone allatostatin C, somatostatin homolog. Gut-derived C induces secretion glucagon-like adipokinetic food intake mobilization. Loss Allatostatin or its receptor adipokinetic-hormone-producing impairs lipid sugar mobilization during fasting, leading hypoglycemia. Our findings illustrate nutrient-responsive maintains homeostasis under nutrient-stress conditions, function essential health whose failure can lead disorders.

Язык: Английский

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Endocrine cybernetics: neuropeptides as molecular switches in behavioural decisions

Open Biology, Год журнала: 2022, Номер 12(7)

Опубликована: Июль 1, 2022

Plasticity in animal behaviour relies on the ability to integrate external and internal cues from changing environment hence modulate activity synaptic circuits of brain. This context-dependent neuromodulation is largely based non-synaptic signalling with neuropeptides. Here, we describe select peptidergic systems Drosophila brain that act at different levels a hierarchy associated physiology. These regions, such as central complex mushroom bodies, which supervise specific behaviours. At top level there are small numbers large neurons arborize widely multiple areas orchestrate or global state manner. bottom local provide executive sensory gain intrinsically restricted parts neuronal circuits. The orchestrating receive interoceptive signals mediate energy sleep homeostasis, metabolic circadian timing, well affect food search, aggression mating. Some these can be triggers conflicting behaviours mating versus aggression, feeding, participate circuits, enabling choices switches.

Язык: Английский

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Dietary cysteine drives body fat loss via FMRFamide signaling in Drosophila and mouse

Cell Research, Год журнала: 2023, Номер 33(6), С. 434 - 447

Опубликована: Апрель 13, 2023

Abstract Obesity imposes a global health threat and calls for safe effective therapeutic options. Here, we found that protein-rich diet significantly reduced body fat storage in fruit flies, which was largely attributed to dietary cysteine intake. Mechanistically, increased the production of neuropeptide FMRFamide (FMRFa). Enhanced FMRFa activity simultaneously promoted energy expenditure suppressed food intake through its cognate receptor (FMRFaR), both contributing loss effect. In body, signaling lipolysis by increasing PKA lipase activity. sweet-sensing gustatory neurons, appetitive perception hence We also demonstrated worked similar way mice via FF (NPFF) signaling, mammalian RFamide peptide. addition, or FMRFa/NPFF administration provided protective effect against metabolic stress flies without behavioral abnormalities. Therefore, our study reveals novel target development therapies obesity related diseases.

Язык: Английский

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Dietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 25, 2024

Abstract Amino acid availability is monitored by animals to adapt their nutritional environment. Beyond gustatory receptors and systemic amino sensors, enteroendocrine cells (EECs) are believed directly percept dietary acids secrete regulatory peptides. However, the cellular machinery underlying acid-sensing EECs how EEC-derived hormones modulate feeding behavior remain elusive. Here, developing tools specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female inhibits feeding, similar human PYY. Mechanistically, L-Glutamate acts through metabotropic glutamate receptor mGluR decelerate calcium oscillations in thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive relay an anorexigenic signal brain. Thus, our findings provide mechanistic insights into assess food quality identify a conserved mode of action explains gut NPF/PYY modulates intake.

Язык: Английский

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Nutritional state-dependent modulation of insulin-producing cells in Drosophila

eLife, Год журнала: 2025, Номер 13

Опубликована: Янв. 29, 2025

Insulin plays a key role in metabolic homeostasis. Drosophila insulin-producing cells (IPCs) are functional analogues of mammalian pancreatic beta and release insulin directly into circulation. To investigate the vivo dynamics IPC activity, we quantified effects nutritional internal state changes on IPCs using electrophysiological recordings. We found that strongly modulates activity. activity decreased with increasing periods starvation. Refeeding flies glucose or fructose, two nutritive sugars, significantly increased whereas non-nutritive sugars had no effect. In contrast to feeding, perfusion did not affect This was reminiscent incretin effect, where ingestion drives higher than intravenous application. Contrary IPCs, Diuretic hormone 44-expressing neurons pars intercerebralis (DH44 PI Ns) responded perfusion. Functional connectivity experiments demonstrated these DH44 Ns do while other DH44Ns inhibit them. Hence, populations autonomously systemically sugar-sensing work parallel maintain Accordingly, activating small, satiety-like effect food-searching behavior reduced starvation-induced hyperactivity, hyperactivity. Taken together, demonstrate an integral part modulatory network orchestrates homeostasis adaptive response shifts state.

Язык: Английский

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Cholecystokinin/sulfakinin peptide signaling: conserved roles at the intersection between feeding, mating and aggression

Cellular and Molecular Life Sciences, Год журнала: 2022, Номер 79(3)

Опубликована: Март 1, 2022

Neuropeptides are the most diverse messenger molecules in metazoans and involved regulation of daily physiology a wide array behaviors. Some neuropeptides their cognate receptors structurally functionally well conserved over evolution bilaterian animals. Among these peptides related to gastrin cholecystokinin (CCK). In mammals, CCK is produced by intestinal endocrine cells brain neurons, regulates gall bladder contractions, pancreatic enzyme secretion, gut functions, satiety food intake. Additionally, plays important roles neuromodulation several circuits that regulate reward, anxiety, aggression sexual behavior. invertebrates, CCK-type (sulfakinins, SKs) are, with few exceptions, neurons only. Common among invertebrates SKs mediate ingestion variety mechanisms. Also secretion digestive enzymes has been reported. Studies genetically tractable fly Drosophila have advanced our understanding SK signaling mechanisms feeding, but also gustatory sensitivity, locomotor activity, reproductive A set eight SK-expressing competing males, they integrate internal state external stimuli diminish sex drive increase aggression. The same sugar gustation, induce reduce feeding. Although functional CCK/SK appear between available data suggest underlying differ.

Язык: Английский

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Sex determination gene transformer regulates the male-female difference in Drosophila fat storage via the adipokinetic hormone pathway

eLife, Год журнала: 2021, Номер 10

Опубликована: Окт. 21, 2021

Sex differences in whole-body fat storage exist many species. For example, Drosophila females store more than males. Yet, the mechanisms underlying this sex difference remain incompletely understood. Here, we identify a key role for determination gene transformer ( tra ) regulating male-female storage. Normally, functional Tra protein is present only females, where it promotes female sexual development. We show that loss of reduced storage, whereas gain males augmented Tra’s promoting was largely due to its function neurons, specifically Adipokinetic hormone (Akh)-producing cells (APCs). Our analysis Akh pathway regulation revealed male bias APC activity and function, sex-biased influenced by limiting triglyceride accumulation Importantly, increased activity, genetically manipulating rescued Tra-dependent effects on This identifies sex-specific as one mechanism levels, provides important insight into conserved dimorphism

Язык: Английский

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Interorgan communication through peripherally derived peptide hormones in Drosophila

Fly, Год журнала: 2022, Номер 16(1), С. 152 - 176

Опубликована: Май 1, 2022

In multicellular organisms, endocrine factors such as hormones and cytokines regulate development homoeostasis through communication between different organs. For understanding interorgan communications factors, the fruit fly Drosophila melanogaster serves an excellent model system due to conservation of essential systems flies mammals availability powerful genetic tools. other insects, functions neuropeptides or peptide from central nervous have been extensively studied. However, a series recent studies conducted in revealed that derived peripheral tissues also play critical roles regulating multiple biological processes, including growth, metabolism, reproduction, behaviour. Here, we summarise advances target organs/tissues peripherally describe how these contribute various events communications.

Язык: Английский

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