Food & Function · Nov 9, 2026
n-3 polyunsaturated fatty acids ameliorate obesity with cognitive impairment by promoting adipose browning and remodeling of brain lipid metabolism
By Mu R, Zhang Y, Zhou C et al.
In the context of population aging, the global prevalence of obesity and mild cognitive impairment (MCI) continues to rise, underscoring the need for effective interventions. While n-3 polyunsaturated fatty acids (n-3 PUFAs) benefit weight reduction and cognition, the underlying mechanism remains unclear. This study investigated this mechanism using human data and animal models. Cross-sectional analysis of UK Biobank data showed that plasma n-3 PUFA levels were significantly lower in patients with MCI than in healthy controls, indicating an association between lower n-3 PUFA levels and MCI. In a mouse model of obesity with underlying Alzheimer's disease (AD)-like pathology (high-fat diet-fed 5xFAD mice, a transgenic model of familial AD), dietary fish oil intervention reduced white adipocyte size, upregulated beige fat markers (UCP1 and Prdm16), and improved cognitive performance alongside increased synaptic protein PSD95. Furthermore, n-3 PUFAs decreased plasma pro-inflammatory factors (GROα and Eotaxin) and remodeled the brain lipid profile of obese mice with cognitive impairment. Dietary fish oil intervention significantly increased the brain PUFA content, along with marked elevations in the relative levels of sphingomyelin, diglyceride, triglyceride, fatty acids, phosphatidylcholine, phosphatidic acid, phosphatidylserine, and phosphatidylethanolamine, whereas ceramide levels were significantly reduced. These findings suggest that n-3 PUFAs may ameliorate obesity and cognitive impairment in the context of underlying AD pathology through two parallel mechanisms linked to lipid metabolism: promoting adipose tissue browning and directly reprogramming brain lipid metabolism.