Biology subjects

Ishimoto, T.

Publications and source records attributed to Ishimoto, T..

4 recordsLinked to original sources

bioRxiv2026

Identification of Bone Morphogenetic Protein 7 as a Master Regulator of Gastric Cancer-Associated Cachexia

Cachexia is a devastating and multifactorial syndrome characterized by progressive loss of body weight, skeletal muscle wasting, and systemic inflammation, frequently observed in patients with advanced gastric cancer (GC) with peritoneal dissemination. Despite its clinical significance, the molecular mechanisms underlying cancer-associated cachexia remain poorly understood. In this study, comparative transcriptomic analysis using the GEMINI database identified bone morphogenetic protein 7 (BMP7) as a novel candidate cachexia-inducing factor, along with the known cachexia mediators, growth differentiation factor 11 (GDF11) and growth differentiation factor 15 (GDF15). Functional studies demonstrated that BMP7 acts as an upstream regulator that drives cachectic phenotypes by inducing the expression of GDF11 and GDF15. Knockdown of BMP7, GDF11, or GDF15 in the cachexia-inducing GC cell line, MKN45 significantly attenuated weight loss and muscle wasting in vivo. Conversely, overexpression of BMP7 in the non-cachectic GC cell line, NUGC3 induced cachexia and upregulated GDF11 and GDF15 in tumor tissues. Furthermore, clinical analysis revealed that high BMP7 expression in tumor specimens from patients with advanced GC was associated with significantly poorer overall survival. These findings identify BMP7 as a master regulator of cancer-associated cachexia through the induction of GDF11 and GDF15 and suggest its potential as a promising therapeutic target for mitigating cachexia in GC.

cancer biology↗

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↗

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↗