Allometric scaling of dietary linoleic acid on changes in tissue arachidonic acid using human equivalent diets in mice

Abstract

Background: It is hypothesized that dietary linoleic acid (LA) promotes chronic and acute diseases in humans by enriching tissues with arachidonic acid (AA), its downstream metabolite, and dietary studies with rodents have been useful for validation. However, levels of LA in research diets of rodents, as published in the literature, are notoriously erratic making interspecies comparisons unreliable. Therefore, the ability to extrapolate the biological effects of dietary LA from experimental rodents to humans necessitates an allometric scaling model that is rooted within a human equivalent context.

Methods: To determine the physiological response of dietary LA on tissue AA, a mathematical model for extrapolating nutrients based on energy was used, as opposed to differences in body weight. C57BL/6J mice were divided into 9 groups fed a background diet equivalent to that of the US diet (% energy) with supplemental doses of LA or AA. Changes in the phospholipid fatty acid compositions were monitored in plasma and erythrocytes and compared to data from humans supplemented with equivalent doses of LA or AA.

Results: Increasing dietary LA had little effect on tissue AA, while supplementing diets with AA significantly increased tissue AA levels, importantly recapitulating results from human trials.

Conclusions: Thus, interspecies comparisons for dietary LA between rodents and humans can be achieved when rodents are provided human equivalent doses based on differences in metabolic activity as defined by energy consumption.

Figure 1

Effects of increasing/decreasing dietary linoleic acid on changes in plasma/serum phospholipid fatty acid concentration. Mice were fed background diets that mimicked the composition of a Western diet with increasing or decreasing levels (% change, based on energy) of linoleic acid. The data (mole %) is presented as mean ± SD. Means with the same superscript within the same row (i.e., individual fatty acid) are not statistically different at (p < 0.05). Groups of bars within each fatty acid without superscripts indicate no significant differences were observed among groups. Abbreviations: LA, linoleic acid.

Figure 2

Effects of increasing dietary arachidonic acid on changes in plasma/serum phospholipid fatty acid concentration. Mice were fed background diets that mimicked the composition of a Western diet with increasing levels (% change, based on energy) of arachidonic acid. The data (mole %) is presented as mean ± SD. Means with the same superscript within the same row (i.e., individual fatty acid) are not statistically different at (p < 0.05). Groups of bars within each fatty acid without superscripts indicate no significant differences were observed among groups. Abbreviations: AA, arachidonic acid.

Figure 3

Effects of increasing/decreasing dietary linoleic acid on changes in erythrocyte phospholipid fatty acid concentration. Mice were fed background diets that mimicked the composition of a Western diet with increasing or decreasing levels (% change, based on energy) of linoleic acid. The data (mole %) is presented as mean ± SD. Means with the same superscript within the same row (i.e., individual fatty acid) are not statistically different at (p < 0.05). Groups of bars within each fatty acid without superscripts indicate no significant differences were observed among groups. Abbreviations: LA, linoleic acid.

Figure 4

Effects of increasing dietary arachidonic acid on changes in erythrocyte phospholipid fatty acid concentration. Mice were fed background diets that mimicked the composition of a Western diet with increasing levels (% change, based on energy) of arachidonic acid. The data (mole %) is presented as mean ± SD. Means with the same superscript within the same row (i.e., individual fatty acids) are not statistically different at (p < 0.05). Groups of bars within each fatty acid without superscripts indicate no significant differences were observed among groups. Abbreviations: AA, arachidonic acid.

Figure 5

Comparison of LA data in the mouse to similar data generated in human clinical trials; increasing levels of supplemented LA (% change based on energy) on changes in plasma/serum AA content. The changes in AA levels of plasma phospholipids from this study (red squares) were plotted against archival data from human clinical trials (blue diamonds) (used with permission, see ref. 11). Abbreviations: AA, arachidonic acid; LA, linoleic acid; PL phospholipids.

Figure 6

Comparison of AA data in the mouse to similar data generated in human clinical trials; increasing levels of supplemented AA (% change based on energy) on changes in plasma/serum AA content. The changes in AA levels of plasma phospholipids from this study (red squares) were plotted against archival data from human clinical trials (blue diamonds) (used with permission, see ref. 11). Abbreviations: AA, arachidonic acid; PL phospholipids.