Docosahexaenoic acid‐acylated astaxanthin monoester ameliorates chronic high‐fat diet‐induced autophagy dysfunction via ULK1 pathway in the hypothalamus of mice

Abstract Background Dietary astaxanthin (AST) exhibits the ability to resist lipid accumulation and stimulate hepatic autophagy. Natural AST predominantly exists in stable esterified forms. More importantly, in our previous study, docosahexaenoic acid‐acylated AST monoester (AST‐DHA) possessed better stability, bioavailability, and neuroprotective ability than AST in free and diester form. However, the AST‐DHA mechanisms of action in regulating the obese phenotype and autophagy of the central nervous system remain unclear. Results High‐fat diet (HFD)‐fed C57BL/6J mice were orally administered AST‐DHA (50 mg/kg body weight/d) for 3 days or 8 weeks. AST‐DHA supplementation alleviated HFD‐induced abnormal body weight gain, significantly enhanced autophagy with an increased microtubule‐associated protein light chain 3 II/I (LC3II/I) ratio, and reduced the accumulation of p62/sequestosome 1 (SQSTM1) in the hypothalamus rather than in the hippocampus. Mechanistically, AST‐DHA effectively promoted autophagy and autophagosome formation, and most notably rescued the HFD‐impaired autophagosome‐lysosome fusion (indicated by the colocalization of LC3 and LAMP1) by regulating mTOR‐ and AMPK‐induced phosphorylation of ULK1. Consequently, AST‐DHA enhanced hypothalamic autophagy, leading to pro‐opiomelanocortin (POMC) cleavage to produce alpha‐melanocyte‐stimulating hormone (α‐MSH). Conclusions This study identified AST‐DHA as an enhancer of autophagy that plays a beneficial role in restoring hypothalamic autophagy, and as a new potential therapeutic agent against HFD‐induced obesity. © 2023 Society of Chemical Industry.