{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T09:03:55Z","timestamp":1772787835404,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T00:00:00Z","timestamp":1659139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FAR funds (Italian Ministry for Instruction, University and Research)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>PPAR\u03b3 agonists are implicated in the regulation of diabetes and metabolic syndrome and have therapeutic potential in brain disorders. PPAR\u03b3 modulates appetite through its central effects, especially on the hypothalamic arcuate nucleus (ARC). Previous studies demonstrated that the small molecule GL516 is a PPAR\u03b3 agonist able to reduce oxidative stress and apoptosis with a potential neuroprotective role. Herein, we investigated the effects of GL516, in vitro and ex vivo, on the levels of hypothalamic dopamine (DA) and serotonin (5-HT). The gene expressions of neuropeptide Y, CART, AgRP, and POMC, which play master roles in the neuroendocrine regulation of feeding behavior and energy balance, were also evaluated. HypoE22 cells were treated with H2O2 (300 \u03bcM) for 2 h e 30\u2019 and with different concentrations of GL516 (1 nM-100 \u00b5M). The cell viability was evaluated after 24 and 48 h of culturing using the MTT test. DA and 5-HT levels in the HypoE22 cell supernatants were analyzed through HPLC; an ex vivo study on isolated hypothalamic specimens challenged with scalar concentrations of GL516 (1\u2013100 \u00b5M) and with pioglitazone (10 \u00b5M) was carried out. The gene expressions of CART, NPY, AgRP, and POMC were also determined by a quantitative real-time PCR. The results obtained showed that GL516 was able to reduce DA and 5-HT turnover; moreover, it was effective in stimulating NPY and AgRP gene expressions with a concomitant reduction in CART and POMC gene expressions. These results highlight the capability of GL516 to modulate neuropeptide pathways deeply involved in appetite control suggesting an orexigenic effect. These findings emphasize the potential use of GL516 as a promising candidate for therapeutical applications in neurodegenerative diseases associated with the reduction in food intake and stimulation of catabolic pathways.<\/jats:p>","DOI":"10.3390\/molecules27154882","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T04:04:00Z","timestamp":1659326640000},"page":"4882","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Small Molecule PPAR\u03b3 Agonist GL516 Induces Feeding-Stimulatory Effects in Hypothalamus Cells Hypo-E22 and Isolated Hypothalami"],"prefix":"10.3390","volume":"27","author":[{"given":"Annalisa","family":"Chiavaroli","sequence":"first","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3332-993X","authenticated-orcid":false,"given":"Viviana","family":"di Giacomo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7718-5814","authenticated-orcid":false,"given":"Barbara","family":"De Filippis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia","family":"Cataldi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9431-9407","authenticated-orcid":false,"given":"Claudio","family":"Ferrante","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8483-1885","authenticated-orcid":false,"given":"Letizia","family":"Giampietro","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, \u201cG. d\u2019Annunzio\u201d University, Via dei Vestini 31, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.phrs.2004.07.012","article-title":"An overview on biological mechanisms of PPARs","volume":"51","author":"Kota","year":"2005","journal-title":"Pharmacol. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.tem.2012.05.001","article-title":"PPARs at the crossroads of lipid signaling and inflammation","volume":"23","author":"Wahli","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.neuroscience.2003.08.064","article-title":"Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS","volume":"123","author":"Moreno","year":"2004","journal-title":"Neuroscience"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"864140","DOI":"10.1155\/2008\/864140","article-title":"Regulation of Glial Cell Functions by PPAR-\u03b3 Natural and Synthetic Agonists","volume":"2008","author":"Bernardo","year":"2008","journal-title":"PPAR Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1161\/CIRCRESAHA.110.216523","article-title":"Control of macrophage activation and function by PPARs","volume":"106","author":"Chawla","year":"2010","journal-title":"Circ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sanjay, S.A., and Lee, H.-J. (2021). Role of Phytoconstituents as PPAR Agonists: Implications for Neurodegenerative Disorders. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121914"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Behl, T., Madaan, P., Sehgal, A., Singh, S., Sharma, N., Bhatia, S., Al-Harrasi, A., Chigurupati, S., Alrashdi, I., and Bungau, S.G. (2021). Elucidating the Neuroprotective Role of PPARs in Parkinson\u2019s Disease: A Neoteric and Prospective Target. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810161"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s12272-021-01333-7","article-title":"Peroxisome proliferator-activated receptor gamma: A novel therapeutic target for cognitive impairment and mood disorders that functions via the regulation of adult neurogenesis","volume":"44","author":"Lim","year":"2021","journal-title":"Arch. Pharmacal Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10571-017-0554-5","article-title":"Roles of Peroxisome Proliferator-Activated Receptor Gamma on Brain and Peripheral Inflammation","volume":"38","author":"Villapol","year":"2018","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.pneurobio.2017.10.002","article-title":"Peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3): A master gatekeeper in CNS injury and repair","volume":"163","author":"Cai","year":"2018","journal-title":"Prog. Neurobiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1007\/s11064-021-03402-1","article-title":"Peroxisome Proliferator-Activated Receptor-Gamma (PPAR-\u0263): Molecular Effects and Its Importance as a Novel Therapeutic Target for Cerebral Ischemic Injury","volume":"46","author":"Mannan","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_12","first-page":"95","article-title":"Exploring targets and therapies for amyotrophic lateral sclerosis: Current insights into dietary interventions","volume":"7","author":"Ngo","year":"2017","journal-title":"Degener. Neurol. Neuromuscul. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1136\/jnnp-2017-315795","article-title":"Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis","volume":"88","author":"Gorges","year":"2017","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1080\/21678421.2019.1621346","article-title":"Loss of appetite is associated with a loss of weight and fat mass in patients with amyotrophic lateral sclerosis","volume":"20","author":"Ngo","year":"2019","journal-title":"Amyotroph. Lateral Scler. Front. Degener."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1523\/JNEUROSCI.2129-14.2015","article-title":"Peroxisome proliferator-activated receptor \u03b3 controls ingestive behavior, agouti-related protein, and neuropeptide Y mRNA in the arcuate hypothalamus","volume":"35","author":"Garretson","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/nm.2332","article-title":"Brain PPAR-\u03b3 promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones","volume":"17","author":"Lu","year":"2011","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nm.2349","article-title":"A role for central nervous system PPAR-\u03b3 in the regulation of energy balance","volume":"17","author":"Ryan","year":"2011","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1210\/en.2008-0899","article-title":"Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis","volume":"150","author":"Sarruf","year":"2009","journal-title":"Endocrinology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ygcen.2015.12.021","article-title":"Effects of intracerebroventricular injection of rosiglitazone on appetite-associated parameters in chicks","volume":"246","author":"Matias","year":"2017","journal-title":"Gen. Comp. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0196-9781(96)00025-3","article-title":"Leptin enters the brain by a saturable system independent of insulin","volume":"17","author":"Banks","year":"1996","journal-title":"Peptides"},{"key":"ref_21","first-page":"68","article-title":"Interacting appetite-regulating pathways in the hypothalamic regulation of body weight","volume":"20","author":"Kalra","year":"1999","journal-title":"Endocr. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S0006-8993(99)01961-7","article-title":"Peptides crossing the blood\u2013brain barrier: Some unusual observations","volume":"848","author":"Kastin","year":"1999","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.numecd.2007.06.004","article-title":"Neuroendocrine control of food intake","volume":"18","author":"Valassi","year":"2008","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1177\/039463200501800203","article-title":"The regulation of feeding: A cross talk between peripheral and central signalling","volume":"18","author":"Brunetti","year":"2005","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7662","DOI":"10.1016\/j.bmcl.2012.09.111","article-title":"Synthesis and structure\u2013activity relationships of fibrate-based analogues inside PPARs","volume":"22","author":"Giampietro","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1021\/acsmedchemlett.8b00574","article-title":"Novel Phenyldiazenyl Fibrate Analogues as PPAR \u03b1\/\u03b3\/\u03b4 Pan-Agonists for the Amelioration of Metabolic Syndrome","volume":"10","author":"Giampietro","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6224","DOI":"10.1021\/jm900878u","article-title":"Synthesis and Biological Evaluation of 2-Heteroarylthioalkanoic Acid Analogues of Clofibric Acid as Peroxisome Proliferator-Activated Receptor \u03b1 Agonists","volume":"52","author":"Giampietro","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1002\/cmdc.201900128","article-title":"Development of Fibrates as Important Scaffolds in Medicinal Chemistry","volume":"14","author":"Giampietro","year":"2019","journal-title":"ChemMedChem"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/chir.20505","article-title":"Candida rugosa lipase-catalysed kinetic resolution of 2-substituted-aryloxyacetic esters with dimethylsulfoxide and isopropanol as additives","volume":"20","author":"Ammazzalorso","year":"2008","journal-title":"Chirality"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1002\/ejp.649","article-title":"Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) across acute and chronic pain conditions","volume":"19","author":"Moore","year":"2015","journal-title":"Eur. J. Pain"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.ejmech.2014.04.085","article-title":"Design and synthesis of novel indole-chalcone fibrates as lipid lowering agents","volume":"81","author":"Sashidhara","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.2174\/1570180815666180321163246","article-title":"Synthesis, Characterization and Evaluation of Gemfibrozil-stilbene Hybrid as Antioxidant Agent","volume":"15","author":"Amoroso","year":"2018","journal-title":"Lett. Drug Des. Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.ejmech.2005.03.022","article-title":"Synthesis and antiplatelet activity of thioaryloxyacids analogues of clofibric acid","volume":"40","author":"Ammazzalorso","year":"2005","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.neuint.2019.03.021","article-title":"PPAR-\u03b3 agonist GL516 reduces oxidative stress and apoptosis occurrence in a rat astrocyte cell line","volume":"126","author":"Giampietro","year":"2019","journal-title":"Neurochem. Int."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Orlando, G., Leone, S., Ferrante, C., Chiavaroli, A., Mollica, A., Stefanucci, A., Macedonio, G., Dimmito, M.P., Leporini, L., and Menghini, L. (2018). Effects of Kisspeptin-10 on Hypothalamic Neuropeptides and Neurotransmitters Involved in Appetite Control. Molecules, 24.","DOI":"10.3390\/molecules23123071"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"di Giacomo, V., Chiavaroli, A., Orlando, G., Cataldi, A., Rapino, M., Di Valerio, V., Leone, S., Brunetti, L., Menghini, L., and Recinella, L. (2020). Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus. Antioxidants, 13.","DOI":"10.3390\/antiox9010071"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1016\/j.cmet.2021.07.006","article-title":"Astrocyte-neuron metabolic cooperation shapes brain activity","volume":"33","author":"Bonvento","year":"2021","journal-title":"Cell Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1161\/STROKEAHA.116.013977","article-title":"Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis","volume":"48","author":"Lee","year":"2017","journal-title":"Stroke"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"666958","DOI":"10.3389\/fnins.2021.666958","article-title":"Reassessment of Pioglitazone for Alzheimer\u2019s Disease","volume":"15","author":"Saunders","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.ghir.2017.10.007","article-title":"Effects of growth hormone-releasing hormone gene targeted ablation on ghrelin-induced feeding","volume":"37","author":"Recinella","year":"2017","journal-title":"Growth Horm. IGF Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/4882\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:59:51Z","timestamp":1760140791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/15\/4882"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,30]]},"references-count":40,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["molecules27154882"],"URL":"https:\/\/doi.org\/10.3390\/molecules27154882","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,30]]}}}