Biology subjects

Abe, C.

Publications and source records attributed to Abe, C..

7 recordsLinked to original sources

bioRxiv2026

Chronic elevation of 1.25(OH)2D enhances cholesterol excretion through coordinated regulation of hepatic and intestinal elimination pathways

Cholesterol elimination in mammals depends largely on the biliary secretion of cholesterol and its conversion to bile acids, followed by their fecal loss. Human studies suggest an association between blood vitamin D levels and blood cholesterol; however, the mechanistic impact of sustained elevation of 1,25(OH)2D3 (active vitamin D) on cholesterol flux remains unclear. Here, we used two complementary mouse models, a genetic model with chronically elevated plasma 1,25(OH)2D3 (a klotho KO mice) and a pharmacological model of repeated 1,25(OH)2D3 administration in wild type mice, to define the mechanism by which 1.25(OH)2D3 regulates the hepatic intestinal programs controlling cholesterol elimination. a klotho KO mice showed increased fecal excretion of both cholesterol and total bile acids. Hepatically, Sr-b1, Abcg5/Abcg8, Abca1, Cyp7a1, and Mrp2 transcriptions were increased, whereas Cyp27a1 and Bsep was unchanged. Duodenal Npc1l1 was reduced, and ileal Asbt showed a decreasing trend. In the administration model, fecal bile acid levels increased by day 3, consistent with the induction of hepatic Mrp2 expression from day 3. Bsep exhibited a biphasic change, enhanced at early phase and downregulated to basal levels later and Asbt was unchanged. Increased fecal cholesterol emerged later (day 15), accompanied by late-phase induction of Abcg5/Abcg8 and suppression of Npc1l1. Together, we propose that sustained elevation of 1.25(OH)2D3 is associated with coordinated hepatic and intestinal transcriptional remodeling that promotes cholesterol disposal, with an early increase in fecal bile acid loss preceding the enhanced fecal cholesterol excretion.

biochemistry↗

bioRxiv2026

Gut-derived GLP-1 released by rare sugar D-allulose cooperates with insulin to activate left-sided vagal afferents and enhance insulin sensitivity

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear, largely because of its limited access to pancreatic {beta} cells. Here, we show that D-allulose-induced intestinal GLP-1 secretion (AIGS) cooperates with insulin to reduce blood glucose levels by enhancing insulin action, rather than insulin secretion, in male mice. This cooperation and remote signaling require left-sided vagal afferents forming the common hepatic branch, but not right-sided afferents. AIGS-enhanced insulin action required both GLP-1 receptors and insulin receptor substrate 2 in these neurons. Remarkably, AIGS improved insulin resistance and hyperglycemia more rapidly and potently than the GLP-1RA exendin-4. These findings reveal that a subclass of vagal afferent neurons synergistically activated by endogenous intestinal GLP-1 and insulin does not stimulate insulin secretion but augments insulin action to improve glucose tolerance. This novel extra-pancreatic GLP-1 action mediated by vagal afferents provides a promising basis for innovative type 2 diabetes therapies. ARTICLE HIGHLIGHTO_LICompared with GLP-1 receptor agonists, the physiological roles and mechanisms of endogenous, short-lived GLP-1 in glucose metabolism remain poorly understood. C_LIO_LIWe utilized the rare sugar D-allulose, a noncaloric GLP-1 secretagogue, as a tool to elucidate the physiological actions of endogenous GLP-1. C_LIO_LID-allulose-induced intestinal GLP-1 release cooperates with insulin to activate left-sided vagal afferents, enhancing insulin action rather than insulin secretion and thereby regulating glycemic control. C_LIO_LIBecause this acute mechanism improved hyperglycemia in type 2 diabetes more effectively than GLP-1 receptor agonists, targeting GLP-1/insulin-vagal signaling may inform novel therapies and dietary or nutritional interventions for T2DM. C_LI

physiology↗

bioRxiv2025

Lateralized vagal oxytocin signaling separately controls feeding and socioemotional functions via hypothalamic oxytocin signaling

Oxytocin neurons in the paraventricular hypothalamus (PVHOxt) regulate feeding, anxiety, and social behaviors. Activation of Oxt receptor (Oxtr) -expressing vagal sensory neurons engages these PVHOxt neurons and improves hyperphagic obesity; however, their roles in anxiety and sociability remain unclear. Here, we activated vagal Oxtr-expressing neurons in male mice using a single intraperitoneal (IP) Oxt injection or chemogenetics. IP Oxt reduced anxiety-like behavior, enhanced social interaction, and suppressed feeding while activating both vagal sensory neurons and PVHOxt neurons. These effects were abolished by chemogenetic inhibition of PVHOxt neurons or central Oxtr blockade. Subdiaphragmatic vagotomy revealed lateralized functions: right-side vagotomy eliminated anxiolytic and prosocial effects, whereas left-side vagotomy blocked feeding suppression. Consistently, chemogenetic activation of left-sided neurons suppressed feeding, while right-sided activation reduced anxiety and increased sociability. These findings identify Oxtr-expressing vagal sensory neurons as a major peripheral pathway in which left- and right-sided inputs differentially control feeding and socioemotional behaviors.

physiology↗

bioRxiv2024

The cochlear hook region detects harmonics beyond the canonical hearing range

Ultrasound, or sound at frequencies exceeding the conventional range of human hearing, is not only audible to mice, microbats, and dolphins, but also creates an auditory sensation when delivered through bone conduction in humans. Although ultrasound is utilized for brain activation and in hearing aids, the physiological mechanism of ultrasonic hearing remains unknown. In guinea pigs, we found that ultrasound above the hearing range delivered through ossicles of the middle ear evokes an auditory brainstem response and a mechano-electrical transduction current through hair cells, as shown by the local field potential called the cochlear microphonic potential (CM). The CM synchronizes with ultrasound, and like the response to audible sounds is actively and nonlinearly amplified. In vivo optical nano-vibration analysis revealed that the sensory epithelium in the hook region, the basal extreme of the cochlear turns, resonates in response both to ultrasound within the hearing range and to harmonics beyond the hearing range. The results indicate that hair cells can respond to stimulation at the optimal frequency and its harmonics, and the hook region detects ultrasound stimuli with frequencies more than two octaves higher than the upper limit of the ordinary hearing range.

physiology↗

bioRxiv2023

MPL36, a major plasminogen (PLG) receptor in pathogenic Leptospira, has an essential role during infection

Leptospirosis, a zoonosis with worldwide distribution, is caused by pathogenic spirochetes belonging to the genus Leptospira. Bacterial outer membrane proteins (OMPs), particularly those with surface-exposed regions, play crucial roles in pathogen dissemination and virulence mechanisms. Here we characterized the leptospiral Membrane Protein L36 (MPL36), a rare lipoprotein A (RlpA) homolog with a C-terminal Sporulation related (SPOR) domain, as an important virulence factor in pathogenic Leptospira. Our results showed that MPL36 is surface exposed and expressed during infection. Recombinant MPL36 (rMPL36) showed high plasminogen (PLG)-binding ability determined by lysine residues of the C-terminal region of the protein, with ability to convert bound-PLG to active plasmin. Using Kochs molecular postulates, we determined that a mutant of mpl36 has a reduced PLG-binding ability, leading to a decreased capacity to adhere and translocate MDCK cell monolayers. Using recombinant protein and mutant strains, we determined that the MPL36-bound plasmin (PLA) can degrade fibrinogen. Finally, our mpl36 mutant had a significant attenuated phenotype in the hamster model for acute leptospirosis. Our data indicates that MPL36 is the major PLG binding protein in pathogenic Leptospira, and crucial to the pathogens ability to attach and interact with host tissues during infection. The MPL36 characterization contributes to the expanding field of bacterial pathogens that explore PLG for their virulence, advancing the goal to close the knowledge gap regarding leptospiral pathogenesis while offering a novel potential candidate to improve diagnostic and prevention of this important zoonotic neglected disease. Author SummaryAs part of their diverse virulence machinery, bacterial pathogens bind to human plasminogen (PLG) providing them with a proteolytic platform that promotes invasiveness, dissemination, and virulence. Leptospirosis is the leading zoonotic disease in morbidity and mortality worldwide. The burden of this neglected disease will continue to raise given the effects of climate change and social inequality, important drivers of disease. Furthermore, the gap of knowledge regarding leptospiral pathogenesis has negatively impacted the development of sensitive diagnostic tools and effective prevention methods. Previous studies have shown that pathogenic Leptospira, the causative agent of leptospirosis, can interact with PLG through different protein candidates. In this work, we characterized one of those candidates, Membrane Protein L36 (MPL36), as the main leptospiral plasminogen binding protein. Using genetically modified mutants, in vivo, and in vitro assays we provided evidence that MPL36 can bound PLG, promotes adherence to host cells and subsequent translocation, and degrades fibrinogen by converting bound-PLG to PLA, thus essential to leptospiral virulence. This work contributes to the growing field of bacterial pathogens exploring PLG to increase their virulence, while highlighting important new knowledge on leptospiral pathogenesis. MPL36 is an important candidate to be explored on the continued effort to improve diagnostic and prevention of this important zoonotic disease.

microbiology↗

bioRxiv2020

Stock market fluctuations impact the emotional brain on a population level.

The stock market is a bellwether of socio-economic changes that may directly affect individual well-being. Using large-scale UK-biobank data generated over 14 years, we applied specification curve analysis to rigorously identify significant associations between the local stock market index (FTSE100) and 479,791 UK residents mood, as well as their alcohol intake and blood pressure adjusting the results for a large number of potential confounders, including age, sex, linear and non-linear effects of time, research site, other stock market indexes. Furthermore, we found similar associations between FTSE100 and volumetric measures of affective brain regions in a subsample (n=39,755; measurements performed over 5.5 years), which were particularly strong around phase transitions characterized by maximum volatility in the market. The main findings did not depend on applied effect-size estimation criteria (linear methods or mutual information criterion) and were replicated in two independent US-based studies (Parkinsons Progression Markers Initiative; n=424; performed over 2,5 years and MyConnectome; n=1; 81 measurements over 1,5 years). Our results suggest that phase transitions in the society, indexed by stock market, exhibit close relationships with human mood, health and the affective brain from an individual to population level.

neuroscience↗

bioRxiv2017

Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.\n\nSignificance StatementLeft-right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population, and how biological factors such as age, sex and genetic variation affect these asymmetries. Here we describe by far the largest ever study of cerebral cortical brain asymmetry, based on data from 17,141 participants. We found a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an on-line resource that will serve future studies of human brain anatomy in health and disease.

neuroscience↗