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It is important to develop effective approaches for obesity treatment. Oral supplementation with spermidine retards age\u2010related processes, but its influences on obesity and various metabolic tissues remain largely unknow. This study aims to investigate the effects of oral spermidine on brown adipose tissue (BAT) and skeletal muscle as well as its roles in counteracting obesity and metabolic disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Spermidine is orally administrated into high\u2010fat diet (HFD)\u2010fed mice. The weight gain, insulin resistance, and hepatic steatosis are attenuated by oral spermidine in HFD\u2010fed mice, accompanied by an alleviation of white adipose tissue inflammation. Oral spermidine promotes BAT activation and metabolic adaptation of skeletal muscle in HFD\u2010fed mice, evidenced by UCP\u20101 induction and CREB activation in both tissues. Notably, oral spermidine upregulates tyrosine hydroxylase in hypothalamus of HFD\u2010fed mice; spermidine treatment increases tyrosine hydroxylase expression and norepinephrine production in neurocytes, which leads to CREB activation and UCP\u20101 induction in brown adipocytes and myotubes. Spermidine also directly promotes UCP\u20101 and PGC\u20101\u03b1 expression in brown adipocytes and myotubes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Spermidine serves as an oral supplement to attenuate obesity and metabolic disorders through hypothalamus\u2010dependent or \u2010independent BAT activation and skeletal muscle adaptation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202100315","type":"journal-article","created":{"date-parts":[[2021,8,7]],"date-time":"2021-08-07T14:20:35Z","timestamp":1628346035000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Oral Spermidine Targets Brown Fat and Skeletal Muscle to Mitigate Diet\u2010Induced Obesity and Metabolic Disorders"],"prefix":"10.1002","volume":"65","author":[{"given":"Di","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Infection and Immunity of Shandong Province Shandong Provincial Clinical 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