Biology subjects

Ikeda, T.

Publications and source records attributed to Ikeda, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Maternal progesterone signaling establishes lifelong oral homeostasis

Pregnancy is accompanied by profound endocrine remodeling, yet the mechanisms by which maternal hormonal signals establish long-term tissue homeostasis remain largely unknown. Here we identify maternal progesterone signaling as a developmental cue that establishes lifelong oral homeostasis through a hormone-lipid-microbiome axis. We show that the membrane progesterone receptor mPR{delta} is selectively expressed in the developing and maternal submandibular glands, where it mediates non-genomic progesterone signaling to promote epithelial differentiation by driving the selective mobilization of docosahexaenoic acid (DHA). Loss of this pathway disrupts salivary gland maturation, reshapes the oral microbial ecosystem through the selective expansion of Pasteurellaceae, and causes local inflammation as well as systemic metabolic dysfunction. Mechanistically, antibiotic treatment abolishes these phenotypes, whereas transfer of the oral microbiota recapitulates disease, demonstrating that developmental defects in the host are translated into long-term pathology through the oral microbiome. Remarkably, maternal--but not adult--DHA supplementation restores salivary gland development and microbial homeostasis and prevents adult disease phenotypes, identifying a critical developmental window during which oral homeostasis is durably established. Collectively, these findings reveal a previously unrecognized maternal endocrine mechanism that establishes lifelong host-microbiome homeostasis and identify developmental programming as a fundamental principle linking maternal physiology to adult health. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/743932v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@178cc90org.highwire.dtl.DTLVardef@1be04beorg.highwire.dtl.DTLVardef@29759dorg.highwire.dtl.DTLVardef@1e89994_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2026

Iterative co-creation of harmonized human and non-human primate cellular and structural ontologies and 3D common coordinate frameworks for the basal ganglia

A major goal of the BRAIN Initiative Cell Atlas Network (BICAN) is to create a suite of foundational reference cell atlases and associated standards for human and non-human primate brains. Central to this goal is the creation of cross-species harmonized cellular taxonomies and structural parcellations with formal ontologies that can be mapped into 3D reference frameworks bridging neuroimaging and cellular and histological resolutions. We describe here an iterative approach, focused initially on the basal ganglia, to co-create structural and cellular ontologies in human, macaque and marmoset brains, including a Harmonized Ontology of Mammalian Brain Anatomy (HOMBA), and to map and refine structural parcellations into neuroimaging-based common coordinate frameworks. These references provide the framework for documenting and mapping all experimental sampling in BICAN, allowing analyses of cellular and molecular variation as a function of topographic position, and enabling comparisons of cellular, molecular and neuroimaging-based functional variation within and between primate species. HighlightsO_LIA hierarchical Harmonized Ontology of Mammalian Brain Anatomy (HOMBA) covering 2348 structures C_LIO_LIHOMBA-annotated 3D common coordinate frameworks (CCFs) of the basal ganglia across species C_LIO_LIHistologically informed 3D parcellation/atlas of 280 human subcortical structures indexed by HOMBA C_LIO_LIMapping and integration of structural, cellular and functional data with HOMBA and CCFs C_LI

neuroscience↗

bioRxiv2026

Arabidopsis hydathodes contain a dense and heterogeneous epithem for apoplastic fluid release

Hydathodes are specialized leaf tissues that mediate guttation, the release of liquid water droplets from vascular plants. They consist of xylem endings, water pores, and the epithem. The epithem comprises small cells whose cell types and functional properties remain poorly understood. While molecular genetic information on hydathodes has accumulated--particularly in the model plant Arabidopsis thaliana through recent RNA-seq analyses--high-resolution anatomical insights into their spatial organization remain limited. In this study, we aimed to characterize the specialized anatomy of Arabidopsis hydathodes using complementary imaging approaches. A fluorescent dye taken up from roots stained hydathodes, consistent with a connection between hydathodes and the vasculature. Microfocus-X-ray computed tomography revealed that the hydathodes protrude from the abaxial leaf surface and are more densely packed internally than surrounding tissues. Light microscopy showed that the epithem was heterogeneous, with elongated cells proximally and rounded cells distally. We found that the epithem was surrounded by cells (hereafter referred to as "boundary cells") with plastids that resembled those of mesophyll cells. Transmission electron microscopy showed that the organelles in epithem cells were immature, and the apoplast contained electron-dense material. Finally, using transgenic plants expressing a secreted fluorescent marker protein, we detected GFP in guttation droplets, indicating that the droplets can contain apoplastic material. Together, these findings reveal that Arabidopsis hydathodes possess a dense and spatially heterogeneous epithem associated with the release of apoplastic fluid.

plant biology↗

bioRxiv2026

Food preference is associated with distinct large-scale cortical functional connectivity patterns during food-image observation

Food preference influences behavior toward food-related stimuli, yet the large-scale neural mechanisms underlying this process remain unclear. This study investigated whether preferred and nonpreferred food cues are associated with distinct patterns of cortical functional connectivity during the observation of food images. Data from 25 of the 40 recruited healthy adults were included in the final analysis after excluding individuals with highly unbalanced response tendencies. Participants viewed 150 food images and rated each image on a four-point preference scale. Trials were classified as favorite food (FF) or disliked food (DF). High-density electroencephalography (EEG) was recorded during the task, and source-level ROI-to-ROI functional connectivity was analyzed using amplitude envelope correlation in the alpha (8-13 Hz) and beta (13-25 Hz) frequency bands over the 1000-ms period after food-picture onset. Response time did not differ significantly between FF and DF trials. However, distinct functional connectivity patterns were observed between conditions in both frequency bands. In the alpha band, FF trials involved a network including the cuneus, parietal regions, cingulate regions, and lateral occipital cortex, whereas DF trials involved the isthmus cingulate, caudal middle frontal gyrus, inferior temporal cortex, superior parietal lobule, and lateral occipital cortex. In the beta band, FF trials involved the isthmus cingulate, precuneus, parietal regions, and pericalcarine cortex, whereas DF trials additionally involved frontal regions, including the superior frontal gyrus and pars triangularis. These findings indicate that food preference is associated with distinct large-scale cortical functional connectivity patterns during food image observation, suggesting differential neural processing of preferred and nonpreferred food cues.

neuroscience↗

bioRxiv2026

APOBEC3 antagonism fully explains HIV-1 Vif essentiality under interferon and differentiation conditions

HIV-1 virion infectivity factor (Vif) counteracts APOBEC3 (A3) proteins by targeting them for proteasomal degradation, thereby preventing lethal G-to-A mutations and loss of infectivity. However, Vif also degrades additional cellular proteins, raising the possibility that its essential role in infectious virion production may extend beyond A3 antagonism, particularly under inflammatory or differentiation conditions. Whether such conditions reveal additional essential Vif targets remains unresolved. Here, using interferon (IFN)-stimulated or phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 monocytic cells, we directly addressed this question. Although type I IFN and PMA markedly suppressed viral production through Vif-independent mechanisms, {Delta}Vif viruses produced from stimulated parental cells exhibited severely reduced infectivity. In contrast, disruption of A3A-A3G fully restored {Delta}Vif infectivity to wild-type levels under all conditions tested. G-to-A mutations were attributable exclusively to A3 proteins under both IFN and PMA stimulation, whereas IFN-induced, A3-independent blocks to reverse transcription were not antagonized by Vif. Across diverse HIV-1 strains, the requirement for Vif was strictly dependent on A3 family proteins. These findings demonstrate that the essential role of Vif is fully explained by antagonism of A3-mediated restriction and that evolutionary pressure on Vif is driven predominantly by the need to counteract A3-mediated restriction and mutagenesis. ImportanceA3 proteins are potent intrinsic antiviral factors that restrict HIV-1 by inducing lethal mutations and impairing reverse transcription. The viral protein Vif counteracts A3-mediated restriction, yet it also targets additional host proteins, raising questions about whether its essential role extends beyond A3 antagonism under inflammatory conditions. Myeloid cells mount IFN responses and undergo transcriptional reprogramming upon differentiation, environments in which additional Vif functions could emerge. Using an A3A-A3G-null monocytic cell model, we show that even under IFN stimulation or PMA-induced differentiation, the requirement for Vif in maintaining HIV-1 infectivity is due to A3 proteins. In contrast, Vif does not counteract IFN-induced, A3-independent restriction pathways, highlighting functional specificity. These findings establish the A3-Vif axis as the central determinant of Vif dependency and indicate that evolutionary pressure on Vif is driven predominantly by the need to evade A3-mediated restriction. Targeting Vif may therefore expose HIV-1 to intrinsic inactivation, even in inflammatory environments.

microbiology↗

bioRxiv2025

Altered Motor Gamma Activity and Hemispheric Lateralisation Reflect Perinatal Maturity in Preterm Children during Motor Control

Preterm birth, defined as delivery before 37 weeks of gestation, is associated with differences in neurodevelopment and an increased likelihood of motor challenges that may persist throughout childhood. However, the neurophysiological correlates of these motor differences remain insufficiently understood. Oscillatory activity in the primary motor cortex is closely linked to motor execution, yet motor-related oscillations have rarely been examined in children born preterm. In this cross-sectional observational study, we investigated motor-related gamma oscillations in 5- to 7-year-old children using a child-customised magnetoencephalography system. Nineteen children born full-term and 18 children born preterm of comparable age performed a child-friendly dominant-hand finger movement task. Movement-related gamma activity was quantified from bilateral precentral gyrus regions used as anatomical proxies for the primary motor cortices. The preterm group showed longer mean response times and greater intra-individual response-time variability than the full-term group (P = 0.003 and P = 0.030, respectively). Contralateral gamma power was also lower in the preterm group (full-term: 59.89 {+/-} 28.87%; preterm: 37.97 {+/-} 25.82%; t(35) = 2.43, P = 0.020, Cohen's d = 0.80). A significant Group x Hemisphere interaction (F(1, 35) = 13.36, P < 0.001, partial 2 = 0.276) further indicated differences in the hemispheric organisation of gamma activity between groups. The gamma laterality index was also lower in children born preterm (full-term: 0.24 {+/-} 0.21; preterm: -0.11 {+/-} 0.37; t(26.4) = 3.51, P = 0.002, Cohen's d = 1.17), consistent with reduced contralateral dominance. Across the whole sample, greater contralateral gamma lateralisation was associated with higher scores on the Hand Movements subtest of the Kaufman Assessment Battery for Children ({rho} = 0.40, P = 0.014, false discovery rate-adjusted q = 0.042) and earlier independent walking ({rho} = 0.57, P < 0.001, q = 0.002). The association with independent walking was also observed within the preterm group ({rho} = 0.78, P < 0.001, q = 0.002). These findings suggest that reduced contralateral gamma power and reduced hemispheric lateralisation in children born preterm may reflect differences in the developmental organisation of motor cortical networks. This study provides new insight into motor cortical organisation and its relationship with motor development following preterm birth.

neuroscience↗

bioRxiv2025

Genetic basis of R-phase H:z27 antigen expression and phylogenetic relationships of Salmonella enterica serovar Senftenberg

Salmonella enterica serovar Senftenberg (S. Senftenberg) is one of the most prevalent Salmonella serovars and can be isolated from various animals and humans. According to the White-Kauffmann-Le Minor (WKL) scheme, the antigenic formula of S. Senftenberg is defined as 1,3,19:g,[s],t:-. Although the antigenic formula 1,3,19:z27:- was formerly designated as serovar Simsbury, this name was later removed from the WKL scheme due to reports of interconvertibility between serovars Senftenberg and Simsbury. The H:z27 antigen is currently recognized as one of the R-phase H antigens of S. Senftenberg. To elucidate the genetic basis of H:z27 antigen expression in S. Senftenberg, we determined the whole-genome sequences of isolates expressing the H:z27 antigen. These isolates belonged to sequence type (ST) 185 and harbored a horizontally acquired chromosomal region containing the fljA, fljB, and pinR genes, which are predicted to encode a translational repressor of fliC mRNA, a phase 2 flagellin, and an invertase, respectively. A deletion mutant lacking this region expressed the H:g,s,t antigen instead of H:z27, as confirmed by serotyping and Western blot analysis. Phylogenetic analysis based on S. Senftenberg genome archives, together with the sequences obtained in this study, suggested that the S. Senftenberg ST185 lineage acquired the fljAB-pinR locus around 1867. In contrast, our broader phylogenetic analysis of Salmonella serovars indicated that S. Senftenberg ST14 is genetically closer to certain other serovars than to ST185, while ST185 shows a closer relationship to a different serovar than to ST14. These findings suggest that S. Senftenberg comprises at least two distinct genomic lineages. IMPORTANCELimited information is available on the genetic basis of R-phase H antigen expression in S. enterica. In this study, we first demonstrated that the R-phase H:z27 antigen of S. Senftenberg is determined by a horizontally acquired chromosomal region. The ST 185 lineage of S. Senftenberg appears to have acquired this chromosomal region around 1867 and subsequently disseminated worldwide. We also demonstrated that S. Senftenberg comprises at least two distinct genomic lineages. The combined use of serotyping and multilocus sequence typing may provide a typing framework that better reflects the disease potential of Salmonella.

microbiology↗

bioRxiv2025

Clonal Dynamics in the Male Germline from Development to Next Generation

Germ cells secure the continuity and evolutionary potential of species. Yet how reproductive success is allocated among the founder cells of the mammalian male germline, the primordial germ cells (PGCs), remains unknown. Here, we quantitatively traced individual PGCs, non-invasively barcoded in mouse embryos, across their establishment, lifelong maintenance within the testis, spermatogenesis, and transmission to the next generation. We found that highly skewed clonal contributions arise from a very early stochastic bottleneck during migration to the developing testes and remain stable throughout adult reproductive life. Reproductive success during adulthood was proportional to the embryonically established PGC clone size. Mathematical modeling shows that the patchy compartmentalization of PGC clones within the extended thin seminiferous tubules maintain clonal diversity and safeguard against the expansion of clones that gain a selective advantage. These findings uncover fundamental principles governing the development, stability, and evolutionary transmission of the mammalian germline.

developmental biology↗

bioRxiv2025

Structural insights into YheS-mediated release of SecM-arrested ribosome.

ATPase-binding cassette subfamily F (ABCF) proteins interact with the ribosome to resolve translation defects near the peptidyl-transferase center, induced by ribosome-targeting antibiotics or "hard-to-translate" nascent peptides. In Escherichia coli, four ABCF proteins resolve the translation of distinct problematic sequences, but their molecular mechanisms remain unclear. Here, we present a 2.8-[A] cryo-EM structure of the SecM-stalled ribosome in complex with an ATPase-deficient mutant of YheS, an ABCF protein that releases ribosomes stalled during the translation of SecM, a representative ribosome-arresting peptide. YheS is bound to the E-site and relocates the P-site tRNA (P-tRNA) by displacing its CCA-end. Notably, the density of the SecM nascent chain mostly disappeared upon YheS binding. Molecular dynamics simulations support that the P-tRNA relocation generates a pulling force that disrupts key intratunnel interactions essential for arrest. This mechanism is functionally analogous to, yet mechanistically distinct from, the translocon-mediated external pulling force for SecM release. TeaserThe release mechanism of the SecM-arrested ribosome by the ABCF protein YheS was elucidated by structure-based analyses.

biochemistry↗

bioRxiv2025

Ketone-body receptor GPR109A suppresses hepatic inflammation via gut-liver axis regulation

The ketogenic diet (KD) promotes ketone body synthesis and has been used as an effective treatment for disorders such as epilepsy. Although elevated ketone bodies, including {beta}-hydroxybutyrate ({beta}HB) and acetoacetate, are thought to meditate the beneficial effects of the KD, the mechanisms underlying their metabolic actions remain incompletely understood. In this study, we focused on GPR109A, a receptor for {beta}HB with an unclear role in metabolic homeostasis. We employed KD and fasting models to examine metabolic changes under two distinct ketogenic conditions. Under KD conditions, Gpr109a-/- mice exhibited increased hepatic lipid accumulation, and subsequent hepatic inflammation and fibrosis. However, Gpr109a deletion did not exacerbate hepatic lipid accumulation or inflammation during short-term fasting, suggesting that GPR109A-mediated liver protection is specific to KD-induced metabolic stress rather than under fasting conditions. Mechanistic analysis revealed that GPR109A protects the liver from inflammation by maintaining intestinal barrier integrity. These findings highlight the novel protective mechanism of GPR109A, via the gut-liver axis, to sustain metabolic homeostasis during the KD. This study provides valuable insights into the physiological effects of ketone bodies.

physiology↗

bioRxiv2025

Differential spreading behaviors of Nodal signalling molecules in the extracellular space cooperatively shape left-right asymmetry

Left-right (LR) patterning of vertebrate embryos is mediated by diffusive proteins secreted mainly from the left-right organizer (LRO), such as TGF-{beta} superfamily ligands Nodal and Gdf1, as well as their inhibitors Dand5 and Lefty. However, precise modes of action for these proteins remain unclear due to difficulties in visualizing and manipulating their extracellular behaviors. Here we visualize and manipulate the extracellular dynamics of these proteins employing novel transgenic zebrafish lines and extracellular trapping molecules including the morphotrap. We demonstrate that the heterodimer of Nodal and Gdf1, which is the major signal transducer in vertebrate Nodal signalling, spreads from the LRO through the extracellular space in the paraxial mesoderm (PM) to its target tissue, the lateral plate mesoderm (LPM), in a free-diffusion-like manner. By contrast, Dand5 is highly enriched in the right PM, where it is immobilized through interaction with heparan sulfate proteoglycans and asymmetrically suppresses Nodal signalling. Our study uncovers diverse modes of action for LR-related secreted proteins in the extracellular space, providing a new framework for understanding how spatially organized Nodal signalling molecules shape embryonic LR asymmetry.

developmental biology↗

bioRxiv2025

Lenacapavir binding to immature Gag triggers the emergence of giant HIV-1 virions

Lenacapavir (LEN), a potent capsid inhibitor, suppresses reverse transcription and nuclear import by disrupting capsid core formation in human immunodeficiency virus type 1 (HIV-1). However, its effect on the late-stage viral assembly remains unclear. Although p24 ELISA suggested that LEN inhibited HIV-1, both RT-dPCR and Vpr-HiBiT assays indicated no reduction in the viral output. This discrepancy was attributed to LEN-induced epitope masking of p24, which was reversed by altered sample processing. Furthermore, LEN induced numerous abnormal, discrete clusters of Gag at the plasma membrane. Mass photometry and transmission electron microscopy revealed heterogeneous viral-like particles (LENiVLPs; diameter >200 nm), containing both Gag and Env proteins. Although LENiVLPs retained membrane fusion capability, they were non-infectious owing to post-entry defects. Thus, LEN binds to the precursor Gag and promotes aberrant particle formation, offering novel insights that could guide the development of next-generation LEN-based therapeutics targeting the late stages of the viral life cycle.

microbiology↗

bioRxiv2025

Wakeful targeted memory reactivation during short rest periods modulates motor learning via the lateral orbitofrontal cortex network

This study investigated whether wakeful targeted memory reactivation (TMR) during short rest intervals improves motor learning. Participants were randomly assigned to the following four groups and performed a sequential key-press task under each condition: (1) TMRno group: no auditory stimuli, (2) TMRregular group: auditory cues played at the same speed as the previous task, (3) TMRfast group: auditory cues played 1.3 times faster, and (4) TMRrandom group: auditory cues randomized in pitch. The TMRregular group suppressed early learning gains compared with the TMRno and TMRfastgroups. Electroencephalogram revealed reduced functional connectivity centered on the lateral orbitofrontal cortex (lOFC) in the TMRregular group. In contrast, the TMRfastgroup preserved early learning and exhibited improved lOFC-centered functional connectivity compared with the TMRregulargroup. Therefore, wakeful TMR might either hinder or support motor learning, depending on cue timing and structure, emphasizing the need to optimize sensory parameters for effective learning improvement.

neuroscience↗

bioRxiv2025

A non-spike nucleocapsid R204P mutation in SARS-CoV-2 Omicron XEC enhances inflammation and pathogenicity

The global circulation of SARS-CoV-2 in human populations has driven the emergence of Omicron subvariants, which have become highly diversified through recombination. In late 2024, SARS-CoV-2 Omicron XEC variant emerged from the recombination of two JN.1 progeny, KS.1.1 and KP.3.3, and became predominant worldwide. Here, we investigated virological features of the XEC variant. Epidemic dynamics modeling suggested that spike substitutions in XEC mainly contribute to its increased viral fitness. Additionally, four licensed antivirals were effective against XEC. Although the fusogenicity of XEC spike is comparable to that of the JN.1 spike, the intrinsic pathogenicity of XEC in hamsters was significantly higher than that of JN.1. Notably, we found that the nucleocapsid R204P mutation of XEC enhanced inflammation through NF-{kappa}B activation. Recent studies suggest that the evolutionary potential of spike protein is reaching its limit. Indeed, our findings highlight the critical role of non-spike mutations in the future evolution of SARS-CoV-2.

microbiology↗

bioRxiv2025

HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis

mTORC1 is a central regulator of cell growth that is directly activated by the small GTPase Rheb on the lysosomal membrane in response to growth factors. We recently reported that polyubiquitinated Rheb facilitates its interaction with mTORC1, leading to mTORC1 activation. However, the molecular mechanisms underlying the ubiquitination of Rheb and its interaction with mTORC1 for activation are not fully understood. In this study, we demonstrate that HUWE1, an E3 ubiquitin ligase, preferentially interacts with ubiquitinated Rheb and is essential for the interaction between Rheb and mTOR, as well as for mTORC1 activation. Additionally, HUWE1 is necessary for Rheb to interact with CAD, a crucial enzyme involved in de novo pyrimidine biosynthesis, and for its activation through the mTORC1-S6K1 pathway. Knocking down HUWE1 in cultured cells or in the liver tissues of mice inhibits mTORC1 activity without affecting the phosphorylation of Akt or TSC2, nor does it affect the lysosomal localization of TSC2 or mTORC1. Furthermore, HUWE1 specifically enhances the expression of CAD without influencing other enzymes involved in de novo pyrimidine synthesis and maintains UMP levels in the hepatocytes of liver tissues. These findings indicate that HUWE1 serves as a key organizer of the Rheb ubiquitin complex, amplifying mTORC1 activity and playing a vital role in stimulating de novo pyrimidine synthesis by enhancing CAD expression and activity. HighlightsO_LIHUWE1 and CAD preferentially interact with ubiquitinated Rheb. C_LIO_LIHUWE1 further ubiquitinates Rheb and supports Rheb interaction with mTORC1 and CAD. C_LIO_LIHUWE1 stimulates mTORC1 activity through its E3 ligase activity. C_LIO_LIHUWE1 also supports pyrimidine synthesis by enhancing CAD expression. C_LI

biochemistry↗

bioRxiv2025

β-III tubulin identifies anti-fibrotic state of pericytes in pulmonary fibrosis

Pericytes have been implicated in pulmonary fibrosis, yet their activated cellular states and functional roles remain largely unclear. Here, we identified {beta}-III tubulin (Tuj1) as a distinctive marker for fibrosis-associated lung pericytes. Most pericytes in fibrotic regions are Tuj1-positive and interact uniquely with multiple endothelial cells, localizing near collagen-producing fibroblasts and pro-fibrotic SPP1+/arginase+ macrophages. Tuj1 expression is predominantly induced in pericytes during the fibrotic phase, and Tuj1 gene (Tubb3) knockout in mice exacerbates lung fibrosis, accompanied by an increase in the neighboring pro-fibrotic fibroblasts and macrophages, suggesting an anti-fibrotic role for Tuj1-expressing pericytes. Mechanistically, the anti-fibrotic chemokine CXCL10 is upregulated in Tuj1-expressing pericytes, whereas this upregulation is not observed in Tubb3 knockout. Moreover, CXCL10 inhibits the pro-fibrotic differentiation of macrophages induced by lung fibroblasts in culture, implying that CXCL10 may mediate the anti-fibrotic effects of Tuj1-expressing pericytes. These findings underscore the role of lung pericytes in negatively regulating fibrotic process and their potential as therapeutic targets for pulmonary fibrosis patients. SummaryIn response to fibrotic stimuli, lung pericytes upregulate {beta}-III tubulin (Tuj1) expression, adopting an anti-fibrotic phenotype. This phenotype acts as a negative immune regulator of pro-fibrotic macrophage differentiation by releasing CXCL10, thereby counteracting the progression of pulmonary fibrosis.

pathology↗

bioRxiv2025

Hexanoic acid improves metabolic health in mice fed high-fat diet.

BackgroundOverweight and obesity is currently a worldwide problem with undesirable health consequences such as type 2 diabetes. Therefore, much attention has been paid to preventing obesity through diet. Free fatty acids (FFAs) are an important energy source, and they also serve as signaling molecules in many biological processes leading to an increased energy expenditure and insulin secretion. Short-chain fatty acids (SCFAs) such as acetic, propionic and butyric acid are the bioactive metabolites produced by gut microbes, and their beneficial effects on host metabolism are well-studied. In addition, medium-chain fatty acids (MCFAs) such as octanoic and decanoic acid also play a positive role in regulating lipid and glucose metabolisms. However, the effects of hexanoic acid on metabolism are poorly understood. Therefore, this study investigated the role of hexanoic acid on lipid and glucose metabolism in mice. MethodsMale C57BL/6J mice were fed normal chow diet, high-fat diet (HFD), HFD-containing 5% butyric acid or HFD-containing 5% hexanoic acid for 4 weeks, and the effects of hexanoic acid on lipid and glucose metabolism were examined. ResultsButyric acid and hexanoic acid prevented body weight gain and fat accumulation in white adipose tissues under HFD-feeding. In addition, both FFAs suppressed the elevated plasma levels of non-esterified fatty acid (NEFA) and hepatic triglyceride content induced by HFD. The expression levels of genes involved in fatty acid biosynthesis were decreased in white adipose tissues by oral supplementation of butyric acid or hexanoic acid. Mice fed HFD also exhibited hyperglycemia and hyperinsulinemia, and these impaired glucose metabolisms improved by hexanoic acid. Hexanoic acid increased the expression levels of genes associated with gluconeogenesis, and improved insulin sensitivity in mice fed HFD. ConclusionsThis study highlights the importance of hexanoic acid in improvement of lipid and glucose metabolisms. Thus, our findings provide insight into the development of functional foods which prevent obesity-related disease such as type 2 diabetes.

physiology↗

bioRxiv2025

The pivotal role of a novel free fatty acid receptor GPR164 in the intestinal barrier function

GPR164 is a novel free fatty acid receptor, activated by both short-chain fatty acids and medium-chain fatty acids, and expressed throughout the gastrointestinal tract. Although GPR164 is reported to be involved in the release of gut hormones, the physiological functions of this receptor in the maintenance of intestinal homeostasis remain unclear. In this study, we explored the role of GPR164 in regulating intestinal barrier function using mice lacking Gpr164 gene (Gpr164-/-). A loss-of-function mutation in GPR164 promoted cell proliferation and disrupted the intestinal barrier function in both Caco-2 cell line and mice. Genome-wide RNA-seq analysis revealed that GPR164 deletion caused aberrant wnt/{beta}-catenin signaling, and the intraperitoneal injection of wnt/{beta}-catenin inhibitor ameliorated a series of abnormalities of Gpr164-/- mice. Gpr164-/- mice also exhibited gut microbial dysbiosis and severe inflammation, indicating that deletion of Gpr164 causes similar pathologies observed in patients with inflammation bowel disease (IBD). Thus, our findings uncover the pivotal role of GPR164 in the maintenance of intestinal barrier function, providing an attractive clinical target for IBD.

physiology↗