Biology subjects

Toda, C.

Publications and source records attributed to Toda, C..

7 recordsLinked to original sources

bioRxiv2026

R-spondin 1 restores hypothalamic glucose-sensing and systemic glucose homeostasis via Wnt signaling in diet-induced obese mice

High-fat diet (HFD) feeding disrupts systemic glucose metabolism, yet the underlying neural mechanisms remain incompletely understood. Here, we demonstrate that glucose-excited (GE) neurons in the ventromedial hypothalamus (VMHGE) are essential for acute glucose regulation and that their function is compromised by HFD via structural synaptic remodeling. We found that HFD feeding suppresses canonical Wnt signaling and downregulates R-spondin 1 (RSPO1), a Wnt enhancer, in the VMH. This Wnt inhibition leads to a loss of dendritic spines and blunted glucose-sensing in VMHGE neurons. Conversely, central administration of RSPO1 restores Wnt/{beta}-catenin signaling, promotes synaptogenesis, and recovers neuronal glucose responsiveness. Consequently, RSPO1 treatment ameliorates HFD-induced glucose intolerance by enhancing peripheral glucose utilization. These findings identify the RSPO1-Wnt signaling axis as a critical regulator of VMH neuronal plasticity and metabolic homeostasis, providing a mechanistic link between diet-induced synaptic pathology and systemic metabolic dysfunction. Highlights- Glucose-excited neurons in VMH were labeled with TRAP - VMH glucose-excited neurons regulates systemic glucose metabolism - Wnt signaling regulates synaptogenesis in VMH and maintain neuronal glucose-sensitivity - R-spondin1 recovers VMH neuronal glucose sensitivity in HFD fed obese mice

neuroscience↗

bioRxiv2025

Chronic social defeat causes dysregulation of systemic glucose metabolism via the cerebellar fastigial nucleus

Chronic psychological stress leads to hyperglycemia through the endocrine and sympathetic nervous systems, which contributes to the development of type II diabetes mellitus (T2DM). Higher plasma corticosteroids after stress is one well-established driver of insulin resistance in peripheral tissues. However, previous studies have indicated that only a fraction of patients with depression and post-traumatic disorder (PTSD) who develop T2DM exhibit hypocortisolism, so corticosteroids do not fully explain psychological stress-induced T2DM. Here, we find that chronic social defeat stress (CSDS) in mice enhances gluconeogenesis, which is accompanied by a decrease in plasma insulin, an increase in plasma catecholamines, and a drop in plasma corticosterone levels. We further reveal that these metabolic and endocrinological changes are mediated by the activation of neurons projecting from the cerebellar fastigial nucleus (FN) to the medullary parasolitary nucleus (PSol). These neurons are crucial in shifting the bodys primary energy source from glucose to lipids. Additionally, data from patients with depression reveal correlations between the presence of cerebellar abnormalities and both worsening depressive symptoms and elevated HbA1c levels. These findings highlight a previously unappreciated role of the cerebellum in metabolic regulation and its importance as a potential therapeutic target in depression, PTSD, and similar psychological disorders.

neuroscience↗

bioRxiv2024

Hypothalamic prostaglandins facilitate recovery from hypoglycemia but exacerbate recurrent hypoglycemia in mice

The hypothalamus monitors blood glucose levels and regulates glucose production in the liver. In response to hypoglycemia, glucose-inhibited (GI) neurons trigger counter-regulatory responses (CRRs), which stimulate the release of glucagon, epinephrine, and cortisol to elevate blood glucose. Recurrent hypoglycemia (RH), however, reduces the effectiveness of these CRRs. This study examined the role of hypothalamic prostaglandins in glucose recovery during acute hypoglycemia and RH. Using imaging mass spectrometry and liquid chromatography/mass spectrometry, phospholipid and prostaglandin levels in the hypothalamus of C57BL mice were increased following insulin or 2-deoxy-glucose administration. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), was infused into the ventromedial hypothalamus (VMH) to analyze its effect on glucose production during hypoglycemia, revealing that prostaglandin inhibition decreased glucagon secretion. Additionally, RH-treated mice decreased glucagon release and glucose production during hypoglycemia. Inhibiting prostaglandin production via short-hairpin RNA against cytosolic phospholipase A2 (cPLA2) in the hypothalamus restored CRRs diminished by RH via increasing glucagon sensitivity. These findings suggest that hypothalamic prostaglandins play a critical role in glucose recovery from acute hypoglycemia by activating VMH neurons and are also crucial for the attenuation of CRRs during RH. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/600540v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@9e2cf0org.highwire.dtl.DTLVardef@984c29org.highwire.dtl.DTLVardef@b04e6borg.highwire.dtl.DTLVardef@ec6dd3_HPS_FORMAT_FIGEXP M_FIG C_FIG Article HighlightsO_LIInsulin decreases arachidonic acid-containing phospholipids and increases prostaglandin production in the hypothalamus. C_LIO_LIProstaglandin in the hypothalamus increases glucagon secretion and glucose production during hypoglycemia. C_LIO_LIRecurrent hypoglycemia decreases glucagon secretion and glucose production during hypoglycemia. C_LIO_LIProstaglandin in the hypothalamus during recurrent hypoglycemia decreases glucagon sensitivity and glucose production. C_LI

neuroscience↗

bioRxiv2024

Body temperature regulates glucose metabolism and torpid

Glucose is a significant energy resource for maintaining physiological activities, including body temperature homeostasis, and glucose homeostasis is tightly regulated in mammals. Although ambient temperature tunes glucose metabolism to maintain euthermia, the significance of body temperature in metabolic regulation remains unclear owing to strict thermoregulation. Activation of Qrfp neurons in the preoptic area induced a harmless hypothermic state known as Q-neuron-induced hypothermia and hypometabolism (QIH), which is suitable for studying glucose metabolism under hypothermia. In this study, we first observed that QIH mice had hyperinsulinemia and insulin resistance. This glucose hypometabolic state was abolished by increasing the body temperature to euthermia. Moreover, QIH-mediated inappetence and locomotor inactivity were recovered in euthermia QIH mice. These results indicate that body temperature is considerably more powerful than ambient temperature in regulating glucose metabolism and behavior, and hypometabolism in QIH is secondary to hypothermia rather than modulated by Qrfp neurons. HighlightsO_LIQIH reorganizes glucose homeostasis which is unchanged by fasting. C_LIO_LIQIH mice exhibit glucose hypometabolism with hyperinsuliemia and insulin resistance. C_LIO_LIIncreased body temperature abolishes QIH-mediated hypometabolism and torpid behaviors. C_LIO_LIBody temperature is a strong factor in controlling metabolism and behavior. C_LIO_LIBody temperature-mediated glucose metabolism is reversible. C_LI

physiology↗

bioRxiv2022

Expectation for sweet taste changes peripheral glucose metabolism via basolateral amygdala

Anticipatory physiological responses to food were first reported by Ivan Pavlov a century ago but the associated neural mechanism is still ill-defined. Here, we identified two types of neurons in the basolateral amygdala (BLA), which are activated by sweetener (saccharin) or water after sucrose conditioning, representing expected sweet taste and unmet expectation, respectively. Saccharin-induced met-expectation of sweet taste enhances, while H2O-induced unmet-expectation deteriorates, glucose metabolism in peripheral tissues. Deletion of saccharin-responsive neurons in BLA impaired saccharin-induced increase in insulin sensitivity. Deletion of H2O-responsive neurons in BLA improved glucose intolerance by unmet-expectation. Saccharin- and H2O-responsive neurons had different gene expressions. Our data suggest that the gap between the expected incoming sugar and sweet taste is evaluated by distinct BLA neurons to control peripheral glucose metabolism. One-Sentence SummaryNeurons in the basolateral amygdala control blood glucose levels by comparing anticipated sugar intake and sweet taste

physiology↗

bioRxiv2020

Activation of prodynorphin neurons in the dorsomedial hypothalamus inhibits food intake and promotes positive valence

The regulation of food intake is one of the major research areas in the study of metabolic syndromes such as obesity. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behaviour. However, our understanding of neural function under physiological conditions is still limited. Immediate early genes, such as activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), are useful markers of neuronal activity. Here, we investigated the role of Arc/Arg3.1 gene-expressing neurons in the hypothalamus after refeeding using the targeted recombination in active populations method. We identified refeeding-responsive prodynorphin/cholecystokinin neurons in the dorsomedial hypothalamus that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of these neurons decreased food intake and promoted positive valence. Our findings provide insight into the role of newly identified hedonic neurons in the process of feeding-induced satiety.

physiology↗

bioRxiv2020

Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism

The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induced changes in hypothalamic distribution and amount of phospholipids, especially arachidonic-acid-containing phospholipids, that were then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowered insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding was improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism.

physiology↗