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This study evaluated the impact of chronic caffeine consumption on weight gain, food intake, and metabolic parameters in C57BL\/6 male mice. Methods: Eight-week-old male mice (28 animals) were divided into four groups: control (chow diet), caffeine (chow diet + 1 g\/L caffeine in drinking water), high-fat diet (HFD), and HFD + caffeine (HFD + 1 g\/L caffeine in drinking water). Diets and caffeine were provided ad libitum for 8 weeks. Food and water intake were recorded weekly, and blood glucose was measured every 4 weeks. After 8 weeks of diet and caffeine exposure, metabolic tests were conducted, and tissues were collected for biochemical analysis. Results: HFD consumption for 8 weeks induced an increase in body weight and adiposity compared to the chow diet, without changes in food intake. Caffeine consumption prevented body weight gain and adiposity, although it increased food intake. Caffeine also improved glucose tolerance in the HFD mouse model, without changes in random blood glucose, triglyceride, or cholesterol levels. Analysis of hypothalamic neuropeptide (Agrp, NPY, Pomc, Cart), involved in the control of food intake, showed no differences in expression. There were also no changes observed in locomotion nor in anxiety-like behavior. Conclusions: In conclusion, chronic high-fat diet (HFD) exposure induced obesity characterized by increased body weight and adiposity without altering food intake. Chronic caffeine consumption counteracted HFD-induced weight gain and fat accumulation and improved glucose tolerance, despite increasing food intake. Importantly, caffeine consumption in the HFD group did not affect locomotor activity or anxiety-like behavior, suggesting that its metabolic effects are not driven by changes in general activity or emotional state. Overall, these findings indicate that chronic caffeine consumption improves metabolic homeostasis in HFD-fed mice.<\/jats:p>","DOI":"10.3390\/metabo16060381","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:11:01Z","timestamp":1780333861000},"page":"381","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chronic Caffeine Consumption Prevents Body Weight Gain and Glucose Intolerance in High-Fat Diet-Induced Obesity Mice Model"],"prefix":"10.3390","volume":"16","author":[{"given":"Giuseppe","family":"Faraco","sequence":"first","affiliation":[{"name":"Laboratory of Neuroimmune-Metabolism, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9032-1411","authenticated-orcid":false,"given":"Nat\u00e1lia F.","family":"Mendes","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Department of Translational Medicine (Section of Pharmacology), University of Campinas, Campinas 13083-887, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5127-5640","authenticated-orcid":false,"given":"Luisa O.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimmune-Metabolism, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"},{"name":"Graduate Program in Biochemistry, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7066-2907","authenticated-orcid":false,"given":"Tamires S.","family":"Stivanin","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimmune-Metabolism, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"},{"name":"Graduate Program in Biochemistry, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimmune-Metabolism, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolle","family":"Platt","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Neuroscience, Department of Biochemistry, Federal University of Santa Catarina (UFSC), Florianopolis 88040-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0258-6204","authenticated-orcid":false,"given":"Manuella P.","family":"Kaster","sequence":"additional","affiliation":[{"name":"Graduate Program in Biochemistry, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"},{"name":"Laboratory of Translational Neuroscience, Department of Biochemistry, Federal University of Santa Catarina (UFSC), Florianopolis 88040-970, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3151-4234","authenticated-orcid":false,"given":"Joana M.","family":"Gaspar","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimmune-Metabolism, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"},{"name":"Graduate Program in Biochemistry, Federal University of Santa Catarina, Florianopolis 88040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/S0140-6736(25)00355-1","article-title":"Global, regional, and national prevalence of adult overweight and obesity, 1990\u20132021, with forecasts to 2050: A forecasting study for the Global Burden of Disease Study 2021","volume":"405","author":"Ng","year":"2025","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S2213-8587(24)00316-4","article-title":"Definition and diagnostic criteria of clinical obesity","volume":"13","author":"Rubino","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1016\/S0140-6736(24)00933-4","article-title":"Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990\u20132021: A systematic analysis for the Global Burden of Disease Study 2021","volume":"403","author":"Brauer","year":"2024","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"284","DOI":"10.7861\/clinmed.2023-0168","article-title":"Causes of obesity: A review","volume":"23","author":"Masood","year":"2023","journal-title":"Clin. 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