{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T05:59:46Z","timestamp":1773899986557,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T00:00:00Z","timestamp":1744329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pfizer","award":["67562227"],"award-info":[{"award-number":["67562227"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Recent advances in drug development allowed for the identification of THR\u03b2-selective thyromimetic TG68 as a very promising lipid lowering and anti-amyloid agent. In the current study, we first investigated the neuroprotective effects of TG68 on in vitro human models of neuroinflammation and \u03b2-amyloid neurotoxicity in order to expand our knowledge of the therapeutic potential of this novel thyromimetic. Subsequently, we examined metabolic and inflammatory profiles, along with cognitive changes, using a high-fat diet (HFD) mouse model of obesity. Our data demonstrated that TG68 was able to prevent either LPS\/TNF\u03b1-induced inflammatory response or \u03b2-amyloid-induced cytotoxicity in human microglial (HMC3) cells. Next, we demonstrated that in HFD-fed mice, treatment with TG68 (10 mg\/kg\/day; 2 weeks) significantly reduced anxiety-like behavior in stretch\u2013attend posture (SAP) tests while producing a 12% BW loss and a significant decrease in blood glucose and lipid levels. Notably, these data highlight a close relationship between improved serum metabolic parameters and a reduction of anxious behavior. Moreover, TG68 administration was observed to efficiently counteract HFD-altered central and peripheral expressions in mice with selected biomarkers of metabolic dysfunction, inflammation, and neurotoxicity, revealing promising neuroprotective effects. In conclusion, our work provides preliminary evidence that TG68 may represent a novel therapeutic opportunity for the treatment of interlinked diseases such as obesity and neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/cells14080580","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T07:42:01Z","timestamp":1744616521000},"page":"580","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel Thyroid Hormone Receptor-\u03b2 Agonist TG68 Exerts Anti-Inflammatory, Lipid-Lowering and Anxiolytic Effects in a High-Fat Diet (HFD) Mouse Model of Obesity"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-6091","authenticated-orcid":false,"given":"Beatrice","family":"Polini","sequence":"first","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Via Roma 56, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Ricardi","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Via Roma 56, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Di Lupo","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Via Roma 56, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3608-2031","authenticated-orcid":false,"given":"Massimiliano","family":"Runfola","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Bacci","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0146-6358","authenticated-orcid":false,"given":"Simona","family":"Rapposelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-2672","authenticated-orcid":false,"given":"Ranieri","family":"Bizzarri","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Via Roma 56, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Scalese","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, Italian National Research Council, 56124 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0277-1648","authenticated-orcid":false,"given":"Federica","family":"Saponaro","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Via Roma 56, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6703-5820","authenticated-orcid":false,"given":"Grazia","family":"Chiellini","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Via Roma 56, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature14177","article-title":"Genetic studies of body mass index yield new insights for obesity biology","volume":"518","author":"Locke","year":"2015","journal-title":"Nature"},{"key":"ref_2","first-page":"111","article-title":"Current Perspectives: Obesity and Neurodegeneration\u2014Links and Risks","volume":"13","author":"Kueck","year":"2023","journal-title":"Degener. Neurol. Neuromuscul. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tobeh, N.S., and Bruce, K.D. (2023). Emerging Alzheimer\u2019s disease therapeutics: Promising insights from lipid metabolism and microglia-focused interventions. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1259012"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101755","DOI":"10.1016\/j.molmet.2023.101755","article-title":"Chronic inflammation and the hallmarks of aging","volume":"74","author":"Baechle","year":"2023","journal-title":"Mol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13024-020-00391-7","article-title":"Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer\u2019s disease","volume":"15","author":"Guo","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107615","DOI":"10.1016\/j.phrs.2025.107615","article-title":"High-fat diet and neuroinflammation: The role of mitochondria","volume":"212","author":"Song","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Le Moli, R., Vella, V., Tumino, D., Piticchio, T., Naselli, A., Belfiore, A., and Frasca, F. (2022). Inflammasome activation as a link between obesity and thyroid disorders: Implications for an integrated clinical management. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.959276"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1152\/physrev.2001.81.3.1097","article-title":"Physiological and Molecular Basis of Thyroid Hormone Action","volume":"81","author":"Yen","year":"2001","journal-title":"Physiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sep\u00falveda, P., Ferreira, A.F.F., Sandoval, C., Bergoc, G., Moreno, A.C.R., Nunes, M.T., and Torr\u00e3o, A.D.S. (2024). Thyroid Hormone Supplementation Restores Cognitive Deficit, Insulin Signaling, and Neuroinflammation in the Hippocampus of a Sporadic Alzheimer\u2019s-like Disease Rat Model. Cells, 13.","DOI":"10.3390\/cells13211793"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1089\/thy.2013.0058","article-title":"Hippocampal Volume Is Decreased in Adults with Hypothyroidism","volume":"24","author":"Cooke","year":"2014","journal-title":"Thyroid"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Lasa, M., and Contreras-Jurado, C. (2022). Thyroid hormones act as modulators of inflammation through their nuclear receptors. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.937099"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chamas, L., Seugnet, I., Poirier, R., Clerget-Froidevaux, M.-S., and Enderlin, V. (2022). A Fine Regulation of the Hippocampal Thyroid Signalling Protects Hypothyroid Mice against Glial Cell Activation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911938"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hsieh, C.-T., Yen, T.-L., Chen, Y.-H., Jan, J.-S., Teng, R.-D., Yang, C.-H., and Sun, J.-M. (2023). Aging-Associated Thyroid Dysfunction Contributes to Oxidative Stress and Worsened Functional Outcomes Following Traumatic Brain Injury. Antioxidants, 12.","DOI":"10.3390\/antiox12020217"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"G\u0142ombik, K., Detka, J., Bobula, B., B\u0105k, J., Kusek, M., Tokarski, K., and Budziszewska, B. (2021). Contribution of Hypothyroidism to Cognitive Impairment and Hippocampal Synaptic Plasticity Regulation in an Animal Model of Depression. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041599"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14633","DOI":"10.1002\/jcp.28198","article-title":"The effects of thyroid hormones on memory impairment and Alzheimer\u2019s disease","volume":"234","author":"Bavarsad","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1007\/s12035-018-1111-z","article-title":"Thyroid Hormone Supplementation Restores Spatial Memory, Hippocampal Markers of Neuroinflammation, Plasticity-Related Signaling Molecules, and \u03b2-Amyloid Peptide Load in Hypothyroid Rats","volume":"56","author":"Chaalal","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1007\/s10571-023-01392-y","article-title":"Primary Hypothyroidism and Alzheimer\u2019s Disease: A Tale of Two","volume":"43","author":"AlAnazi","year":"2023","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_18","first-page":"184","article-title":"Thyroid Hormone Receptors: Multiple Forms, Multiple Possibilities*","volume":"14","author":"Lazar","year":"1993","journal-title":"Endocr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Saponaro, F., Sestito, S., Runfola, M., Rapposelli, S., and Chiellini, G. (2020). Selective Thyroid Hormone Receptor-Beta (TR\u03b2) Agonists: New Perspectives for the Treatment of Metabolic and Neurodegenerative Disorders. Front. Med., 7.","DOI":"10.3389\/fmed.2020.00331"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1089\/thy.2020.0071","article-title":"Thyroid Hormone Analogues: An Update","volume":"30","author":"Zucchi","year":"2020","journal-title":"Thyroid"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/thy.2007.0248","article-title":"Metabolic Effects of Thyroid Hormone Derivatives","volume":"18","author":"Moreno","year":"2008","journal-title":"Thyroid"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3727\/105221617X14968563796227","article-title":"GC-1: A Thyromimetic With Multiple Therapeutic Applications in Liver Disease","volume":"17","author":"Columbano","year":"2017","journal-title":"Gene Expr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1007\/s40265-017-0791-4","article-title":"Potential Role of Thyroid Receptor \u03b2 Agonists in the Treatment of Hyperlipidemia","volume":"77","author":"Jakobsson","year":"2017","journal-title":"Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"112006","DOI":"10.1016\/j.ejmech.2019.112006","article-title":"Design, synthesis and biological evaluation of novel TR\u03b2 selective agonists sustained by ADME-toxicity analysis","volume":"188","author":"Runfola","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Caddeo, A., Kowalik, M.A., Serra, M., Runfola, M., Bacci, A., Rapposelli, S., Columbano, A., and Perra, A. (2021). TG68, a Novel Thyroid Hormone Receptor-\u03b2 Agonist for the Treatment of NAFLD. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313105"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhao, M., Xie, H., Shan, H., Zheng, Z., Li, G., Li, M., and Hong, L. (2022). Development of Thyroid Hormones and Synthetic Thyromimetics in Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031102"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103034","DOI":"10.1016\/j.dsx.2024.103034","article-title":"Intrahepatic hypothyroidism in MASLD: Role of liver-specific thyromimetics including resmetirom","volume":"18","author":"Kuchay","year":"2024","journal-title":"Diabetes Metab. Syndr. Clin. Res. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3402","DOI":"10.1038\/s41591-024-02958-z","article-title":"Opportunities and challenges following approval of resmetirom for MASH liver disease","volume":"30","author":"Lazarus","year":"2024","journal-title":"Nat. Med."},{"key":"ref_30","first-page":"614","article-title":"Selective thyromimetics: Tissue-selective thyroid hormone analogs","volume":"4","author":"Scanlan","year":"2001","journal-title":"Curr. Opin. Drug Discov. Devel."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Baldassarro, V.A., Quadalti, C., Runfola, M., Manera, C., Rapposelli, S., and Calz\u00e0, L. (2023). Synthetic Thyroid Hormone Receptor-\u03b2 Agonists Promote Oligodendrocyte Precursor Cell Differentiation in the Presence of Inflammatory Challenges. Pharmaceuticals, 16.","DOI":"10.3390\/ph16091207"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Kim, B., Ko, Y.H., Runfola, M., Rapposelli, S., Ortore, G., Chiellini, G., and Kim, J.H. (2021). Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073488"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1538\/expanim1978.35.4_505","article-title":"Chaacteristics of Open Field Behavior of Wistar and Sprague-Dawley Rats","volume":"35","author":"Asano","year":"1986","journal-title":"Exp. Anim."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1002\/2327-6924.12510","article-title":"Obesity: Risk factors, complications, and strategies for sustainable long-term weight management","volume":"29","author":"Fruh","year":"2017","journal-title":"J. Am. Assoc. Nurse Pract."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrn2038","article-title":"Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms","volume":"8","author":"Block","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"P\u00e9rez, S., and Rius-P\u00e9rez, S. (2022). Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective. Antioxidants, 11.","DOI":"10.3390\/antiox11071394"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"307","DOI":"10.3109\/00207454.2013.833510","article-title":"Microglia, neuroinflammation, and beta-amyloid protein in Alzheimer\u2019s disease","volume":"124","author":"Cai","year":"2014","journal-title":"Int. J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1002\/eji.201545855","article-title":"Gx-50 reduces \u03b2-amyloid-induced TNF-\u03b1, IL-1\u03b2, NO, and PGE2 expression and inhibits NF-\u03baB signaling in a mouse model of Alzheimer\u2019s disease","volume":"46","author":"Shi","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"38","DOI":"10.4103\/1673-5374.343891","article-title":"Adipose tissue, systematic inflammation, and neurodegenerative diseases","volume":"18","author":"Frihling","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Friesen, J.A., and Rodwell, V.W. (2004). The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biol., 5.","DOI":"10.1186\/gb-2004-5-11-248"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.gendis.2020.05.005","article-title":"Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia","volume":"9","author":"Wu","year":"2020","journal-title":"Genes. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Li, Y., Xu, H., Wang, H., Yang, K., Luan, J., and Wang, S. (2023). TREM2: Potential therapeutic targeting of microglia for Alzheimer\u2019s disease. Biomed. Pharmacother., 165.","DOI":"10.1016\/j.biopha.2023.115218"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/oby.21714","article-title":"Increased expression of triggering receptor expressed on myeloid cells-1 in the population with obesity and insulin resistance","volume":"25","author":"Subramanian","year":"2017","journal-title":"Obesity"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.chembiol.2021.07.014","article-title":"TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor","volume":"29","author":"Ferrara","year":"2022","journal-title":"Cell Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wiens, K.R., Wasti, N., Ulloa, O.O., and Klegeris, A. (2024). Diversity of Microglia-Derived Molecules with Neurotrophic Properties That Support Neurons in the Central Nervous System and Other Tissues. Molecules, 29.","DOI":"10.3390\/molecules29235525"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Jurga, A.M., Paleczna, M., and Kuter, K.Z. (2020). Overview of General and Discriminating Markers of Differential Microglia Phenotypes. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.00198"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"113949","DOI":"10.1016\/j.expneurol.2021.113949","article-title":"High fat diet-induced obesity leads to depressive and anxiety-like behaviors in mice via AMPK\/mTOR-mediated autophagy","volume":"348","author":"Li","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_48","first-page":"52434","article-title":"Use of the Open Field Maze to Measure Locomotor and Anxiety-like Behavior in Mice","volume":"96","author":"Seibenhener","year":"2015","journal-title":"JoVE"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Holly, K.S., Orndorff, C.O., and Murray, T.A. (2016). MATSAP: An automated analysis of stretch-attend posture in rodent behavioral experiments. Sci. Rep., 6.","DOI":"10.1038\/srep31286"},{"key":"ref_50","first-page":"1088","article-title":"Elevated Plus Maze for Mice","volume":"22","author":"Komada","year":"2008","journal-title":"JoVE"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.nlm.2018.11.008","article-title":"High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss","volume":"157","author":"Duffy","year":"2019","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/S2213-8587(20)30113-3","article-title":"Central nervous pathways of insulin action in the control of metabolism and food intake","volume":"8","author":"Kullmann","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1172\/JCI59903","article-title":"Demonstrated brain insulin resistance in Alzheimer\u2019s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline","volume":"122","author":"Talbot","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.mito.2021.08.014","article-title":"Altered insulin pathway compromises mitochondrial function and quality control both in in vitro and in vivo model systems","volume":"60","author":"Galizzi","year":"2021","journal-title":"Mitochondrion"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Salas-Venegas, V., Flores-Torres, R.P., Rodr\u00edguez-Cort\u00e9s, Y.M., Rodr\u00edguez-Retana, D., Ram\u00edrez-Carreto, R.J., Concepci\u00f3n-Carrillo, L.E., P\u00e9rez-Flores, L.J., Alarc\u00f3n-Aguilar, A., L\u00f3pez-D\u00edazguerrero, N.E., and G\u00f3mez-Gonz\u00e1lez, B. (2022). The Obese Brain: Mechanisms of Systemic and Local Inflammation, and Interventions to Reverse the Cognitive Deficit. Front. Integr. Neurosci., 16.","DOI":"10.3389\/fnint.2022.798995"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cmet.2017.05.015","article-title":"Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility","volume":"26","author":"Valdearcos","year":"2017","journal-title":"Cell Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"220","DOI":"10.2174\/1871527316666170113120853","article-title":"Synaptic Plasticity, Dementia and Alzheimer Disease","volume":"16","author":"Skaper","year":"2017","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.tins.2017.02.005","article-title":"Obesity-Induced Neuroinflammation: Beyond the Hypothalamus","volume":"40","author":"Muccioli","year":"2017","journal-title":"Trends Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/oby.2007.608","article-title":"High-fat Diets: Modeling the Metabolic Disorders of Human Obesity in Rodents","volume":"15","author":"Buettner","year":"2007","journal-title":"Obesity"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.bbi.2021.05.010","article-title":"High-fat diet induces neuroinflammation and reduces the serotonergic response to escitalopram in the hippocampus of obese rats","volume":"96","author":"Hersey","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Pirozzi, C., Opallo, N., Del Piano, F., Melini, S., and Lama, A. (2025). Body and mind: How obesity triggers neuropsychiatric and neurodegenerative disorders. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1524555"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Mohamed, W., and Kobeissy, F. (2024). The Western Diet Puzzle: Connecting Metabolic Dysfunction to Cognitive and Neurological Consequences. Nutrition and Psychiatric Disorders, Springer Nature. Nutritional Neurosciences.","DOI":"10.1007\/978-981-97-2681-3"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.biopsych.2016.12.031","article-title":"Targeting the Microbiota-Gut-Brain Axis: Prebiotics Have Anxiolytic and Antidepressant-like Effects and Reverse the Impact of Chronic Stress in Mice","volume":"82","author":"Burokas","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"479","DOI":"10.4103\/0976-3147.120200","article-title":"Parasympathetic overactivity: A manifestation of temporal lobe epilepsy","volume":"4","author":"Taksande","year":"2013","journal-title":"J. Neurosci. Rural. Pract."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9481819","DOI":"10.1155\/2019\/9481819","article-title":"Inflammatory Mediators in Obesity","volume":"2019","author":"Kumar","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"164","DOI":"10.4082\/kjfm.2016.37.3.164","article-title":"The Association between Frailty and Cognition in Elderly Women","volume":"37","author":"Kang","year":"2016","journal-title":"Korean J. Fam. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"173411","DOI":"10.1016\/j.ejphar.2020.173411","article-title":"Amisulpride alleviates chronic mild stress-induced cognitive deficits: Role of prefrontal cortex microglia and Wnt\/\u03b2-catenin pathway","volume":"885","author":"Mohamed","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s12974-022-02465-3","article-title":"TLR4 mutation protects neurovascular function and cognitive decline in high-fat diet-fed mice","volume":"19","author":"Obadia","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e249","DOI":"10.1038\/tp.2013.27","article-title":"Anxiety disorders and inflammation in a large adult cohort","volume":"3","author":"Vogelzangs","year":"2013","journal-title":"Transl. Psychiatry"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/npp.2016.146","article-title":"Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond","volume":"42","author":"Michopoulos","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1097\/PSY.0000000000000049","article-title":"Stimulation of Systemic Low-Grade Inflammation by Psychosocial Stress","volume":"76","author":"Rohleder","year":"2014","journal-title":"Psychosom. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/s41398-019-0570-y","article-title":"Inflammation-related biomarkers in major psychiatric disorders: A cross-disorder assessment of reproducibility and specificity in 43 meta-analyses","volume":"9","author":"Yuan","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"108825","DOI":"10.1016\/j.pharmthera.2025.108825","article-title":"The (neuro)inflammatory system in anxiety disorders and PTSD: Potential treatment targets","volume":"269","author":"Sah","year":"2025","journal-title":"Pharmacol. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/978-1-4939-8994-2_4","article-title":"The Elevated Plus Maze Test for Measuring Anxiety-Like Behavior in Rodents","volume":"Volume 1916","author":"Guest","year":"2019","journal-title":"Pre-Clinical Models"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e14522","DOI":"10.1016\/j.heliyon.2023.e14522","article-title":"Comparative analysis between Open Field and Elevated Plus Maze tests as a method for evaluating anxiety-like behavior in mice","volume":"9","author":"Castro","year":"2023","journal-title":"Heliyon"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0166-4328(01)00452-1","article-title":"Evaluation of the elevated plus-maze and open-field tests for the assessment of anxiety-related behaviour in inbred mice","volume":"134","author":"Carola","year":"2002","journal-title":"Behav. Brain Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"8474","DOI":"10.1523\/JNEUROSCI.0378-09.2009","article-title":"Sustained Conditioned Responses in Prelimbic Prefrontal Neurons Are Correlated with Fear Expression and Extinction Failure","volume":"29","author":"Quirk","year":"2009","journal-title":"J. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/8\/580\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:13:06Z","timestamp":1760029986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/8\/580"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,11]]},"references-count":77,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["cells14080580"],"URL":"https:\/\/doi.org\/10.3390\/cells14080580","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,11]]}}}