hashiuchi/published_papers/54315391 Kunio Kondoh Emi Hashiuchi Yuka Inaba Hiroshi Inoue Serika Yamada Kazunari Miyamichi Yuki Yoshimura Ken-Ichiro Nakajima Takeshi Y Hiyama Yasuhiko Minokoshi Nos1 neurons in the paraventricular hypothalamic area modulate lipid metabolism via the sympathetic nervous system in male mice. The selection of the appropriate energy substrate under different physiological conditions is a key aspect of the energy metabolism homeostasis. We here show that Nos1 (nitric oxide synthase 1)-expressing cells in the paraventricular hypothalamic nucleus (PVH) serve as a pivotal node for controlling whole-body fat consumption in male mice. Nos1 neurons account for ~30% of PVH neurons that convey signals via polysynaptic pathways to individual peripheral tissues, including skeletal muscle and brown (BAT) and white (WAT) adipose tissues. Activation of these Nos1 neurons in the PVH area induces WAT lipolysis and fat oxidation in other peripheral tissues via the sympathetic nervous system, thereby increasing whole-body fat consumption. Inhibition of these neurons abolishes the increase in fat consumption during the light period, whereas long-term silencing lead to obesity independent of energy intake. These neurons are also necessary for cold-induced thermogenesis in BAT and the rapid increase in fat consumption elicited by food deprivation or other stressors. Nos1 neurons in the PVH area are therefore essential for controlling fat consumption and energy homeostasis. Nature communications null null 20260629 10.1038/s41467-026-74362-9 42373618 hashiuchi/published_papers/54136558 Emi Hashiuchi Yuka Inaba Hikaru Sugimoto Kumi Kimura Hitoshi Watanabe Mayu Kajino Shun-Ichiro Asahara Masaki Kobayashi Osamu Kikuchi Yoshitaka Hayashi Shin-Ichi Horike Takiko Daikoku Michihiro Mieda Takeshi Sakurai Mashito Sakai Michihiro Matsumoto Tadahiro Kitamura Makoto Sato Kim Ravnskjaer Masato Kasuga Mamoru Tanida Shinya Kuroda Hiroshi Inoue Vagal activation inhibits insulin release through neuronal nitric oxide synthase in obese male mice. The vagus nerve connects the brain and pancreas and enhances postprandial endocrine secretion from the pancreas through cholinergic signaling, such as increasing insulin release immediately after food intake in the cephalic-phase insulin response (CPIR). Here, we investigated how obesity affects vagal regulation of pancreatic endocrine function using designer receptors exclusively activated by designer drugs (DREADDs) to manipulate vagal activity. As expected, the plasma concentration of insulin was increased by vagal activation in mice expressing the excitatory DREADD hM3Dq (M3 mice) and decreased by vagal inactivation in mice expressing inhibitory DREADD hM4Di (M4 mice). However, vagal activation in M3 mice with diet-induced obesity did not elicit an early increase in insulin and instead produced a delayed insulin decrease. Mathematical modeling showed that plasma insulin dynamics in these mice were best explained by a model incorporating both the insulin-increasing and insulin-decreasing effects of the vagus nerve. Furthermore, the insulin-decreasing effect was mediated by nitric oxide (NO)-dependent, noncholinergic signaling and was enhanced in obesity. In obese M3 mice, vagal deficiency of neuronal NO synthase (nNOS) abolished the insulin-decreasing effect and restored insulin release after vagal activation. Vagal nNOS deficiency also enhanced insulin release after voluntary feeding, consistent with the CPIR. These findings suggest that vagal NO action inhibits postprandial insulin release, particularly in obesity. Science signaling 19 939 eadz8805 null 20260526 10.1126/scisignal.adz8805 42189938 hashiuchi/published_papers/49000100 Akinori Taniguchi Hitoshi Watanabe Kumi Kimura Emi Hashiuchi Nami Ohashi Hirofumi Sato Mashito Sakai Michihiro Matsumoto Shun-Ichiro Asahara Hiroshi Inoue Yuka Inaba Proline enhances the hepatic induction of lipogenic gene expression in male hepatic fasn reporter mice. Hepatic de novo lipogenesis (DNL) is increased by both carbohydrate intake and protein consumption. In hepatic fat synthesis, a key role is played by the induction of the hepatic expression of lipogenic genes, including Fasn, Scd1, and Srebf1. Regarding carbohydrate intake, increased blood glucose and insulin levels promote the expression of hepatic lipogenic genes. However, although amino acids serve as a carbon source for hepatic DNL during protein consumption, their effects on hepatic lipogenic gene expression remain unclear. We investigated the effects of amino acids on hepatic lipogenic gene induction using primary cultured mouse hepatocytes and hepatic Fasn reporter (l-FasnGLuc) mice. In primary cultured hepatocytes, lipogenic gene expression (Fasn, Scd1, Srebf1) was induced under postprandial-mimicking conditions (treatment with insulin and LXR agonist). When hepatocytes were stimulated with an amino acid mixture containing 20 amino acids, the induction of lipogenic gene expression was enhanced, but this effect disappeared when proline was removed from the mixture. Furthermore, when each amino acid was tested individually, only proline potentiated the induction of lipogenic gene expression in hepatocytes under postprandial-mimicking conditions. In mouse liver, continuous proline infusion via osmotic pump increased Fasn gene expression and showed a trend toward increased Srebf1 expression. In l-FasnGLuc mice, continuous proline infusion resulted in sustained enhancement of hepatic Fasn transcription, measured by secreted luciferase activity. These results demonstrate that proline enhances the induction of hepatic lipogenic gene expression both in vitro and in vivo. Biochemical and biophysical research communications 747 151314 151314 20250202 10.1016/j.bbrc.2025.151314 39799864 hashiuchi/published_papers/44016735 Yuka Inaba Emi Hashiuchi Hitoshi Watanabe Kumi Kimura Yu Oshima Kohsuke Tsuchiya Shin Murai Chiaki Takahashi Michihiro Matsumoto Shigetaka Kitajima Yasuhiko Yamamoto Masao Honda Shun-ichiro Asahara Kim Ravnskjaer Shin-ichi Horike Shuichi Kaneko Masato Kasuga Hiroyasu Nakano Kenichi Harada Hiroshi Inoue The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice Abstract Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis. In severe hepatic steatosis, after partial hepatectomy, hepatic ATF3-deficient or -overexpressing mice display decreased or increased RIPK3 expression and necroptosis, respectively. In cultured hepatocytes, ATF3 changes TNFα-dependent cell death mode from apoptosis to necroptosis, as revealed by live-cell imaging. In non-alcoholic steatohepatitis (NASH) mice, hepatic ATF3 deficiency suppresses RIPK3 expression and hepatocellular death. In human NASH, hepatocellular damage is correlated with the frequency of hepatocytes expressing ATF3 or RIPK3, which overlap frequently. ATF3-dependent RIPK3 induction, causing a modal shift of hepatocellular death, can be a therapeutic target for steatosis-induced liver damage, including NASH. Springer Science and Business Media LLC Nature Communications 2041-1723 14 1 null null 20230123 10.1038/s41467-023-35804-w hashiuchi/published_papers/44016736 Emi Hashiuchi Hitoshi Watanabe Kumi Kimura Michihiro Matsumoto Hiroshi Inoue Yuka Inaba Diet intake control is indispensable for the gluconeogenic response to sodium–glucose cotransporter 2 inhibition in male mice Abstract Aims/Introduction Sodium–glucose cotransporter 2 inhibitor (SGLT2i) lowers blood glucose and causes a whole‐body energy deficit by boosting renal glucose excretion, thus affecting glucose and energy metabolism. This energy deficit not only decreases bodyweight, but also increases food intake. This food intake increase offsets the SGLT2i‐induced bodyweight decrease, but the effect of the food intake increase on the SGLT2i regulation of glucose metabolism remains unclear. Materials and Methods We administered SGLT2i (luseogliflozin) for 4 weeks to hepatic gluconeogenic enzyme gene G6pc reporter mice with/without obesity, which were either fed freely or under a 3‐hourly dietary regimen. The effect of feeding condition on the gluconeogenic response to SGLT2i was evaluated by plasma Gaussia luciferase activity, an index of the hepatic gluconeogenic response, in G6pc reporter mice. Energy expenditure was measured by indirect calorimetry. Results In the lean mice under controlled feeding, SGLT2i decreased bodyweight and plasma glucose, and increased the hepatic gluconeogenic response while decreasing blood insulin. SGLT2i also increased oxygen consumption under controlled feeding. However, free feeding negated all of these effects of SGLT2i. In the obese mice, SGLT2i decreased bodyweight, blood glucose and plasma insulin, ameliorated the upregulated hepatic gluconeogenic response, and increased oxygen consumption under controlled feeding. Under free feeding, although blood glucose was decreased and plasma insulin tended to decrease, the effects of SGLT2i – decreased bodyweight, alleviation of the hepatic gluconeogenic response and increased oxygen consumption – were absent. Conclusions Food intake management is crucial for SGLT2i to affect glucose and energy metabolism during type 2 diabetes treatment. Wiley Journal of Diabetes Investigation 2040-1124 12 1 35 47 20200723 10.1111/jdi.13319 hashiuchi/published_papers/44016745 Tetsuhiro Horie Gyujin Park Yuka Inaba Emi Hashiuchi Takashi Iezaki Kazuya Tokumura Kazuya Fukasawa Takanori Yamada Manami Hiraiwa Yuka Kitaguchi Hikari Kamada Katsuyuki Kaneda Tomohiro Tanaka Hiroshi Inoue Eiichi Hinoi MAPK Erk5 in Leptin Receptor‒Expressing Neurons Controls Body Weight and Systemic Energy Homeostasis in Female Mice Abstract Extracellular signal-regulated kinase 5 (Erk5), a member of the MAPK family, is specifically phosphorylated and activated by MAPK/Erk kinase-5. Although it has been implicated in odor discrimination and long-term memory via its expression in the central nervous system, little is known regarding the physiological importance of neuronal Erk5 in body weight and energy homeostasis. In the current study, systemic insulin injection significantly induced phosphorylation of Erk5 in the hypothalamus. Moreover, Erk5 deficiency in leptin receptor (LepR)‒expressing neurons led to an obesity phenotype, with increased white adipose tissue mass due to increased adipocyte size, only in female mice fed a normal chow diet. Furthermore, Erk5 deficiency in LepR-expressing neurons showed impaired glucose tolerance along with decreased physical activity, food intake, and energy expenditure. These results suggest that Erk5 controls body weight and systemic energy homeostasis probably via its expression in hypothalamic neurons in female mice, thereby providing a target for metabolic diseases such as obesity and type 2 diabetes mellitus. The Endocrine Society Endocrinology 1945-7170 160 12 2837 2848 20190925 10.1210/en.2019-00090 hashiuchi/published_papers/44016740 Yuka Inaba Emi Hashiuchi Hitoshi Watanabe Kumi Kimura Makoto Sato Masaki Kobayashi Michihiro Matsumoto Tadahiro Kitamura Masato Kasuga Hiroshi Inoue Hepatic Gluconeogenic Response to Single and Long-Term SGLT2 Inhibition in Lean/Obese Male Hepatic G6pc-Reporter Mice Abstract Sodium-glucose cotransporter 2 inhibitor (SGLT2i) consistently reduces blood glucose levels in type 2 diabetes mellitus but increases hepatic gluconeogenic gene expression and glucose production, offsetting its glucose-lowering effect. This study aimed to elucidate the effect of SGLT2i on hepatic gluconeogenic response and its mechanism in both insulin-sensitive and insulin-resistant states. A hepatic mouse model was generated to show liver-specific expression of Gaussia luciferase (GLuc) driven by the gluconeogenic enzyme gene G6pc promoter. Hepatic gluconeogenic response was evaluated by measuring plasma GLuc activity. SGLT2i was given to lean and obese mice in single gavage administration or 4-week dietary administration with controlled feeding every 3 hours. In lean mice, single-dose SGLT2i increased plasma GLuc activity from 2 hours after administration, decreasing blood glucose and plasma insulin from 1 to 2 hours after administration. In obese mice, which had higher plasma GLuc activity than lean ones, SGLT2i did not further increase GLuc activity despite decreased blood glucose and plasma insulin. Hepatic Akt and GSK3β phosphorylation was attenuated by single-dose SGLT2i in lean mice in accordance with the plasma insulin decrease, but not in obese mice. Long-term SGLT2i administration, which increased plasma GLuc activity in lean mice, decreased it in obese mice from 3 weeks after initiation, with increased hepatic Akt and GSK3β phosphorylation. In conclusion, single SGLT2i administration increases hepatic gluconeogenic response in lean insulin-sensitive mice, but not in obese insulin-resistant mice. Long-term SGLT2i administration relieves obesity-induced upregulation of the hepatic gluconeogenic response by restoring impeded hepatic insulin signaling in obese insulin-resistant mice. The Endocrine Society Endocrinology 1945-7170 160 12 2811 2824 20190913 10.1210/en.2019-00422 分子糖尿病学研究会 第36回分子糖尿病学研究奨励賞(南條賞) 20251200 分子糖尿病学研究会 第36回分子糖尿病学シンポジウム Research Travel Grant 20251200 日本内分泌学会 第26回若手研究奨励賞 20250600 日本糖尿病学会 第15回若手研究奨励賞 20250500 日本糖尿病・肥満動物学会 2025年 若手研究奨励賞 20250300 内分泌代謝学サマーセミナー 第5回サマーセミナーポスター賞 20210700 The Keystone Symposium on Obesity and NAFLD: Mechanism and Therapeutics Keystone Symposia Scholarship 20200200