High dose of an n-3 polyunsaturated fatty acid diet lowers activity of C57BL/6 mice

Abstract

n-3 Polyunsaturated fatty acids (PUFA) are increasingly consumed as food additives and supplements; however, the side effects of these fatty acids, especially at high doses, remain unclear. We previously discovered a high fat n-3 PUFA diet made of fish/flaxseed oils promoted significant weight gain in C57BL/6 mice, relative to a control, without changes in food consumption. Therefore, here we tested the effects of feeding mice high fat (HF) and low fat (LF) n-3 PUFA diets, relative to a purified control diet (CD), on locomotor activity using metabolic cages. Relative to CD, the HF n-3 PUFA diet, but not the LF n-3 PUFA diet, dramatically reduced ambulatory, rearing, and running wheel activities. Furthermore, the HF n-3 PUFA diet lowered the respiratory exchange ratio. The data suggest mixed fish/flaxseed oil diets at high doses could exert some negative side effects and likely have limited therapeutic applications.

Introduction

n-3 Polyunsaturated fatty acids (PUFAs), the bioactive components of fish and flaxseed oil, are routinely consumed by the public as food additives or supplements. They are also recognized to have utility for treating metabolic and inflammatory diseases [1], [2], [3], [4], [5]. Generally, dietary studies evaluating n-3 PUFA efficacy in differing model systems have relied on low doses of n-3 PUFAs. With animal studies, investigators have commonly used ∼5% (weight/weight) fish or flaxseed oil as intervention, corresponding to approximately 2–6% of total energy as n-3 PUFAs [6]. This dose, especially of fish oil, is often selected to model n-3 PUFA intake of Greenland Eskimos that consume n-3 PUFAs in the range of 1–6% of total energy [7], [8]. A few studies have tested the effects of fish or flaxseed oils at higher doses with mixed results on functional endpoints [9], [10], [11]. Overall, very little is known about the effects of high doses of n-3 PUFAs, which could have a unique therapeutic niche or could exert negative side effects, raising potential safety issues for the general public.

We previously reported long-term administration of high levels of a mixed fish/flaxseed oil diet to C57BL/6 mice promoted significant body weight gain [12]. These findings suggested high doses of n-3 PUFAs increased body weight by lowering activity since we ruled out changes in food consumption [12]. Therefore, the objective of this study was to determine if short-term dietary consumption of a high dose of n-3 PUFAs could lower energy expenditure prior to any large differences in body weight. Studies were conducted in comparison to a low fat (LF) purified mouse control diet (CD) and a LF n-3 PUFA diet.