Biology subjects

Tanida, M.

Publications and source records attributed to Tanida, M..

3 recordsLinked to original sources

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

A vagal sensory--hypothalamic oxytocin--brown adipose tissue pathway mediates cholecystokinin-induced thermogenesis

Thermoregulation is essential for survival in homeothermic animals. Vagal sensory nerves are well known to detect visceral signals and regulate physiological functions, including feeding, metabolism and immunity. However, their role in thermoregulation remains poorly understood. Cholecystokinin (CCK), a gut hormone released postprandially, activates vagal sensory nerves via CCK-A receptors (CCK-AR). Exogenous CCK has been reported to induce thermogenesis in the intrascapular brown adipose tissue (iBAT), but the involvement of vagal sensory nerves and the central neural mechanisms that mediate this effect are not fully understood. In this study, we assessed the thermogenic effect of intraperitoneally (I.P.) administered CCK-8 and investigated the underlying autonomic reflex pathways. I.P. CCK-8 transiently and dose-dependently increased rectal temperature. This response was significantly attenuated by pharmacological blockade of CCK-AR, subdiaphragmatic vagotomy, or knockdown of CCK-AR primarily targeting in vagal sensory neurons. In addition, CCK-8 activated sympathetic nerve activity via vagal afferents. CCK-8-induced thermogenesis was blunted by iBAT sympathectomy or {beta}3-adrenergic receptor blockade. Furthermore, I.P. CCK-8 activated oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVHOXT). Chemogenetic inhibition of PVHOXT neurons or intracerebroventricular administration of an oxytocin receptor (OXTR) antagonist attenuated the thermogenic response. These findings demonstrate, for the first time, the full neural circuitry underlying CCK-induced thermogenesis by delineating its afferent input (CCK-AR-expressing vagal sensory neurons), central integrative hub (PVHOXT neurons and OXTR signaling), and efferent output (iBAT sympathetic nerves). This study further suggests that CCK-AR -expressing vagal sensory neurons may contribute to thermoregulation under physiological conditions in which CCK is endogenously released. Key points summaryO_LIVagal sensory nerves, which connect the gut and the brain, play a key role in regulating meal-related physiology, however their role in thermoregulation remains incompletely understood. C_LIO_LIThis study reveals for the first time the full autonomic reflex pathways underlying thermogenic effect of the gut hormone cholecystokinin (CCK), comprising afferent input (CCK-A receptor-expressing vagal afferents), a central integrative hub (oxytocin neurons in the hypothalamic paraventricular nucleus; PVHOXT neurons), and efferent output (intrascapular brown adipose tissue via sympathetic nerves). C_LIO_LIBoth CCK-A receptors-expressing vagal afferents and sympathetic nerves innervating brown adipose tissue are required for thermogenesis induced by exogenous CCK-8. C_LIO_LIActivation of PVHOXT neurons by CCK-8 is critically involved in mediating this thermogenic effect. C_LIO_LIThis newly identified gut-brain-fat axis may contribute to part of diet-induced thermogenesis, and its impairment could be involved in the development of metabolic disorders such as obesity. C_LI

physiology↗

bioRxiv2019

Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of spontaneous SR Ca2+ release

Early afterdepolarization (EAD) is known to cause lethal ventricular arrhythmias in long QT syndrome (LQTS). In this study, dynamical mechanisms of EAD formation in human ventricular myocytes (HVMs) were investigated using the mathematical model developed by ten Tusscher & Panfilov (Am J Physiol Heart Circ Physiol, 2006). We explored how the rapid (IKr) and slow (IKs) components of delayed-rectifier K+ channel currents, L-type Ca2+ channel current (ICaL), Na+/Ca2+ exchanger current (INCX), and intracellular Ca2+ handling via the sarcoplasmic reticulum (SR) contribute to initiation, termination and modulation of phase-2 EADs during pacing in relation to bifurcation phenomena in non-paced model cells. Dynamical behaviors of the non-paced model cell were determined by calculating stabilities of equilibrium points (EPs) and limit cycles, and bifurcation points. EADs during pacing were reproduced by numerical simulations. Results are summarized as follows: 1) A modified version of the ten Tusscher-Panfilov model with accelerated ICaL inactivation could reproduce bradycardia-related EADs and {beta}-adrenergic stimulation-induced EADs in LQTS. 2) Two types of EADs with different initiation mechanisms, ICaL reactivation-dependent and spontaneous SR Ca2+ release-mediated EADs, were detected. 3) Spontaneous SR Ca2+ releases occurred at higher Ca2+ uptake rates, attributable to the instability of steady-state intracellular Ca2+ concentrations. Dynamical mechanisms of EAD formation and termination in the paced model cell are closely related to stability changes (bifurcations) in dynamical behaviors of the non-paced model cell, but they are model-dependent. Nevertheless, the modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of EAD-related arrhythmias in LQTS.\n\nKey pointsO_LIWe investigated dynamical mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of the human ventricular myocyte model developed by ten Tusscher and Panfilov.\nC_LIO_LIA modified version of ten Tusscher-Panfilov model with accelerated inactivation of the L-type Ca2+ channel current could reproduce phase-2 EADs in long QT syndrome type 1 and 2 cardiomyocytes.\nC_LIO_LIDynamical mechanisms of EAD formation in the paced model cell are closely related to stability and bifurcations of the non-paced model cell.\nC_LIO_LIEAD mechanisms in the modified ten Tusscher-Panfilov model are different from those in other human ventricular myocyte models in the following respects: 1) EAD formation is partially attributable to spontaneous sarcoplasmic reticulum Ca2+ releases; and 2) EAD termination (action potential repolarization) during pacing requires the slowly-activating delayed-rectifier K+ channel current.\nC_LIO_LIThe modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of initiation and termination of EAD-related arrhythmias in LQTS.\nC_LI

physiology↗