{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:33:58Z","timestamp":1781512438564,"version":"3.54.1"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI Grant","award":["JP20K22741 to K.F., JP19K06768 to E.I.-U., and JP19H03258 to K.U."],"award-info":[{"award-number":["JP20K22741 to K.F., JP19K06768 to E.I.-U., and JP19H03258 to K.U."]}]},{"DOI":"10.13039\/100007449","name":"the Takeda Science Foundation","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008732","name":"the Uehara Memorial Foundation","doi-asserted-by":"publisher","award":["none"],"award-info":[{"award-number":["none"]}],"id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Ono Medical Research Foundation","award":["none"],"award-info":[{"award-number":["none"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A high-fat diet (HFD) quickly induces obesity with insulin resistance and hyperglycemia. We previously reported that a novel hypothalamic small protein, named neurosecretory protein GL (NPGL), stimulates feeding and fat accumulation in mice. However, the effects of NPGL on insulin sensitivity and glucose homeostasis remain unknown. Hence, we subjected NPGL-precursor gene (Npgl)-overexpressing mice to the oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) under normal chow (NC) and HFD conditions. Npgl overexpression promoted body mass gain and tended to increase food intake of NC-fed mice, whereas it had little effect on HFD-fed mice. The OGTT showed elevated blood glucose and insulin levels in Npgl-overexpressing NC-fed mice 15 min after glucose administration. Both the OGTT and IPITT demonstrated that Npgl overexpression decreased blood glucose levels in HFD-fed mice 60 min after glucose and insulin treatments. Notably, Npgl overexpression increased adipose tissue masses only in NC-fed mice, and it decreased blood glucose and insulin levels in HFD-fed mice at the experimental end point. It also increased the mRNA expression of galanin, one of the feeding and metabolic regulatory neuropeptides, in the hypothalamus of HFD-fed mice. Therefore, NPGL may alleviate HFD-induced hyperglycemia and insulin resistance in mice.<\/jats:p>","DOI":"10.3390\/ijms22094681","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T10:41:58Z","timestamp":1619606518000},"page":"4681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Effects of Overexpression of Neurosecretory Protein GL-Precursor Gene on Glucose Homeostasis and Insulin Sensitivity in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Keisuke","family":"Fukumura","sequence":"first","affiliation":[{"name":"Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Narimatsu","sequence":"additional","affiliation":[{"name":"Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shogo","family":"Moriwaki","sequence":"additional","affiliation":[{"name":"Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiko","family":"Iwakoshi-Ukena","sequence":"additional","affiliation":[{"name":"Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Furumitsu","sequence":"additional","affiliation":[{"name":"Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0942-6035","authenticated-orcid":false,"given":"Kazuyoshi","family":"Ukena","sequence":"additional","affiliation":[{"name":"Laboratory of Neurometabolism, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/S0140-6736(05)67483-1","article-title":"Obesity","volume":"366","author":"Haslam","year":"2005","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s40273-014-0243-x","article-title":"The epidemiology of obesity: A big picture","volume":"33","author":"Hruby","year":"2015","journal-title":"Pharmacoeconomics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nrg.2017.72","article-title":"Convergence between biological, behavioural and genetic determinants of obesity","volume":"18","author":"Ghosh","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1126\/science.7678183","article-title":"Adipose expression of tumor necrosis factor-\u03b1: Direct role in obesity-linked insulin resistance","volume":"259","author":"Hotamisligil","year":"1993","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1126\/science.271.5249.665","article-title":"IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance","volume":"271","author":"Hotamisligil","year":"1996","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1172\/JCI200319246","article-title":"Obesity is associated with macrophage accumulation in adipose tissue","volume":"112","author":"Weisberg","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1126\/science.1104344","article-title":"Diabetes, obesity, and the brain","volume":"307","author":"Schwartz","year":"2005","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/nature05026","article-title":"Central nervous system control of food intake and body weight","volume":"443","author":"Morton","year":"2006","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nrn3745","article-title":"Neurobiology of food intake in health and disease","volume":"15","author":"Morton","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.2337\/diabetes.50.11.2438","article-title":"Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats","volume":"51","author":"Kamegai","year":"2001","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/35051587","article-title":"A role for ghrelin in the central regulation of feeding","volume":"409","author":"Nakazato","year":"2001","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0896-6273(03)00063-1","article-title":"The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis","volume":"37","author":"Cowley","year":"2003","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.neuron.2017.09.043","article-title":"Dynamics of gut-brain communication underlying hunger","volume":"96","author":"Beutler","year":"2017","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/35078085","article-title":"Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus","volume":"411","author":"Cowley","year":"2001","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.neuron.2011.05.028","article-title":"Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons","volume":"71","author":"Vong","year":"2011","journal-title":"Neuron"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/372425a0","article-title":"Positional cloning of the mouse obese gene and its human homologue","volume":"372","author":"Zhang","year":"1994","journal-title":"Nature"},{"key":"ref_17","first-page":"2132","article-title":"Central insulin action regulates peripheral glucose and fat metabolism in mice","volume":"118","author":"Koch","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of insulin action and insulin resistance","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.bbrc.2014.02.090","article-title":"Identification of a cDNA encoding a novel small secretory protein, neurosecretory protein GL, in the chicken hypothalamic infundibulum","volume":"446","author":"Ukena","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ygcen.2017.09.019","article-title":"Avian and murine neurosecretory protein GL participates in the regulation of feeding and energy metabolism","volume":"260","author":"Ukena","year":"2018","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/s41598-017-18822-9","article-title":"Localization and function of neurosecretory protein GM, a novel small secretory protein, in the chicken hypothalamus","volume":"8","author":"Shikano","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ygcen.2017.05.016","article-title":"Effects of chronic intracerebroventricular infusion of neurosecretory protein GL on body mass and food and water intake in chicks","volume":"256","author":"Shikano","year":"2018","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3389\/fendo.2019.00392","article-title":"Neurosecretory protein GL induces fat accumulation in chicks","volume":"10","author":"Shikano","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1210\/en.2017-00064","article-title":"Neurosecretory protein GL, a hypothalamic small secretory protein, participates in energy homeostasis in male mice","volume":"158","author":"Matsuura","year":"2017","journal-title":"Endocrinology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/JOE-19-0112","article-title":"Neurosecretory protein GL induces fat accumulation in mice","volume":"244","author":"Shikano","year":"2020","journal-title":"J. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e28527","DOI":"10.7554\/eLife.28527","article-title":"Neurosecretory protein GL stimulates food intake, de novo lipogenesis, and onset of obesity","volume":"6","author":"Shikano","year":"2017","journal-title":"Elife"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Narimatsu, Y., Fukumura, K., Shikano, K., Iwakoshi-Ukena, E., Furumitsu, M., Bentley, G.E., Kriegsfeld, L.J., and Ukena, K. (2021). Hypothalamic overexpression of neurosecretory protein GL leads to obesity in Mice. bioRxiv.","DOI":"10.1101\/2021.03.01.433475"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1146\/annurev.psych.59.103006.093551","article-title":"The brain, appetite, and obesity","volume":"59","author":"Berthoud","year":"2008","journal-title":"Annu. Rev. Psychol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.neuron.2017.06.014","article-title":"Toward a wiring diagram understanding of appetite control","volume":"95","author":"Andermann","year":"2017","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E1323","DOI":"10.1152\/ajpendo.90617.2008","article-title":"Evaluating the glucose tolerance test in mice","volume":"295","author":"Andrikopoulos","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1677\/JOE-07-0460","article-title":"The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice","volume":"197","author":"Winzell","year":"2008","journal-title":"J. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6156","DOI":"10.1038\/s41598-019-42531-0","article-title":"Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport","volume":"9","author":"Horakova","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15259","DOI":"10.1038\/ncomms15259","article-title":"Neuronal control of peripheral insulin sensitivity and glucose metabolism","volume":"8","author":"Ruud","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"100801","DOI":"10.1016\/j.yfrne.2019.100801","article-title":"Galanin peptide family regulation of glucose metabolism","volume":"56","author":"Fang","year":"2020","journal-title":"Front. Neuroendocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Fukumura, K., Shikano, K., Narimatsu, Y., Iwakoshi-Ukena, E., Furumitsu, M., Naito, M., and Ukena, K. (2021). Effects of neurosecretory protein GL on food intake and fat accumulation under different dietary nutrient compositions in rats. Biosci. Biotechnol. Biochem., zbab064.","DOI":"10.1093\/bbb\/zbab064"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1002\/nbm.1327","article-title":"Sources of hepatic triglyceride accumulation during high-fat feeding in the healthy rat","volume":"22","author":"Delgado","year":"2009","journal-title":"NMR Biomed."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1194\/jlr.M052308","article-title":"A high-fat diet suppresses de novo lipogenesis and desaturation but not elongation and triglyceride synthesis in mice","volume":"55","author":"Duarte","year":"2014","journal-title":"J. Lipid Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cmet.2017.07.004","article-title":"Sweet sixteenth for ChREBP: Established roles and future goals","volume":"26","author":"Guilmeau","year":"2017","journal-title":"Cell Metab."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Dentin, R., Benhamed, F., P\u00e9gorier, J.P., Foufelle, F., Viollet, B., Vaulont, S., Girard, J., and Postic, C. (2005). Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J. Clin. Investig., 2843\u20132854.","DOI":"10.1172\/JCI25256"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/nyas.13263","article-title":"Neuronal systems and circuits involved in the control of food intake and adaptive thermogenesis","volume":"1391","author":"Caron","year":"2017","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"113039","DOI":"10.1016\/j.physbeh.2020.113039","article-title":"Effects of metabolic state on the regulation of melanocortin circuits","volume":"224","author":"Lieu","year":"2020","journal-title":"Physiol. Behav."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1210\/en.2004-1397","article-title":"Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y\/Agouti-related protein neurons","volume":"146","author":"Takahashi","year":"2005","journal-title":"Endocrinology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5486","DOI":"10.1523\/JNEUROSCI.4861-12.2014","article-title":"Leptin modulates the intrinsic excitability of AgRP\/NPY neurons in the arcuate nucleus of the hypothalamus","volume":"34","author":"Baver","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.celrep.2017.11.102","article-title":"Activation of AMPK-regulated CRH neurons in the PVH is sufficient and necessary to induce dietary preference for carbohydrate over fat","volume":"22","author":"Okamoto","year":"2018","journal-title":"Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cmet.2015.12.003","article-title":"FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver","volume":"23","author":"BonDurant","year":"2016","journal-title":"Cell Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cmet.2015.12.008","article-title":"FGF21 regulates sweet and alcohol preference","volume":"23","author":"Talukdar","year":"2016","journal-title":"Cell Metab."},{"key":"ref_47","first-page":"56672","article-title":"Study of in vivo glucose metabolism in high-fat diet-fed mice using oral glucose tolerance test (OGTT) and insulin tolerance test (ITT)","volume":"131","author":"Nagy","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_48","unstructured":"Franklin, K.B.J., and Paxinos, G. (1997). The Mouse Brain in Stereotaxic Coordinates, Academic Press."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4681\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:54:51Z","timestamp":1760162091000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/9\/4681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,28]]},"references-count":48,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22094681"],"URL":"https:\/\/doi.org\/10.3390\/ijms22094681","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,28]]}}}