| Summary: | Increased levels of reactive oxygen species (ROS) and a low-grade chronic inflammation in multiple organs have been demonstrated in obesity. <i>Morus alba</i> leaves extracts (MAEs) have been used in traditional medicine as anti-inflammatory agents. In this work, the bioactive compounds of different genotypes of <i>M. alba L.</i> (<i>Filipina</i>, <i>Valenciana Temprana</i>, <i>Kokuso</i>, and <i>Italia</i>) were analyzed not only by reverse phase high performance liquid chromatography–electrospray ionization-time of flight-mass spectrometry (RP-HPLC-ESI-TOF-MS) and hydrophilic interaction chromatography–electrospray ionization-time of flight-mass spectrometry (HILIC-ESI-TOF-MS), but also screened for in vitro and in vivo antioxidant activity by means of DPPH• radical scavenging assay and <i>Caenorhabditis elegans</i> model. These MAEs were administered daily in a model of diet-induced obesity in mice. <i>Filipina</i> and <i>Italia</i> genotypes significantly reduced weight gain, the glycemic levels in high fat diet, as well as, levels of LDL-cholesterol and triglycerides. <i>Filipina</i> and <i>Italia</i> MAEs also reduced the expression of proinflammatory mediators such as <i>Tnf-α</i>, <i>Il-1β</i>, <i>Il-6</i> and increased the levels of adiponectin and AMPK, which exert anti-inflammatory effects. Moreover, <i>Italia</i> genotype ameliorated the intestinal barrier function. In conclusion, <i>Filipina</i> and <i>Italia</i> methanolic extracts show the highest antioxidant and anti-inflammatory effect, due to the presence of compounds such as protocatechuic acid or quercetin-3-glucoside, and they could be developed as a complementary treatment for obesity and metabolic disorders.
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