(P23-055-23) Effects of Eicosapentaenoic Acid (EPA) on Brown Adipose Tissue Metabolism in Diet Induced Obese Female APPswePS1dE9 Alzheimer’s Disease Mouse Model

Objectives: Alzheimer’s disease (AD) is a neurodegenerative disease characterized in part by accumulation of amyloid-beta (Ab) plaques in the brain.Obesity and its related white adipose tissue and systemic inflammation are important risk factors for AD. Moreover, brown adipose tissue (BAT) dysfunction is an important contributor to obesity, and age-related thermoregulatory deficit has been linked to AD. Besides thermogenesis, BAT plays a key role in metabolic regulations such as increasing glucose utilization and energy expenditure, reducing insulin resistance, all of which may prevent or reduce AD. We previously reported that eicosapentaenoic acid (EPA) reduced serum amyloid β (Aβ) and improved metabolic outcomes in transgenic (TG) amyloidogenic AD mice fed high fat (HF) diets, compared to mice consuming HF devoid of fish oil. Thus, we hypothesized that EPA may improve metabolic dysfunctions in obese AD mice, partly through activation of BAT thermogenic program.

Methods: Two-month-old female APPswePS1dE9 TG mice and non-TG wild type (WT) littermates were fed low-fat (LF; 10% kcal fat), or HF (45% kcal fat) diets without or with EPA supplementation (36g/kg) for 32 weeks. Glucose tolerance tests and body composition were conducted.Following euthanasia, BAT and other tissues were collected and used for gene and protein expression analyses by qRT-PCR and western blots, respectively.

Results: In both genotypes, HF diet significantly reduced glucose clearance, and increased fat mass compared to the LF diet.In TG mice, HF group had higher expression levels of thermogenic markers including CIDEA,SIRT3, and PPAR-γ, compared to LF group (p < 0.05). Additionally, supplementation with EPA increased mRNA levels of Sirt1 compared to HF in TG mice (p < 0.01).Furthermore, inflammatory markers IL-1β and TNF-α were significantly increased in TG mice fed HF compared to LF diets (p < 0.01), and supplementation with EPA reduced IL-1β compared to HF in mice (p < 0.01).

Conclusions: HF diet increased thermogenesis and inflammatory markers in BAT of AD mice. EPA further increased thermogenic markers and decreased inflammatory markers in AD mice, warranting further investigations into BAT mechanisms of EPA in AD-associated obesity.

Funding Sources: NIH National Center for Complementary and Integrated Health (NCCIH) and a Supplement from the National Institute on Aging (R15 AT008879‐01A1S1)