{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:53:19Z","timestamp":1789073599322,"version":"build-2803163510"},"reference-count":86,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T00:00:00Z","timestamp":1661385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministrio de Ciencia e Innovaci\u00f3n (Spain) and European Regional Development Fund (ERDF)","award":["SAF2016-79794-R"],"award-info":[{"award-number":["SAF2016-79794-R"]}]},{"name":"Ministrio de Ciencia e Innovaci\u00f3n (Spain) and European Regional Development Fund (ERDF)","award":["B-CTS-102-UGR20"],"award-info":[{"award-number":["B-CTS-102-UGR20"]}]},{"name":"University of Granada &amp; FEDER Andaluc\u00eda-UGR 2020","award":["SAF2016-79794-R"],"award-info":[{"award-number":["SAF2016-79794-R"]}]},{"name":"University of Granada &amp; FEDER Andaluc\u00eda-UGR 2020","award":["B-CTS-102-UGR20"],"award-info":[{"award-number":["B-CTS-102-UGR20"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Experimental data have revealed that melatonin at high doses reduced obesity and improved metabolic outcomes in experimental models of obesity, mainly by enhancing brown adipose tissue (BAT) thermogenesis. A potential dose-response relationship has yet to be performed to translate these promising findings into potential clinical therapy. This study aimed to assess the effects of different doses of melatonin on interscapular BAT (iBAT) thermogenic capacity in Z\u00fccker diabetic fatty (ZDF) rats. At 6 wk of age, male ZDF rats were divided into four groups (n = 4 per group): control and those treated with different doses of melatonin (0.1, 1, and 10 mg\/kg of body weight) in their drinking water for 6 wk. Body weight (BW) was significantly decreased at doses of 1 and 10 mg\/kg of melatonin, but not at 0.1 mg\/kg compared with the control, with a similar rate of BW decrease being reached at the dose of 1 mg\/kg (by ~11%) and 10 mg\/kg (by ~12%). This effect was associated with a dose-dependent increase in the thermal response to the baseline condition or acute cold challenge in the interscapular area measurable by infrared thermography, with the highest thermal response being recorded at the 10 mg\/kg dose. Upon histology, melatonin treatment markedly restored the typical brownish appearance of the tissue and promoted a shift in size distribution toward smaller adipocytes in a dose-dependent fashion, with the most pronounced brownish phenotype being observed at 10 mg\/kg of melatonin. As a hallmark of thermogenesis, the protein level of uncoupled protein 1 (UCP1) from immunofluorescence and Western blot analysis increased significantly and dose-dependently at all three doses of melatonin, reaching the highest level at the dose of 10 mg\/kg. Likewise, all three doses of melatonin modulated iBAT mitochondrial dynamics by increasing protein expression of the optic atrophy protein type 1 (OPA1) fusion marker and decreasing that of the dynamin-related protein1 (DRP1) fission marker, again dose-dependently, with the highest and lowest expression levels, respectively, being reached at the 10 mg\/kg dose. These findings highlight for the first time the relevance of the dose-dependency of melatonin toward BW control and BAT thermogenic activation, which may have potential therapeutic implications for the treatment of obesity. To clinically apply the potential therapeutic of melatonin for obesity, we consider that the effective animal doses that should be extrapolated to obese individuals may be within the dose range of 1 to 10 mg\/kg.<\/jats:p>","DOI":"10.3390\/antiox11091646","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T21:28:12Z","timestamp":1661462892000},"page":"1646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Dose-Dependent Effect of Melatonin on BAT Thermogenesis in Z\u00fccker Diabetic Fatty Rat: Future Clinical Implications for Obesity"],"prefix":"10.3390","volume":"11","author":[{"given":"Samira","family":"Aouichat","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Biohealth Institute Granada (IBs Granada) and Neuroscience Institute, School of Medicine, University of Granada, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Raya","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital Clinic San Cecilio, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2955-5064","authenticated-orcid":false,"given":"Antonio","family":"Molina-Carballo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Unit of Pediatric Neurology and Neurodevelopment, University Hospital Clinic San Cecilio, Andalusian Health Service, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Munoz-Hoyos","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Granada, 18016 Granada, Spain"},{"name":"Unit of Pediatric Neurology and Neurodevelopment, University Hospital Clinic San Cecilio, Andalusian Health Service, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelkarim Saleh","family":"Aloweidi","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Intensive Care, Faculty of Medicine, University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4484-3678","authenticated-orcid":false,"given":"Ehab Kotb","family":"Elmahallawy","sequence":"additional","affiliation":[{"name":"Department of Zoonoses, Faculty of Veterinary Medicine, Sohag University, Sohag 82524, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0164-9648","authenticated-orcid":false,"given":"Ahmad","family":"Agil","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Biohealth Institute Granada (IBs Granada) and Neuroscience Institute, School of Medicine, University of Granada, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,25]]},"reference":[{"key":"ref_1","unstructured":"WHO (2018). 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