Alpha-Linolenic Acid Ameliorates Cognitive Impairment and Liver Damage Caused by Obesity

Background: Obesity is a growing global problem that causes various complications such as
diabetes, cognitive dysfunction, cardiovascular diseases, and hepatobiliary disease. Alpha-
linolenic acid (ALA) has been reported to exhibit multiple pharmaceutical effects. This study
aimed to explore the effects of ALA on obesity-induced adipose tissue accumulation, cognitive
impairment, inflammation, and colonic mucosal barrier integrity. Methods: Mice were fed with
high-fat diet (HFD) and were treated with ALA (60 or 100 mg/kg). Body weight, adipose tissue,
serum glucose and lipid levels, glucose resistance, and insulin resistance were measured.
Cognitive ability was analyzed using the behavior tests. PTP1B and IRS/p-AKT/p-GSK3β/p-Tau
signaling were examined to evaluate inflammation and synaptogenesis. Colon mucosal barrier
integrity was examined by Alcian blue staining and expression of the tight junction proteins. The
production of pro-inflammatory cytokines and liver damages were evaluated. 3T3-L1 cells were
used for in vitro experiments. Cell viability, migration and invasion were detected. The levels of
ROS, iron, and ferrous ions were measured to assess ferroptosis. Metabolomic analysis of
adipose tissues was performed. Results: ALA treatment prevented HFD-induced adipose tissue
accumulation, improved glucose and lipid homeostasis and metabolism. Administration of ALA
repressed the HFD-induced increase in insulin levels and insulin resistance index. Serum and
colon levels of pro-inflammatory cytokines were decreased after ALA treatment. ALA elevated
mitochondrial content in brown adipose tissues. ALA ameliorated obesity-induced cognitive
impairment and hippocampal inflammation, enhanced colon mucosa integrity. ALA treatment
ameliorated HFD-induced liver damage and lipid accumulation and inhibited differentiation of
preadipocyte 3T3-L1 cells into mature adipocytes and induces ferroptosis. Metabolomic analysis
suggested that ALA may target the glycerolipid metabolism pathway to ameliorate obesity.
Knockdown of AGPAT2 abolished the protective effects of ALA. Conclusion: ALA treatment
suppressed adipose accumulation in adipocytes, improved cognitive ability and colon integrity,
and alleviated liver damage by modulating the 1-acylglycerol-3-phosphate O-acyltransferase 2
(AGPAT2).