{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T11:08:50Z","timestamp":1785496130739,"version":"3.56.0"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004240","name":"Akademie V\u011bd \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["67985823"],"award-info":[{"award-number":["67985823"]}],"id":[{"id":"10.13039\/501100004240","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nutr. Diabetes"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background\/Objective<\/jats:title>\n                <jats:p>Anorexigenic palmitoylated prolactin-releasing peptide (palm<jats:sup>11<\/jats:sup>-PrRP) is able to act centrally after peripheral administration in rat and mouse models of obesity, type 2 diabetes mellitus and\/or neurodegeneration. Functional leptin and intact leptin signaling pathways are necessary for the body weight reducing and glucose tolerance improving effect of palm<jats:sup>11<\/jats:sup>-PrRP. We have previously shown that palm<jats:sup>11<\/jats:sup>-PrRP31 had glucose-lowering properties but not anti-obesity effect in Koletsky rats with leptin signaling disturbances, so improvements in glucose metabolism appear to be completely independent of leptin signaling. The purpose of this study was to describe relationship between metabolic and neurodegenerative pathologies and explore if palm<jats:sup>11<\/jats:sup>-PrRP31 could ameliorate them in obese fa\/fa rat model with leptin signaling disruption.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Subject\/Methods<\/jats:title>\n                <jats:p>The fa\/fa rats and their age-matched lean controls at the age 32 weeks were used for this study. The rats were infused for 2 months with saline or palm<jats:sup>11<\/jats:sup>-PrRP31 (<jats:italic>n<\/jats:italic>\u2009=\u20097\u20138 per group) at a dose of 5\u2009mg\/kg per day using Alzet osmotic pumps. During the dosing period food intake and body weight were monitored. At the end of experiment the oral glucose tolerance test was performed; plasma and tissue samples were collected and arterial blood pressure was measured. Then, markers of leptin and insulin signaling, Tau phosphorylation, neuroinflammation, and synaptogenesis were measured by western blotting and immunohistochemistry.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Fa\/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm<jats:sup>11<\/jats:sup>-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>We demonstrated that palm<jats:sup>11<\/jats:sup>-PrRP31 had neuroprotective features without anti-obesity and glucose lowering effects in fa\/fa rats. This data suggest that this analog has the potential to exert neuroprotective effect despite of leptin signaling disturbances in this rat model.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1038\/s41387-022-00205-3","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T13:04:02Z","timestamp":1652965442000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Palmitoylated prolactin-releasing peptide treatment had neuroprotective but not anti-obesity effect in fa\/fa rats with leptin signaling disturbances"],"prefix":"10.1038","volume":"12","author":[{"given":"Lucia","family":"Mr\u00e1zikov\u00e1","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvie","family":"Hojn\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Pa\u010desov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Hrub\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Strnadov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Nepra\u0161ov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanka","family":"\u017delezn\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Kune\u0161","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4299-8983","authenticated-orcid":false,"given":"Lenka","family":"Malet\u00ednsk\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"key":"205_CR1","doi-asserted-by":"publisher","first-page":"R47","DOI":"10.1530\/JOE-18-0532","volume":"240","author":"L Maletinska","year":"2019","unstructured":"Maletinska L, Popelova A, Zelezna B, Bencze M, Kunes J. The impact of anorexigenic peptides in experimental models of Alzheimer\u2019s disease pathology. J Endocrinol. 2019;240:R47\u2013R72.","journal-title":"J Endocrinol"},{"key":"205_CR2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.2337\/dc08-0272","volume":"32","author":"C Raffaitin","year":"2009","unstructured":"Raffaitin C, Gin H, Empana JP, Helmer C, Berr C, Tzourio C, et al. Metabolic syndrome and risk for incident Alzheimer\u2019s disease or vascular dementia: the Three-City Study. Diabetes Care. 2009;32:169\u201374.","journal-title":"Diabetes Care"},{"key":"205_CR3","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1001\/archneur.64.1.93","volume":"64","author":"G Razay","year":"2007","unstructured":"Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch Neurol. 2007;64:93\u20136.","journal-title":"Arch Neurol"},{"key":"205_CR4","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1002\/path.2912","volume":"225","author":"Y Liu","year":"2011","unstructured":"Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer\u2019s disease and diabetes. J Pathol. 2011;225:54\u201362.","journal-title":"J Pathol"},{"key":"205_CR5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.nbd.2016.01.005","volume":"88","author":"NB El Khoury","year":"2016","unstructured":"El Khoury NB, Gratuze M, Petry F, Papon MA, Julien C, Marcouiller F, et al. Hypothermia mediates age-dependent increase of tau phosphorylation in db\/db mice. Neurobiol Dis. 2016;88:55\u201365.","journal-title":"Neurobiol Dis"},{"key":"205_CR6","doi-asserted-by":"publisher","first-page":"731","DOI":"10.3233\/JAD-2009-1021","volume":"16","author":"N Tezapsidis","year":"2009","unstructured":"Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, et al. Leptin: a novel therapeutic strategy for Alzheimer\u2019s disease. J Alzheimers Dis. 2009;16:731\u201340.","journal-title":"J Alzheimers Dis"},{"key":"205_CR7","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.2337\/diab.45.8.1141","volume":"45","author":"SC Chua","year":"1996","unstructured":"Chua SC, White DW, Wu-Peng XS, Liu S-M, Okada N, Kershaw EE, et al. Phenotype of <em>fatty<\/em> due to Gln269Pro mutation in the leptin receptor (<em>Lepr<\/em>). Diabetes 1996;45:1141\u20133.","journal-title":"Diabetes"},{"key":"205_CR8","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1006\/bbrc.1996.1133","volume":"225","author":"K Takaya","year":"1996","unstructured":"Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, Masuzaki H, et al. Molecular cloning of rat leptin receptor isoform complementary DNAs\u2014identification of a missense mutation in Zucker fatty (fa\/fa) rats. Biochem Biophys Res Commun. 1996;225:75\u201383.","journal-title":"Biochem Biophys Res Commun"},{"key":"205_CR9","first-page":"6","volume":"80","author":"TF Zucker","year":"1963","unstructured":"Zucker TF, Zucker LM. Fat accretion and growth in the rat. J Nutr. 1963;80:6\u201319.","journal-title":"J Nutr"},{"key":"205_CR10","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.2337\/diab.45.10.1446","volume":"45","author":"I Cusin","year":"1996","unstructured":"Cusin I, Rohner-Jeanrenaud F, Stricker-Krongrad A, Jeanrenaud B. The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese <em>fa\/fa<\/em> rats: reduced sensitivity compared with lean animals. Diabetes 1996;45:1446\u201350.","journal-title":"Diabetes"},{"key":"205_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0083-6729(08)60393-3","volume":"45","author":"GA Bray","year":"1989","unstructured":"Bray GA, York DA, Fisler JS. Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitam Horm. 1989;45:1\u2013125.","journal-title":"Vitam Horm"},{"key":"205_CR12","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1210\/endo-90-5-1320","volume":"90","author":"LM Zucker","year":"1972","unstructured":"Zucker LM, Antoniades HN. Insulin and obesity in the Zucker genetically obese rat \u201cfatty\u201d. Endocrinology 1972;90:1320\u201330.","journal-title":"Endocrinology"},{"key":"205_CR13","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1042\/bj1860525","volume":"186","author":"M Crettaz","year":"1980","unstructured":"Crettaz M, Prentki M, Zaninetti D, Jeanrenaud B. Insulin resistance in soleus muscle from obese Zucker rats. Involvement of several defective sites. Biochem J. 1980;186:525\u201334.","journal-title":"Biochem J"},{"issue":"3 Part 1","key":"205_CR14","first-page":"E374","volume":"255","author":"WM Sherman","year":"1988","unstructured":"Sherman WM, Katz AL, Cutler CL, Withers RT, Ivy JL. Glucose transport: locus of muscle insulin resistance in obese Zucker rats. Am J Physiol. 1988;255(3 Part 1):E374\u201382.","journal-title":"Am J Physiol"},{"key":"205_CR15","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.neuroscience.2015.04.045","volume":"309","author":"AM Stranahan","year":"2015","unstructured":"Stranahan AM. Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience 2015;309:125\u201339.","journal-title":"Neuroscience"},{"key":"205_CR16","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-15-111","volume":"15","author":"A Spolcova","year":"2014","unstructured":"Spolcova A, Mikulaskova B, Krskova K, Gajdosechova L, Zorad S, Olszanecki R, et al. Deficient hippocampal insulin signaling and augmented Tau phosphorylation is related to obesity- and age-induced peripheral insulin resistance: a study in Zucker rats. BMC Neurosci. 2014;15:111.","journal-title":"BMC Neurosci"},{"key":"205_CR17","doi-asserted-by":"publisher","first-page":"65","DOI":"10.3389\/fnmol.2014.00065","volume":"7","author":"T Kimura","year":"2014","unstructured":"Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci. 2014;7:65.","journal-title":"Front Mol Neurosci"},{"key":"205_CR18","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1586\/14789450.5.2.207","volume":"5","author":"N Sergeant","year":"2008","unstructured":"Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin M-L, Grognet P, Bombois S, et al. Biochemistry of Tau in Alzheimer\u2019s disease and related neurological disorders. Expert Rev Proteom. 2008;5:207\u201324.","journal-title":"Expert Rev Proteom"},{"key":"205_CR19","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.neurobiolaging.2014.07.035","volume":"36","author":"Y Wang","year":"2015","unstructured":"Wang Y, Yang R, Gu J, Yin X, Jin N, Xie S, et al. Cross talk between PI3K-AKT-GSK-3\u03b2 and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging. 2015;36:188\u2013200.","journal-title":"Neurobiol Aging"},{"key":"205_CR20","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1042\/CS20191313","volume":"134","author":"M Kacirova","year":"2020","unstructured":"Kacirova M, Zmeskalova A, Korinkova L, Zelezna B, Kunes J, Maletinska L, et al. Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer\u2019s disease-like pathology?. Clin Sci. 2020;134:547\u201370.","journal-title":"Clin Sci"},{"key":"205_CR21","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/s00401-009-0536-x","volume":"118","author":"T Arendt","year":"2009","unstructured":"Arendt T. Synaptic degeneration in Alzheimer\u2019s disease. Acta Neuropathol. 2009;118:167\u201379.","journal-title":"Acta Neuropathol"},{"key":"205_CR22","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1038\/s41591-019-0375-9","volume":"25","author":"EP Moreno-Jim\u00e9nez","year":"2019","unstructured":"Moreno-Jim\u00e9nez EP, Flor-Garc\u00eda M, Terreros-Roncal J, R\u00e1bano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer\u2019s disease. Nat Med. 2019;25:554\u201360.","journal-title":"Nat Med"},{"key":"205_CR23","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.3390\/nu12051356","volume":"12","author":"D Tomassoni","year":"2020","unstructured":"Tomassoni D, Martinelli I, Moruzzi M, Micioni Di Bonaventura MV, Cifani C, Amenta F, et al. Obesity and age-related changes in the brain of the Zucker Lepr (fa\/fa) rats. Nutrients. Nutrients. 2020;12:1356\u201375.","journal-title":"Nutrients"},{"key":"205_CR24","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1210\/endo.143.2.8608","volume":"143","author":"KL Ellacott","year":"2002","unstructured":"Ellacott KL, Lawrence CB, Rothwell NJ, Luckman SM. PRL-releasing peptide interacts with leptin to reduce food intake and body weight. Endocrinology 2002;143:368\u201374.","journal-title":"Endocrinology"},{"key":"205_CR25","doi-asserted-by":"publisher","first-page":"R51","DOI":"10.1530\/JOE-16-0046","volume":"230","author":"J Kunes","year":"2016","unstructured":"Kunes J, Prazienkova V, Popelova A, Mikulaskova B, Zemenova J, Maletinska L, et al. Prolactin-releasing peptide: a new tool for obesity treatment. J Endocrinol. 2016;230:R51\u20138.","journal-title":"J Endocrinol"},{"key":"205_CR26","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1038\/ijo.2015.28","volume":"39","author":"L Malet\u00ednsk\u00e1","year":"2015","unstructured":"Malet\u00ednsk\u00e1 L, Nagelov\u00e1 V, Tich\u00e1 A, Zemenov\u00e1 J, Pirn\u00edk Z, Holubov\u00e1 M, et al. Novel lipidized analogs of prolactin-releasing peptide have prolonged half-lives and exert anti-obesity effects after peripheral administration. Int J Obes. 2015;39:986\u201393.","journal-title":"Int J Obes"},{"key":"205_CR27","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1021\/acs.jproteome.8b00964","volume":"18","author":"M \u010cerm\u00e1kov\u00e1","year":"2019","unstructured":"\u010cerm\u00e1kov\u00e1 M, Pelantov\u00e1 H, Nepra\u0161ov\u00e1 B, \u0160ediv\u00e1 B, Malet\u00ednsk\u00e1 L, Kune\u0161 J, et al. Metabolomic study of obesity and its treatment with palmitoylated prolactin-releasing peptide analog in spontaneously hypertensive and normotensive rats. J Proteome Res. 2019;18:1735\u201350.","journal-title":"J Proteome Res"},{"key":"205_CR28","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1530\/JME-17-0171","volume":"60","author":"M Holubov\u00e1","year":"2018","unstructured":"Holubov\u00e1 M, Hrub\u00e1 L, Nepra\u0161ov\u00e1 B, Majer\u010d\u00edkov\u00e1 Z, Lacinov\u00e1 Z, Kune\u0161 J, et al. Prolactin-releasing peptide improved leptin hypothalamic signaling in obese mice. J Mol Endocrinol. 2018;60:85\u201394.","journal-title":"J Mol Endocrinol"},{"key":"205_CR29","first-page":"121","volume":"67","author":"V Prazienkova","year":"2016","unstructured":"Prazienkova V, Ticha A, Blechova M, Spolcova A, Zelezna B, Maletinska L, et al. Pharmacological characterization of lipidized analogs of prolactin-releasing peptide with a modified C- terminal aromatic ring. J Physiol Pharm. 2016;67:121\u20138.","journal-title":"J Physiol Pharm"},{"key":"205_CR30","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1530\/JME-19-0188","volume":"64","author":"L Ko\u0159\u00ednkov\u00e1","year":"2020","unstructured":"Ko\u0159\u00ednkov\u00e1 L, Holubov\u00e1 M, Nepra\u0161ov\u00e1 B, Hrub\u00e1 L, Pra\u017eienkov\u00e1 V, Bencze M, et al. Synergistic effect of leptin and lipidized PrRP on metabolic pathways in ob\/ob mice. J Mol Endocrinol. 2020;64:77\u201390.","journal-title":"J Mol Endocrinol"},{"key":"205_CR31","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41387-017-0015-8","volume":"8","author":"B Mikul\u00e1\u0161kov\u00e1","year":"2018","unstructured":"Mikul\u00e1\u0161kov\u00e1 B, Holubov\u00e1 M, Pra\u017eienkov\u00e1 V, Zemenov\u00e1 J, Hrub\u00e1 L, Haluz\u00edk M, et al. Lipidized prolactin-releasing peptide improved glucose tolerance in metabolic syndrome: Koletsky and spontaneously hypertensive rat study. Nutr Diabetes. 2018;8:5.","journal-title":"Nutr Diabetes"},{"key":"205_CR32","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1530\/JOE-15-0519","volume":"229","author":"M Holubov\u00e1","year":"2016","unstructured":"Holubov\u00e1 M, Zemenov\u00e1 J, Mikul\u00e1\u0161kov\u00e1 B, Panajotova V, St\u00f6hr J, Haluz\u00edk M, et al. Palmitoylated PrRP analog decreases body weight in DIO rats but not in ZDF rats. J Endocrinol. 2016;229:85\u201396.","journal-title":"J Endocrinol"},{"key":"205_CR33","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.neuropharm.2018.11.002","volume":"144","author":"M Holubova","year":"2019","unstructured":"Holubova M, Hruba L, Popelova A, Bencze M, Prazienkova V, Gengler S, et al. Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of beta-amyloid pathology. Neuropharmacology 2019;144:377\u201387.","journal-title":"Neuropharmacology"},{"key":"205_CR34","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.3233\/JAD-171041","volume":"62","author":"A Popelova","year":"2018","unstructured":"Popelova A, Prazienkova V, Neprasova B, Kasperova BJ, Hruba L, Holubova M, et al. Novel lipidized analog of prolactin-releasing peptide improves memory impairment and attenuates hyperphosphorylation of tau protein in a mouse model of tauopathy. J Alzheimers Dis. 2018;62:1725\u201336.","journal-title":"J Alzheimers Dis"},{"key":"205_CR35","doi-asserted-by":"publisher","first-page":"e0183449","DOI":"10.1371\/journal.pone.0183449","volume":"12","author":"V Pra\u017eienkov\u00e1","year":"2017","unstructured":"Pra\u017eienkov\u00e1 V, Holubov\u00e1 M, Pelantov\u00e1 H, Bug\u00e1\u0148ov\u00e1 M, Pirn\u00edk Z, Mikul\u00e1\u0161kov\u00e1 B, et al. Impact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity. PLoS ONE. 2017;12:e0183449.","journal-title":"PLoS ONE"},{"key":"205_CR36","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1006\/phrs.1996.0015","volume":"33","author":"PA Van Zwieten","year":"1996","unstructured":"Van Zwieten PA, Kam KL, Pijl AJ, Hendriks MG, Beenen OH, Pfaffendorf M, et al. Hypertensive diabetic rats in pharmacological studies. Pharm Res. 1996;33:95\u2013105.","journal-title":"Pharm Res"},{"key":"205_CR37","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.neulet.2013.03.025","volume":"543","author":"D Tomassoni","year":"2013","unstructured":"Tomassoni D, Nwankwo IE, Gabrielli MG, Bhatt S, Muhammad AB, Lokhandwala MF, et al. Astrogliosis in the brain of obese Zucker rat: a model of metabolic syndrome. Neurosci Lett. 2013;543:136\u201341.","journal-title":"Neurosci Lett"},{"key":"205_CR38","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.3390\/ijms21062035","volume":"21","author":"I Martinelli","year":"2020","unstructured":"Martinelli I, Tomassoni D, Moruzzi M, Roy P, Cifani C, Amenta F, et al. Cardiovascular changes related to metabolic syndrome: evidence in obese Zucker rats. Int J Mol Sci. 2020;21:2035.","journal-title":"Int J Mol Sci"},{"key":"205_CR39","doi-asserted-by":"publisher","first-page":"12.","DOI":"10.3390\/nu10121820","volume":"10","author":"I Vildmyren","year":"2018","unstructured":"Vildmyren I, Drotningsvik A, Oterhals \u00c5, Ween O, Halstensen A, Gudbrandsen OA, et al. Cod residual protein prevented blood pressure increase in Zucker fa\/fa rats, possibly by inhibiting activities of angiotensin-converting enzyme and renin. Nutrients. 2018;10:12.","journal-title":"Nutrients"},{"key":"205_CR40","first-page":"315","volume":"17","author":"M D\u00edaz-Silva","year":"2004","unstructured":"D\u00edaz-Silva M, Grasa MM, Blay M, Fern\u00e1ndez-L\u00f3pez JA, Remesar X, Alemany M, et al. Strain variability in Zucker rats affects their response to oral oleoyl-estrone. Diabetes Nutr Metab. 2004;17:315\u201322.","journal-title":"Diabetes Nutr Metab"},{"key":"205_CR41","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1007\/s00401-002-0608-7","volume":"105","author":"CA Maurage","year":"2003","unstructured":"Maurage CA, Sergeant N, Ruchoux MM, Hauw JJ, Delacourte A. Phosphorylated serine 199 of microtubule-associated protein tau is a neuronal epitope abundantly expressed in youth and an early marker of tau pathology. Acta Neuropathol. 2003;105:89\u201397.","journal-title":"Acta Neuropathol"},{"key":"205_CR42","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/nan.12084","volume":"40","author":"S Mondrag\u00f3n-Rodr\u00edguez","year":"2014","unstructured":"Mondrag\u00f3n-Rodr\u00edguez S, Perry G, Luna-Mu\u00f1oz J, Acevedo-Aquino MC, Williams S. Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer\u2019s disease and Down syndrome. Neuropathol Appl Neurobiol. 2014;40:121\u201335.","journal-title":"Neuropathol Appl Neurobiol"},{"key":"205_CR43","doi-asserted-by":"publisher","first-page":"536","DOI":"10.2337\/db08-0822","volume":"58","author":"K Rahmouni","year":"2009","unstructured":"Rahmouni K, Sigmund CD, Haynes WG, Mark AL. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes 2009;58:536\u201342.","journal-title":"Diabetes"},{"key":"205_CR44","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1074\/jbc.M703753200","volume":"283","author":"Z Guo","year":"2008","unstructured":"Guo Z, Jiang H, Xu X, Duan W, Mattson MP. Leptin-mediated cell survival signaling in hippocampal neurons mediated by JAK STAT3 and mitochondrial stabilization. J Biol Chem. 2008;283:1754\u201363.","journal-title":"J Biol Chem"},{"key":"205_CR45","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1517\/14728220903213426","volume":"13","author":"T Chiba","year":"2009","unstructured":"Chiba T, Yamada M, Aiso S. Targeting the JAK2\/STAT3 axis in Alzheimer\u2019s disease. Expert Opin Ther Targets. 2009;13:1155\u201367.","journal-title":"Expert Opin Ther Targets"},{"key":"205_CR46","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1210\/me.2013-1332","volume":"28","author":"M Dhar","year":"2014","unstructured":"Dhar M, Zhu M, Impey S, Lambert TJ, Bland T, Karatsoreos IN, et al. Leptin induces hippocampal synaptogenesis via CREB-regulated microRNA-132 suppression of p250GAP. Mol Endocrinol. 2014;28:1073\u201387.","journal-title":"Mol Endocrinol"},{"key":"205_CR47","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/nn2055","volume":"11","author":"AM Stranahan","year":"2008","unstructured":"Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP, et al. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci. 2008;11:309\u201317.","journal-title":"Nat Neurosci"}],"container-title":["Nutrition &amp; Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41387-022-00205-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-022-00205-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41387-022-00205-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T19:28:35Z","timestamp":1669231715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41387-022-00205-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,19]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["205"],"URL":"https:\/\/doi.org\/10.1038\/s41387-022-00205-3","relation":{},"ISSN":["2044-4052"],"issn-type":[{"value":"2044-4052","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,19]]},"assertion":[{"value":"23 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 May 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"26"}}