Biology subjects

Kosakamoto, H.

Publications and source records attributed to Kosakamoto, H..

9 recordsLinked to original sources

bioRxiv2025

Dual Metabolic Compensation to Dietary Choline Deficiency by the Drosophila Hologenome

Coping with an unbalanced diet is critical in animals. However, the mechanisms that mitigate deficiencies of specific nutrients, such as choline, remain poorly understood. Choline is converted to phosphatidylcholine (PC), a major phospholipid. Using genetic, nutritional, and microbiome manipulation tools in Drosophila melanogaster, we identified two independent mechanisms that ameliorate the effects of choline deficiency. First, a strain of commensal bacteria synthesizes PC via choline-independent pathway and provides it to the host. Second, a host-derived phospholipid, {beta}-methylphosphatidylcholine ({beta}mPC), is generated from carnitine, which compensates choline deficiency as a functional analog of PC. Our findings reveal microbial and host metabolic processes that modulate dietary requirement for choline. This study also provides evidence that hologenomic coordination of metabolism enables animals to adapt to a micronutrient deficiency.

physiology↗

bioRxiv2025

Storage Protein-Mediated Translation Control Links Juvenile Diet to Longevity in Drosophila

Dietary restriction (DR), whether applied during adulthood or juvenile stages, extends lifespan across diverse species. However, the mechanisms by which early-life dietary interventions influence adult physiology and longevity remain poorly understood. Here, using Drosophila as a model, we demonstrate that protein restriction during the larval stage (early-life protein restriction, ePR) promotes adult lifespan by reducing storage protein levels. Stable isotope tracing reveals that dietary amino acids obtained in the larval stage are retained into adulthood, especially incorporated into ribosomal proteins. This is mediated by larval serum protein 2 (Lsp2), a major storage protein, whose expression is durably downregulated by ePR. Both dietary (ePR) and genetic (Lsp2-RNAi) reduction of the protein storage lead to decreased ribosomal protein levels and translation activity in early adulthood. Notably, these storage proteins are enriched in aromatic amino acids such as tyrosine, and larval tyrosine restriction alone is sufficient to suppress translation and promote longevity. These findings show that storage proteins mediate the effect of larval nutrition on adult longevity via controlling translation. Our study uncovers a previously unrecognised mechanism of nutritional memory that links early-life diet to life-long organismal health.

physiology↗

bioRxiv2025

The blood-brain barrier regulates brain tumour growth specifically via the SLC36 amino acid transporter Pathetic in Drosophila

Tumours adapt their metabolism to sustain increased proliferation, rendering them particularly vulnerable to fluctuations in nutrient availability. However, the role of the tumour microenvironment in modulating sensitivity to nutrient restriction (NR) remains poorly understood. Using a Drosophila brain dedifferentiation neural stem cell (NSC) tumour model induced by Prospero (Pros) inhibition, we show that tumour sensitivity to NR is governed by the perineural glial (PG) cells of the blood-brain barrier (BBB), a major component of the glial niche surrounding the tumour. We identify the SLC36 amino acid transporter Pathetic (Path) as a crucial regulator of nutrient sensitivity. Under NR, while wildtype buffers against low nutrient levels by upregulating Path, tumour glia downregulate Path. Furthermore, Path is specifically required by the tumour (but not wildtype) PG; its downregulation causes reduced proliferation of PG cells and, in turn, restricts NSC tumour growth. Path influences PG proliferation via the mTor-S6K pathway, and its expression is controlled by Ilp6 levels and the Insulin/PI3K pathway. Overexpression of Path is sufficient to counteract the inhibitory effects of NR on tumour growth. These findings suggest that Path levels at the BBB play a key role in determining tumour sensitivity to NR.

cancer biology↗

bioRxiv2024

Dietary zinc restriction mimics protein restriction and extends lifespan in Drosophila

Dietary restriction extends lifespan in model organisms, mainly through dietary amino acids. Compared to macronutrients, the effect of dietary micronutrients on organismal lifespan has not been intensively investigated. Here, using a synthetic diet, we test whether restriction of each micronutrient, including vitamins and minerals, affects lifespan and fecundity in adult Drosophila. While restriction of many of these micronutrients have either negative or no impact on lifespan, zinc (Zn) restriction alone can increase it. Dietary Zn restriction (ZnR) decreases fecundity, increases starvation resistance, and promotes preference for feeding amino acids, in adult females, phenocopying dietary amino acid restriction. Our study demonstrates that dietary intake of trace elements has profound impacts on physiology and lifespan, and that limiting dietary zinc may be a strategy to improve the healthspan of animals.

physiology↗

bioRxiv2023

Epidermal tyrosine catabolism is critical for metabolic homeostasis and survival against high-protein diets in Drosophila

The insect epidermis that forms the exoskeleton and determines the body size of an organism has the potential to respond and adapt to the changing nutritional environment. However, the extent to which the tissue contributes to adaptation to varying dietary protein availability, as well as its role as a metabolic regulator, remains incompletely understood. Here, we show that the Drosophila epidermis promptly reacts to dietary protein intake, promoting tyrosine (Tyr) catabolism. Among the enzymes involved in Tyr degradation, 4- hydroxyphenylpyruvate dioxygenase (Hpd) is particularly induced under high-protein regimens. We found that AMP-activated protein kinase (AMPK) pathway and forkhead box O subfamily (FoxO) induce Hpd expression. Impaired Hpd function in the epidermis leads to aberrant increases in internal Tyr levels and its metabolites, disrupting larval development under high-protein diets. Taken together, our findings uncover the critical role of epidermal metabolism in adapting to imbalanced protein environments and hence in promoting animal survival. Summary statementTyrosine degradation is upregulated in Drosophila epidermal tissue via the AMPK-FoxO axis upon dietary high-protein stress.

physiology↗

bioRxiv2023

Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila

Methionine restriction (MetR) extends lifespan in various organisms, but its mechanistic understanding remains incomplete. Whether MetR during a specific period of adulthood increases lifespan is not shown. In Drosophila, MetR is reported to extend lifespan only when amino acid levels are low. Here, by using an exome-matched holidic medium, we show that decreasing Met levels to 10% extends Drosophila lifespan with or without decreasing total amino acid levels. MetR during the first four weeks of adult life robustly extends lifespan. MetR induces the expression of Methionine sulfoxide reductase A (MsrA) in young flies, which reduces the oxidatively-damaged Met. MsrA induction is foxo-dependent and persists for two weeks after cessation of the MetR diet. Loss of MsrA attenuates lifespan extension by early-adult MetR. Our study highlights the age-dependency of the organismal response to specific nutrient and suggests that nutrient restriction at a particular period of life is sufficient for healthspan extension.

physiology↗

bioRxiv2023

Recognition of commensal bacterial peptidoglycans defines Drosophila gut homeostasis and lifespan

Commensal microbes in animals have a profound impact on tissue homeostasis, stress resistance, and ageing. We previously showed in Drosophila melanogaster that Acetobacter persici is a member of the gut microbiota that promotes ageing and shortens fly lifespan. However, the molecular mechanism by which this specific bacterial species changes lifespan and physiology remains unclear. The difficulty in studying longevity using gnotobiotic flies is the high risk of contamination during ageing. To overcome this technical challenge, we used a bacteria-conditioned diet enriched with bacterial products and cell wall components. Here, we demonstrate that an A. persici-conditioned diet shortens lifespan and increases intestinal stem cell (ISC) proliferation. Feeding adult flies a diet conditioned with A. persici, but not with Lactiplantibacillus plantarum, can decrease lifespan but increase resistance to paraquat or oral infection of Pseudomonas entomophila, indicating that the bacterium alters the trade-off between lifespan and host defence. A transcriptomic analysis using fly intestine revealed that A. persici preferably induces antimicrobial peptides (AMPs), while L. plantarum upregulates amidase peptidoglycan recognition proteins (PGRPs). The specific induction of these Imd target genes by peptidoglycans from two bacterial species is due to the stimulation of the receptor PGRP-LC in the anterior midgut for AMPs or PGRP-LE from the posterior midgut for amidase PGRPs. Heat-killed A. persici also shortens lifespan and increases ISC proliferation via PGRP-LC, but it is not sufficient to alter the stress resistance. Our study emphasizes the significance of peptidoglycan specificity in determining the gut bacterial impact on healthspan. It also unveils the postbiotic effect of specific gut bacterial species, which turns flies into a "live fast, die young" lifestyle. Author SummaryMicrobiota plays a vital role in our health, but it can also have a negative impact on the lifespan of certain model organisms, such as the fruit fly Drosophila melanogaster. Despite its impact, the molecular mechanism behind how gut bacteria limits host lifespan remains unclear. In this study, we investigated the mechanism that one specific species of microbiota shortens lifespan and disrupts gut homeostasis of the aged flies, using a "fermented" fly diet. We found that the specific effects of this bacterium on fly healthspan were due to its capability of stimulating a specific receptor in the gut that recognizes peptidoglycan, a component of bacterial cell wall. Paradoxically, the same bacterium also increases stress resistance and defence against oral infection of a pathogen. Our study provides insight into the mechanisms underlying how certain members of the microbiota can lead to a "life fast, die young" lifestyle.

immunology↗

bioRxiv2021

The sugar-responsive enteroendocrine neuropeptide F regulates lipid metabolism through glucagon-like and insulin-like hormones in Drosophila melanogaster

The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, Neuropeptide F (NPF), acts as the sugar-responsive, incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.

physiology↗

bioRxiv2021

Activation of innate immune signalling during development predisposes to inflammatory intestine and shortened lifespan

Early-life inflammatory response is associated with risks of age-related pathologies. How transient immune signalling activity during animal development influences life-long fitness is not well understood. Using Drosophila as a model, we find that activation of innate immune pathway IMD signalling in the developing larvae increases adult starvation resistance, decreases food intake, and shortens organismal lifespan. Interestingly, lifespan is shortened by the IMD activation in the larval gut and fat body, while starvation resistance and food intake are altered by that in neurons. The adult flies developed with IMD activation show sustained IMD activity in the gut, despite complete tissue renewal during metamorphosis. The inflammatory adult gut is associated with a greater amount of Gluconobacter sp., characteristic gut microbiota increased in response to immune activation. Removing gut microbiota by antibiotics attenuates the increase of IMD activity and rescues the shortened lifespan. This study demonstrates a tissue-specific programming effect of early-life immune activation on the adult physiology and organismal lifespan.

genetics↗