BACKGROUND/OBJECTIVE: Anorexigenic palmitoylated prolactin-releasing peptide (palm11-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 palm11-PrRP. We have previously shown that palm11-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 palm11-PrRP31 could ameliorate them in obese fa/fa rat model with leptin signaling disruption. SUBJECT/METHODS: 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 palm11-PrRP31 (n = 7-8 per group) at a dose of 5 mg/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. RESULTS: Fa/fa rats developed obesity, mild glucose intolerance, and peripheral insulin resistance but not hypertension while palm11-PrRP31 treatment neither lowered body weight nor attenuated glucose tolerance but ameliorated leptin and insulin signaling and synaptogenesis in hippocampus. CONCLUSION: We demonstrated that palm11-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.

1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Organic Chemistry and Biochemistry CAS Prague Czech Republic

Institute of Physiology CAS Prague Czech Republic

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Maletinska L, Popelova A, Zelezna B, Bencze M, Kunes J. The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology. J Endocrinol. 2019;240:R47–R72. doi: 10.1530/JOE-18-0532. PubMed DOI

Raffaitin C, Gin H, Empana JP, Helmer C, Berr C, Tzourio C, et al. Metabolic syndrome and risk for incident Alzheimer’s disease or vascular dementia: the Three-City Study. Diabetes Care. 2009;32:169–74. doi: 10.2337/dc08-0272. PubMed DOI PMC

Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch Neurol. 2007;64:93–6. doi: 10.1001/archneur.64.1.93. PubMed DOI

Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol. 2011;225:54–62. doi: 10.1002/path.2912. PubMed DOI PMC

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;88:55–65. doi: 10.1016/j.nbd.2016.01.005. PubMed DOI

Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, et al. Leptin: a novel therapeutic strategy for Alzheimer’s disease. J Alzheimers Dis. 2009;16:731–40. doi: 10.3233/JAD-2009-1021. PubMed DOI PMC

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;45:1141–3. doi: 10.2337/diab.45.8.1141. PubMed DOI

Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N, Masuzaki H, et al. Molecular cloning of rat leptin receptor isoform complementary DNAs—identification of a missense mutation in Zucker fatty (fa/fa) rats. Biochem Biophys Res Commun. 1996;225:75–83. doi: 10.1006/bbrc.1996.1133. PubMed DOI

Zucker TF, Zucker LM. Fat accretion and growth in the rat. J Nutr. 1963;80:6–19. PubMed

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;45:1446–50. doi: 10.2337/diab.45.10.1446. PubMed DOI

Bray GA, York DA, Fisler JS. Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitam Horm. 1989;45:1–125. doi: 10.1016/S0083-6729(08)60393-3. PubMed DOI

Zucker LM, Antoniades HN. Insulin and obesity in the Zucker genetically obese rat “fatty”. Endocrinology. 1972;90:1320–30. doi: 10.1210/endo-90-5-1320. PubMed DOI

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;186:525–34. doi: 10.1042/bj1860525. PubMed DOI PMC

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):E374–82. PubMed

Stranahan AM. Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience. 2015;309:125–39. doi: 10.1016/j.neuroscience.2015.04.045. PubMed DOI PMC

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. doi: 10.1186/1471-2202-15-111. PubMed DOI PMC

Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci. 2014;7:65. doi: 10.3389/fnmol.2014.00065. PubMed DOI PMC

Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin M-L, Grognet P, Bombois S, et al. Biochemistry of Tau in Alzheimer’s disease and related neurological disorders. Expert Rev Proteom. 2008;5:207–24. doi: 10.1586/14789450.5.2.207. PubMed DOI

Wang Y, Yang R, Gu J, Yin X, Jin N, Xie S, et al. Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation. Neurobiol Aging. 2015;36:188–200. doi: 10.1016/j.neurobiolaging.2014.07.035. PubMed DOI

Kacirova M, Zmeskalova A, Korinkova L, Zelezna B, Kunes J, Maletinska L, et al. Inflammation: major denominator of obesity, Type 2 diabetes and Alzheimer’s disease-like pathology? Clin Sci. 2020;134:547–70.. doi: 10.1042/CS20191313. PubMed DOI

Arendt T. Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol. 2009;118:167–79. doi: 10.1007/s00401-009-0536-x. PubMed DOI

Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25:554–60.. doi: 10.1038/s41591-019-0375-9. PubMed DOI

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;12:1356–75. doi: 10.3390/nu12051356. PubMed DOI PMC

Ellacott KL, Lawrence CB, Rothwell NJ, Luckman SM. PRL-releasing peptide interacts with leptin to reduce food intake and body weight. Endocrinology. 2002;143:368–74. doi: 10.1210/endo.143.2.8608. PubMed DOI

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:R51–8. doi: 10.1530/JOE-16-0046. PubMed DOI

Maletínská L, Nagelová V, Tichá A, Zemenová J, Pirník Z, Holubová 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;39:986–93. doi: 10.1038/ijo.2015.28. PubMed DOI

Čermáková M, Pelantová H, Neprašová B, Šedivá B, Maletínská L, Kuneš 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;18:1735–50. doi: 10.1021/acs.jproteome.8b00964. PubMed DOI

Holubová M, Hrubá L, Neprašová B, Majerčíková Z, Lacinová Z, Kuneš J, et al. Prolactin-releasing peptide improved leptin hypothalamic signaling in obese mice. J Mol Endocrinol. 2018;60:85–94. doi: 10.1530/JME-17-0171. PubMed DOI

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;67:121–8. PubMed

Kořínková L, Holubová M, Neprašová B, Hrubá L, Pražienková V, Bencze M, et al. Synergistic effect of leptin and lipidized PrRP on metabolic pathways in ob/ob mice. J Mol Endocrinol. 2020;64:77–90. doi: 10.1530/JME-19-0188. PubMed DOI

Mikulášková B, Holubová M, Pražienková V, Zemenová J, Hrubá L, Haluzík M, et al. Lipidized prolactin-releasing peptide improved glucose tolerance in metabolic syndrome: Koletsky and spontaneously hypertensive rat study. Nutr Diabetes. 2018;8:5. doi: 10.1038/s41387-017-0015-8. PubMed DOI PMC

Holubová M, Zemenová J, Mikulášková B, Panajotova V, Stöhr J, Haluzík M, et al. Palmitoylated PrRP analog decreases body weight in DIO rats but not in ZDF rats. J Endocrinol. 2016;229:85–96. doi: 10.1530/JOE-15-0519. PubMed DOI

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;144:377–87. doi: 10.1016/j.neuropharm.2018.11.002. PubMed DOI

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;62:1725–36. doi: 10.3233/JAD-171041. PubMed DOI

Pražienková V, Holubová M, Pelantová H, Bugáňová M, Pirník Z, Mikulášková 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. doi: 10.1371/journal.pone.0183449. PubMed DOI PMC

Van Zwieten PA, Kam KL, Pijl AJ, Hendriks MG, Beenen OH, Pfaffendorf M, et al. Hypertensive diabetic rats in pharmacological studies. Pharm Res. 1996;33:95–105. doi: 10.1006/phrs.1996.0015. PubMed DOI

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;543:136–41.. doi: 10.1016/j.neulet.2013.03.025. PubMed DOI

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. doi: 10.3390/ijms21062035. PubMed DOI PMC

Vildmyren I, Drotningsvik A, Oterhals Å, 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.. doi: 10.3390/nu10121820. PubMed DOI PMC

Díaz-Silva M, Grasa MM, Blay M, Fernández-López JA, Remesar X, Alemany M, et al. Strain variability in Zucker rats affects their response to oral oleoyl-estrone. Diabetes Nutr Metab. 2004;17:315–22. PubMed

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;105:89–97. doi: 10.1007/s00401-002-0608-7. PubMed DOI

Mondragón-Rodríguez S, Perry G, Luna-Muñoz J, Acevedo-Aquino MC, Williams S. Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer’s disease and Down syndrome. Neuropathol Appl Neurobiol. 2014;40:121–35. doi: 10.1111/nan.12084. PubMed DOI

Rahmouni K, Sigmund CD, Haynes WG, Mark AL. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes. 2009;58:536–42. doi: 10.2337/db08-0822. PubMed DOI PMC

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;283:1754–63. doi: 10.1074/jbc.M703753200. PubMed DOI

Chiba T, Yamada M, Aiso S. Targeting the JAK2/STAT3 axis in Alzheimer’s disease. Expert Opin Ther Targets. 2009;13:1155–67. doi: 10.1517/14728220903213426. PubMed DOI

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;28:1073–87. doi: 10.1210/me.2013-1332. PubMed DOI PMC

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;11:309–17. doi: 10.1038/nn2055. PubMed DOI PMC

Metabolomic Study of Aging in fa/fa Rats: Multiplatform Urine and Serum Analysis