Obesity is a complex disease with numerous molecular and metabolic implications that could be prevented through proper diet and lifestyle. Native corn is a promissory underutilized plant species containing bioactive compounds that could reduce the impact of obesity. This research aimed to characterize and evaluate the anti-obesogenic effect of a polyphenols-rich extract of native corn (‘Elotes Occidentales’) in HFD-fed mice. The powdered extract was administered using gelatins to C57BL/6 J mice randomly divided into four groups (n:8/group) for 13 weeks: standard diet (SD) group, HFD group, HFD+200 mg extract/kg body weight (BW), and HFD+400 mg extract/kg BW/day. Ellagic acid, chlorogenic acid, rutin, and kaempferol were the most abundant phenolics (2022.44–4028.43 µg/g). Among the HFD groups, the highest dose of the extracts promoted the lowest BW gain, and fasting triglycerides and cholesterol levels. Moreover, the HFD+400 mg/kg BW group showed the lowest epididymal and subcutaneous adipose tissue weight and adipocytes’ diameter and area between the HFD-treated animals. The extract administration prevented hepatic lipid accumulation. Rutin demonstrated the highest in silico binding affinity with proteins from the AMPK pathway (ACACA, SIRT1, and SREBP1) (-6.70 to −8.70 kcal/mol). Results indicated beneficial effects in alleviating obesity-associated parameters in vivo due to bioactive compounds from native maize extracts.
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