Turnover of brain DHA in mice is accurately determined by tracer-free natural abundance carbon isotope ratio analysis

The brain is highly enriched in the long-chain omega-3 (n-3) PUFA DHA. Due to the limited capacity for local DHA synthesis in the brain, it relies on a continual supply from the circulation to replenish metabolized DHA. Previous studies investigating brain DHA turnover and metabolism have relied on isotope tracers to determine brain fatty acid kinetics; however, this approach is cumbersome and costly. We applied natural abundance carbon isotope ratio analysis via high-precision gas chromatography combustion isotope ratio mass spectrometry, without the use of labeled tracers, to determine the half-life of brain DHA in mice following a dietary switch experiment. Mice fed diets containing either α-linolenic acid (ALA) or DHA as the sole dietary n-3 PUFA were switched onto diets containing ALA, DHA, or ALA + DHA at 6 weeks of age, while control mice were maintained on their respective background diet. We measured brain DHA carbon isotope ratios (reported as δ13CDHA signatures) over a 168-day time course. Brain δ13CDHA signatures of control mice maintained on background diets over the time course were stable (P > 0.05). Brain δ13CDHA signatures of mice switched to the DHA or ALA + DHA diet from the ALA diet changed over time, yielding brain incorporation half-lives of 40 and 34 days, respectively. These half-lives determined by natural abundance carbon isotope ratio analysis were consistent with estimates from kinetic isotope tracer studies. Our results demonstrate the feasibility of natural abundance carbon isotope ratio analysis in the study of fatty acid metabolism without the use of isotopically labeled fatty acid tracers. The brain is highly enriched in the long-chain omega-3 (n-3) PUFA DHA. Due to the limited capacity for local DHA synthesis in the brain, it relies on a continual supply from the circulation to replenish metabolized DHA. Previous studies investigating brain DHA turnover and metabolism have relied on isotope tracers to determine brain fatty acid kinetics; however, this approach is cumbersome and costly. We applied natural abundance carbon isotope ratio analysis via high-precision gas chromatography combustion isotope ratio mass spectrometry, without the use of labeled tracers, to determine the half-life of brain DHA in mice following a dietary switch experiment. Mice fed diets containing either α-linolenic acid (ALA) or DHA as the sole dietary n-3 PUFA were switched onto diets containing ALA, DHA, or ALA + DHA at 6 weeks of age, while control mice were maintained on their respective background diet. We measured brain DHA carbon isotope ratios (reported as δ13CDHA signatures) over a 168-day time course. Brain δ13CDHA signatures of control mice maintained on background diets over the time course were stable (P > 0.05). Brain δ13CDHA signatures of mice switched to the DHA or ALA + DHA diet from the ALA diet changed over time, yielding brain incorporation half-lives of 40 and 34 days, respectively. These half-lives determined by natural abundance carbon isotope ratio analysis were consistent with estimates from kinetic isotope tracer studies. Our results demonstrate the feasibility of natural abundance carbon isotope ratio analysis in the study of fatty acid metabolism without the use of isotopically labeled fatty acid tracers. The composition of fatty acids in the brain is unique compared with most other tissues in that the brain is highly enriched in the long-chain omega-3 (n-3) PUFA DHA (22:6 n-3) (1Lacombe R.J.S. Chouinard-Watkins R. Bazinet R.P. Brain docosahexaenoic acid uptake and metabolism.Mol. Aspects Med. 2018; 64: 109-134Crossref PubMed Scopus (86) Google Scholar, 2Fliesler S.J. Anderson R.E. Chemistry and metabolism of lipids in the vertebrate retina.Prog. Lipid Res. 1983; 22: 79-131Crossref PubMed Scopus (826) Google Scholar). Mounting evidence indicates a role of DHA and its bioactive products in the support and regulation of optimal neuronal and synaptic function (3Bazinet R.P. Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease.Nat. Rev. Neurosci. 2014; 15: 771-785Crossref PubMed Scopus (827) Google Scholar). Furthermore, consistent with the hypothesis that brain DHA homeostasis is critical in supporting optimal brain function, postmortem analyses suggest that brain DHA levels may be altered, either as cause or consequence, in many neurological and neuropsychiatric disorders (1Lacombe R.J.S. Chouinard-Watkins R. Bazinet R.P. Brain docosahexaenoic acid uptake and metabolism.Mol. Aspects Med. 2018; 64: 109-134Crossref PubMed Scopus (86) Google Scholar). Although it appears to be vital in supporting brain function, DHA is not efficiently synthesized locally within the brain, and therefore DHA must be incorporated preformed from circulating plasma pools to replenish that which has been metabolized (4Demar J.C. Ma K. Chang L. Bell J.M. acid not to docosahexaenoic acid within brain of fed a diet enriched in docosahexaenoic PubMed Scopus Google Scholar, Bazinet R.P. docosahexaenoic acid synthesis from acid to supply the Lipid Res. PubMed Scopus Google Scholar). kinetic tracer studies have been to the incorporation and metabolism of DHA in the brain, as as the that may its the of following of DHA, the brain DHA half-life in has been determined to and and is to n-3 PUFA dietary J.C. Ma K. Bell J.M. of docosahexaenoic acid in brain by weeks of of n-3 fatty PubMed Scopus Google Scholar, Bazinet R.P. dietary PUFA to of acid and of DHA in brain Lipid Res. PubMed Scopus Google Scholar, L. Bazinet R.P. docosahexaenoic acid is the the PubMed Scopus Google Scholar). of DHA have been to the of on brain DHA uptake and turnover R.P. Chang L. the incorporation and turnover of acid not docosahexaenoic acid in brain of the to PubMed Scopus Google Scholar, R.P. Chang L. not the of docosahexaenoic acid within brain of the PubMed Scopus Google Scholar, S. Chang L. Bazinet R.P. not the of or docosahexaenoic acid in brain of the Res. PubMed Scopus Google Scholar, Bell J.M. of docosahexaenoic acid metabolism in the of of Res. PubMed Scopus Google as as to the plasma the brain L. Bazinet R.P. docosahexaenoic acid is the the PubMed Scopus Google Scholar, fatty acids in to efficiently by the brain the PubMed Scopus Google Scholar, incorporation of DHA over DHA in the Google Scholar, R. R.J.S. Bazinet R.P. brain in to docosahexaenoic acid PubMed Scopus Google Scholar). to the use of labeled DHA tracers have been applied to brain DHA and its the brain its docosahexaenoic of dietary docosahexaenoic and in the Res. PubMed Scopus Google Scholar, L. Ma of dietary α-linolenic and docosahexaenoic acids as of in brain and of Res. PubMed Scopus Google Scholar, L. K. of dietary DHA as a as a for brain DHA in Lipid Res. 2014; PubMed Scopus Google Scholar). Although for the of brain DHA to study and a analysis to the with the synthesis of tracer abundance analysis may to the use of tracers investigating fatty acid incorporation and the carbon of a is following incorporation from the highly natural abundance carbon isotope ratio as in of by gas chromatography isotope ratio mass the of a of in the carbon of and in of and for and carbon isotope ratios of natural and mass Google Scholar, isotope in Scopus Google Scholar). the use of dietary switch have the natural in carbon isotope ratios and to turnover to of and analysis and turnover of stable carbon in for analysis of 1983; PubMed Scopus Google Scholar, in vertebrate diets stable PubMed Scopus Google Scholar). dietary studies in have in natural abundance carbon isotope ratios to the of synthesis from fatty acids to the long-chain PUFA acid and DHA in of acid synthesis in natural of PubMed Scopus Google Scholar, of long-chain fatty acids in fed with long-chain fatty PubMed Scopus Google Scholar). Our has on the use of natural abundance carbon isotope ratios measured by isotope analysis to determine the of to plasma DHA levels in Chouinard-Watkins R. Bazinet R.P. is a to in acid following docosahexaenoic acid as determined by isotope analysis in PubMed Scopus Google and in Bazinet R.P. isotope analysis of DHA to of to DHA following a control PubMed Scopus Google and to the dietary of brain DHA R.J.S. Bazinet R.P. isotope analysis the dietary of docosahexaenoic acid in the Lipid Res. PubMed Scopus Google Scholar, R.J.S. Bazinet R.P. stable carbon analysis at the natural abundance to determine the of docosahexaenoic acid in the brain of the 2018; PubMed Scopus Google Scholar). the in carbon isotope ratios and n-3 that brain DHA, by either a diet containing α-linolenic acid (ALA) or DHA, by R.J.S. Bazinet R.P. isotope analysis the dietary of docosahexaenoic acid in the Lipid Res. PubMed Scopus Google Scholar). the applied a dietary switch in which dietary n-3 PUFA and their respective carbon isotope ratios were altered, and in brain, and DHA carbon isotope ratios to as were measured over a 168-day time course. The in δ13CDHA signatures were by a function to determine incorporation Our results that brain incorporation half-lives from the dietary switch were consistent with determined from kinetic that preformed DHA is the of DHA for the brain ALA is at levels in the diet. These results the of natural abundance to study fatty acid metabolism in a without the of labeled tracer were or and were from either or acid and fatty acid were from and were from the were by the of and in with the and of the on and the of of were in a a with to and of mice were maintained on a diet containing either ALA or DHA as the n-3 PUFA for Our has that brain δ13CDHA signatures with the of dietary n-3 PUFA following of 6 weeks of mice were for a dietary switch Mice on the ALA diet were switched onto either the DHA diet or ALA + DHA diet. on the DHA diet were onto either the ALA diet or ALA + DHA diet. to the mice the dietary a of mice were maintained on their respective background either the ALA diet or DHA to the of δ13CDHA signatures over the course of the experiment. Mice were over a time course of and mice were by with of Brain and tissues were in and at on the composition of the R.J.S. Bazinet R.P. isotope analysis the dietary of docosahexaenoic acid in the Lipid Res. PubMed Scopus Google Scholar). study diets were on a n-3 PUFA diet were from and and fatty acid and by the ALA, DHA, and ALA + DHA diets were ALA of and DHA to ALA and DHA diets at of the fatty acids by to fatty acid fatty acid were determined to be by gas chromatography The carbon isotope ratios of ALA and DHA from the study diets were determined to be and R.J.S. Bazinet R.P. isotope analysis the dietary of docosahexaenoic acid in the Lipid Res. PubMed Scopus Google Scholar). were from tissues by from and for the and of lipids from PubMed Google Scholar). Brain and and were in 6 of a containing of and either acid or for fatty acid by and in the of to of in 6 of a containing acid brain, and were at following which of were and at for The containing the and at of lipids by following R.J.S. Bazinet R.P. isotope analysis the dietary of docosahexaenoic acid in the Lipid Res. PubMed Scopus Google Scholar). 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PubMed Scopus Google Scholar, of measured stable to isotope PubMed Scopus Google Scholar). carbon isotope ratio of the and for and and to on a to and S. for and stable fatty acid and PubMed Scopus Google Scholar). were of by and to the were for of from the measured and of for were carbon isotope ratios from gas that is the combustion of or and therefore not from the carbon to fatty acids for the of carbon to measured carbon isotope ratios and the of were mass to the of of carbon in the and fatty acids and the and to the measured carbon isotope ratios of the and fatty respectively. of measured DHA carbon isotope ratios and and respectively. isotope ratios of the determined for of by of and acid as R.J.S. Bazinet R.P. isotope analysis the dietary of docosahexaenoic acid in the Lipid Res. 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Ma K. Bell J.M. of docosahexaenoic acid in brain by weeks of of n-3 fatty PubMed Scopus Google Scholar, Bazinet R.P. dietary PUFA to of acid and of DHA in brain Lipid Res. PubMed Scopus Google Scholar, L. Bazinet R.P. docosahexaenoic acid is the the PubMed Scopus Google Scholar). Previous studies investigating the of dietary PUFA on brain DHA turnover diets with or levels of DHA J.C. Ma K. Bell J.M. of docosahexaenoic acid in brain by weeks of of n-3 fatty PubMed Scopus Google Scholar, Bazinet R.P. dietary PUFA to of acid and of DHA in brain Lipid Res. PubMed Scopus Google Scholar). the study diets DHA at of the dietary fatty to of the mass brain DHA turnover from mice on the ALA background switched to DHA or ALA + DHA diet were with the of not levels of n-3 that the of DHA to a diet with levels of ALA may not brain DHA Although and of DHA half-lives on The estimates half-lives on the of the from the the estimates half-lives on the incorporation of preformed dietary DHA or synthesized DHA the brain that which has been the that the brain DHA is at the of DHA must be to the of DHA incorporation for in incorporation and turnover within brain and critical Res. Brain Res. Rev. PubMed Scopus Google Scholar). Although brain DHA over the time course in mice from the switched to either of the diets containing DHA, that from the in to on the of brain DHA half-lives be Furthermore, in the study to the of plasma DHA determined from studies L. Bazinet R.P. docosahexaenoic acid is the the PubMed Scopus Google Scholar, R.P. Chang L. the incorporation and turnover of acid not docosahexaenoic acid in brain of the to PubMed Scopus Google Scholar, R.P. Chang L. not the of docosahexaenoic acid within brain of the PubMed Scopus Google Scholar, S. Chang L. Bazinet R.P. not the of or docosahexaenoic acid in brain of the Res. PubMed Scopus Google Scholar, Bell J.M. of docosahexaenoic acid metabolism in the of of Res. PubMed Scopus Google Scholar, Chang of acid not turnover and of docosahexaenoic acid and in PubMed Scopus Google Scholar). the half-lives and determined by natural abundance carbon isotope ratio analysis with determined the of estimates and that this fatty acid with mice on the ALA the brain DHA half-life determined from the mice switched onto the ALA diet for either diet of DHA have been to be a to brain DHA diets of preformed DHA brain the brain its docosahexaenoic of dietary docosahexaenoic and in the Res. 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The of DHA from the and in mice to the DHA diet and switched to the ALA diet may have to the brain DHA half-life in this DHA from with enriched δ13CDHA the dietary DHA, to a isotopically enriched circulating DHA for uptake the brain, the measured of in brain δ13CDHA signatures and the The of the study to the of natural abundance to brain DHA half-lives a dietary switch a analysis and the in and δ13CDHA signatures following dietary switch and DHA half-lives in this DHA half-lives were to be and in the and and in the on the diet and dietary switch These results were to in mice from the of in labeled and pools The of of and fatty acids in Google Scholar). estimates from and studies in and suggest half-lives to be of fatty acid turnover in PubMed Scopus Google Scholar, of in for and PubMed Scopus Google Scholar, S. S. of lipids in and of a diet in Lipid Res. 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Bazinet R.P. docosahexaenoic acid is the the PubMed Scopus Google the of and tracers, it is not without the use of tracers, studies be however, natural abundance the use of high-precision that a Furthermore, as in the and diets may to the of the of within a which the of half-lives the may not be at be by to the carbon isotope ratio of the of in the diet while the in the diet. the of DHA, this be by a and a isotopically enriched as of long-chain fatty acids in fed with long-chain fatty PubMed Scopus Google Scholar). to the of must be to not a kinetic isotope that the of measured carbon isotope the of a the of natural abundance be applied as a for of The natural of fatty the of long-chain n-3 compared with dietary of ALA to study the of long-chain PUFA metabolism in without tracer Bazinet R.P. isotope analysis of DHA to of to DHA following a control PubMed Scopus Google natural abundance carbon isotope signatures of plasma long-chain n-3 PUFA following weeks of with to the of PUFA the were to demonstrate that in plasma following DHA not the of in natural abundance isotope ratio Chouinard-Watkins R. Bazinet R.P. is a to in acid following docosahexaenoic acid as determined by isotope analysis in PubMed Scopus Google Scholar, Bazinet R.P. isotope analysis of DHA to of to DHA following a control PubMed Scopus Google Scholar). with unique in long-chain of to study PUFA metabolism in of long-chain fatty acids in fed with long-chain fatty PubMed Scopus Google and with natural abundance carbon isotope ratio analysis to estimates of acid and DHA synthesis in Due to the in carbon isotope ratios of n-3 in the natural abundance carbon isotope ratio analysis is for the of n-3 PUFA metabolism in and over tracer the of and with the use of natural abundance determined brain DHA half-lives to be to in mice on the diet from mice switched to a diet containing DHA determined the use of and via with DHA J.C. Ma K. Bell J.M. of docosahexaenoic acid in brain by weeks of of n-3 fatty PubMed Scopus Google Scholar, Bazinet R.P. dietary PUFA to of acid and of DHA in brain Lipid Res. PubMed Scopus Google Scholar, L. Bazinet R.P. docosahexaenoic acid is the the PubMed Scopus Google Scholar). The of to the that brain DHA in has a half-life of Furthermore, the of to supply the brain with DHA it is not in the diet by the half-life of mice switched to the ALA diet. These results the of natural abundance carbon isotope ratio analysis in a dietary switch to study the metabolism and turnover of fatty acids and the for the of natural abundance isotope for the of fatty acid and metabolism in studies. The for with the α-linolenic acid isotope analysis analysis fatty acid gas chromatography combustion isotope ratio mass gas chromatography

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