Heart DHA turnover is faster in female compared to male ALA- and EPA-fed mice

Abstract

Young females have higher circulating docosahexaenoic acid (DHA) levels than males, though the metabolic basis remains incompletely understood. Building on previous findings that demonstrate higher hepatic synthesis of the DHA precursor, docosapentaenoic acid (DPAn-3), in males, this study extends the investigation to n-3 PUFA turnover in extrahepatic tissues of male and female C57BL/6N mice using compound-specific isotope analysis (CSIA). Animals were fed a 12-week diet enriched in either α-linolenic acid (ALA), eicosapentaenoic acid (EPA), or DHA, starting with a 4-week phase containing low carbon-13 (δ¹³C)-n-3 PUFA, followed by an 8-week phase with high δ¹³C-n-3 PUFA (n = 4 per diet, time point, sex). Heart, perirenal adipose tissue (PRAT), brain, and red blood cells (RBCs) were collected at baseline and at seven time points (1-56 days) post-diet switch, with δ¹³C-n-3 PUFA values modeled by one-phase exponential decay. Compared to males, females exhibited slower turnover of ALA (48%-61% slower) and DPAn-3 (26%-73% slower) from dietary ALA or EPA in the heart, PRAT, and RBCs, resulting from longer half-lives and/or lower DPAn-3 concentrations. Conversely, females showed 26%-28% faster heart DHA turnover from dietary ALA or EPA, despite similar half-lives between sexes. Notably, sex-specific differences in DHA turnover were present only in the heart, whereas DPAn-3 turnover varied across multiple tissues, suggesting a heart-specific mechanism that enhances DHA metabolism in females under low DHA intake. Further research is needed to investigate the physiological significance of these metabolic differences and their potential health implications.

Keywords: DHA turnover; dietary fat; extrahepatic; fatty acid metabolism; kinetics; nutrition; omega-3 fatty acids; polyunsaturated fatty acid; sex differences.

Fig. 1

Mean heart concentrations (μmol/g, bar graph) and relative percent (fatty acid in % total fatty acids, scatterplot) of (A) ALA, (B) EPA, (C) DPAn-3, and (D) DHA of ALA-, EPA-, and DHA-fed mice. ∗ and ∗∗ represent statistically significant differences relative to females within each diet group as determined by an independent t test at P-values < 0.05 and < 0.001, respectively. Values are means ± SEM (n = 28). ALA, α-linolenic acid; DHA, docosahexaenoic acid; DPAn-3, docosapentaenoic acid; EPA, eicosapentaenoic acid.

Fig. 2

Mean perirenal adipose tissue (PRAT) concentrations (nmol/ml, bar graph) and relative percent (fatty acid in % total fatty acids, scatterplot) of (A) ALA, (B) EPA, (C) DPAn-3, and (D) DHA of ALA-, EPA-, and DHA-fed mice. ∗ and ∗∗ represent statistically significant differences relative to females within each diet group as determined by an independent t test at P-values < 0.05 and < 0.001, respectively. Values are means ± SEM (n = 28). ALA, α-linolenic acid; DHA, docosahexaenoic acid; DPAn-3, docosapentaenoic acid; EPA, eicosapentaenoic acid.

Fig. 3

Mean brain concentrations (μmol/g, bar graph) and relative percent (fatty acid in % total fatty acids, scatterplot) of (A) ALA, (B) EPA, (C) DPAn-3, and (D) DHA of ALA-, EPA-, and DHA-fed mice. ∗ and ∗∗ represent statistically significant differences relative to females within each diet group as determined by an independent t test at P-values < 0.05 and < 0.001, respectively. Values are means ± SEM (n = 28). ALA, α-linolenic acid; DHA, docosahexaenoic acid; DPAn-3, n-3 docosapentaenoic acid; EPA, eicosapentaenoic acid.

Fig. 4

Mean red blood cell (RBC) concentrations (nmol/g, bar graph) and relative percent (fatty acid in % total fatty acids, scatterplot) of (A) ALA, (B) EPA, (C) DPAn-3, and (D) DHA of ALA-, EPA-, and DHA-fed mice. ∗ and ∗∗ represent statistically significant differences relative to females within each diet group as determined by an independent t test at P-values < 0.05 and < 0.001, respectively. Values are means ± SEM (n = 28). ALA, α-linolenic acid; DHA, docosahexaenoic acid; DPAn-3, n-3 docosapentaenoic acid; EPA, eicosapentaenoic acid.

Fig. 5

Summary of significant sex differences in the rate of turnover of n-3 PUFA from dietary ALA and EPA in the heart, perirenal adipose tissue, and red blood cells. Created with BioRender.com. ALA, α-linolenic acid; DHA, docosahexaenoic acid; DPAn-3, n-3 docosapentaenoic acid; EPA, eicosapentaenoic acid; F, females; M, males.