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This study assessed the therapeutic effects of chlorogenic acid (CGA), a natural polyphenol, administered at 10 mg and 100 mg\/kg\/day for the last 4 weeks of a 12-week HFD protocol. Both CGA doses reduced body weight gain, abdominal circumference, and visceral fat accumulation, with the higher dose showing greater efficacy. CGA improved metabolic parameters by lowering fasting glucose and insulin and enhancing lipid profiles. CGA suppressed orexigenic genes (Agrp, NPY) and upregulated anorexigenic genes (POMC, CARTPT), suggesting appetite regulation in the hypothalamus. In abdominal white adipose tissue (WAT), CGA boosted antioxidant defenses (SOD, CAT, GPx, HO-1), reduced lipid peroxidation (MDA), and suppressed pro-inflammatory cytokines including TNF-\u03b1, IFN-\u03b3, and IL-1\u03b2, while increasing the anti-inflammatory cytokine IL-10. CGA modulated inflammatory signaling via upregulation of miR-146a and inhibition of IRAK1, TRAF6, and NF-\u03baB. It also reduced apoptosis by downregulating p53, Bax, and Caspase-3, and restoring Bcl-2. These findings demonstrate that short-term CGA administration effectively reverses multiple HFD-induced impairments, highlighting its potential as an effective therapeutic for obesity-related metabolic disorders.<\/jats:p>","DOI":"10.3390\/biom15081086","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T07:57:24Z","timestamp":1753689444000},"page":"1086","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["A Natural Polyphenol, Chlorogenic Acid, Attenuates Obesity-Related Metabolic Disorders in Male Rats via miR-146a-IRAK1-TRAF6 and NRF2-Mediated Antioxidant Pathways"],"prefix":"10.3390","volume":"15","author":[{"given":"Rashid Fahed","family":"Alenezi","sequence":"first","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adel","family":"Abdelkhalek","sequence":"additional","affiliation":[{"name":"Department of Food Safety, Hygiene and Technology, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gehad","family":"El-Sayed","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2157-5009","authenticated-orcid":false,"given":"Ioan","family":"Pet","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Bioengineering of Animals Resources, University of Life Sciences \u201cKing Mihai I\u201d from Timisoara, 300645 Timisoara, Romania"},{"name":"Institute of Applied Biotechnology, 300645 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8033-8463","authenticated-orcid":false,"given":"Mirela","family":"Ahmadi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Faculty of Bioengineering of Animals Resources, University of Life Sciences \u201cKing Mihai I\u201d from Timisoara, 300645 Timisoara, Romania"},{"name":"Institute of Applied Biotechnology, 300645 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El Said El","family":"Sherbini","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Pu\u0219ca\u0219iu","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Victor Babes University of Medicine and Pharmacy Timisoara, 2 Eftimie Murgu Street, 300041 Timisoara, Romania"},{"name":"ANAPATMOL Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, 2 Eftimie Murgu Street, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1330-6311","authenticated-orcid":false,"given":"Ahmed Hamed","family":"Arisha","sequence":"additional","affiliation":[{"name":"Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt"},{"name":"Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s13679-023-00495-3","article-title":"Obesity Stigma: Causes, Consequences, and Potential Solutions","volume":"12","author":"Westbury","year":"2023","journal-title":"Curr. 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