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

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.