n-3 fatty acid metabolism of males and females

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Hi All,

n-3 fatty acid metabolism of males and females differ, it seems to me.

See the pdf-available, as are the referred to Br J Nutr papers

discussed.. It was

interesting regarding the data of FIg. 1 to me.

Pawlosky R, Hibbeln J, Lin Y, Salem N Jr.

n-3 fatty acid metabolism in women.

Br J Nutr. 2003 Nov;90(5):993-4; discussion 994-5. No abstract

available.

PMID: 14667193 [PubMed - indexed for MEDLINE]

Using a stable-isotope tracer technique, Burdge & Wootton

(2002) noted that women of child-bearing age (about 28

years) had a much greater capacity to convert a-linolenic

acid (18 : 3n-3) to docosahexaenoic acid (22 : 6n-3)

compared with men of a similar age (Burdge et al. 2002).

Based on their analysis of the area under the curve of the

time course plot of the plasma 13C-labelled fatty acids,

they reported that there was approximately a 9 % excursion

of 13C-labelled 18 : 3n-3 into 13C-labelled 22 : 6n-3 in

women. In men, however, they found essentially no excur-sion

of the label into plasma 22 : 6n-3 (0 % excursion).

However, they did show excursion of the tracer into both

eicosapentaenoic (20 : 5n-3) and docosapentaenoic (22 : 5n-3)

acids in both groups of subjects (Burdge et al. 2002).

Using similar isotope tracer procedures, we previously

reported that both men (n 4) and women (n 4) were capable

of converting 2H5-labelled 18: 3n-3 ethyl ester into C20 and

C22 polyunsaturated fatty acids, including 2H5-labelled

22 : 6n-3 (Pawlosky et al. 2001). Moreover, we found

that both male (n 5) and female (n 5) subjects were able

to synthesize 22 : 6n-3 from 18 : 3n-3 when they subsisted

on various diets (fish- or beef-based, or ad libitum) that

had different concentrations of long-chain polyunsaturated

fatty acids (Pawlosky et al. 2003). We derived the in vivo

rate constant coefficients for the individual transformations

of n-3 fatty acids beginning with 18 : 3n-3 and calculated

the percentage utilization of each precursor n-3 fatty acid

for product formation (e.g. the percentage of 20 : 5n-3 con-verted

to 22 : 5n-3 was calculated using the rate constant

coefficients describing this transformation) using a com-partmental

modelling procedure. The differences between

men and women in their capacities to utilize 18 : 3n-3 for

22 : 6n-3 production observed by Burdge & Wootton

(2002) prompted us to analyse data from our dietary

study (Pawlosky et al. 2003) in respect of gender.

In evaluating the effects of the beef- or fish-based or

ad libitum diets on the kinetics of n-3 fatty acid

metabolism, we observed that gender exerted a profound

influence in the determination of a rate constant coefficient

involved in one of the steps in the biosynthesis of 22 : 6n-3.

During the period when subjects subsisted on a beef-based

diet, the rate constant coefficient for the conversion of

22 : 5n-3 to 22 : 6n-3 was much greater (P<0·001) in

women (k 0·041 (SD 0·007)) compared with men (k 0·012

(SD 0·004)). The larger rate constant coefficient in

women led to a nearly 3-fold greater amount of 22 : 5n-3

utilized for 22 : 6n-3 synthesis compared with men

(Fig. 1). This was also observed during the ad libitum

dietary phase of study, but did not reach statistical

significance (P=0·08). Very interestingly, while subjects

subsisted on the fish-based diet, both groups showed

about equal capability in their utilization of 22 : 5n-3 for

22 : 6n-3 synthesis (Fig. 1).

The effect of gender on the percentage excursion of labelled

n-3 fatty acids observed by Burdge & Wootton (2002) in

human subjects may be largely explained by the differences

in the magnitude of the rate constant coefficient that describes

the synthesis of 22 : 6n-3 from 22 : 5n-3 in male and female

subjects. Gender appears to be a strong determinant that influ-ences

the synthesis of 22 : 6n-3 in human subjects. It is possible

that Burdge & Wootton (2002) failed to detect excursion of the

tracer into plasma 22 : 6n-3 in male subjects because of the

lower conversion rate of 22 : 5n-3 to 22 : 6n-3, demanding

highly sensitive analytical procedures. It is noteworthy that

the beef-based diet did not appear to stimulate the

synthesis of 22 : 6n-3 in male subjects compared with a

fish-based diet (Fig. 1). This suggests that the regulation of

n-3 fatty acid metabolism in women is more sensitive to diet-ary

alterations and this may possibly be due to hormonal - factors.

References

Burdge GC, AE & Wootton SA (2002) Eicosapentaenoic

and docosapentaenoic acids are the principal products of

a-linolenic acid metabolism in young men. Br J Nutr 88,

355–363.

Burdge GC & Wootton SA (2002) Conversion of a-linolenic acid

to eicosapentaenoic, docosapentaenoic and docosahexaenoic

acids in young women. Br J Nutr 88, 411–420.

Pawlosky RJ, Hibbeln JR & Lin Y, et al. (2003) Effects of beef-and

fish-based diets on the kinetics of n-3 fatty acid metabolism

in human subjects. Am J Clin Nutr 77, 565–572.

Pawlosky RJ, Hibbeln JR, Novotny JA & Salem N Jr (2001)

Physiological compartmental analysis of alpha-linolenic acid

metabolism in adult humans. J Lipid Res 42, 1257–1265.

Graham Burdge replies:

n-3 Fatty acid metabolism in women – Reply

The findings reported by Pawlosky et al. (2003a) are in

good agreement with our results, which show greater con-version

of a-linolenic acid (LNA; 18: 3n-3) to docosahex-aenoic

acid (DHA; 22: 6n-3) in women compared with

men consuming their habitual diet (Burdge et al. 2002;

Burdge & Wootton, 2002). It has long been known that

greater oestrogen exposure increases dihomo-g-linolenic

acid and arachidonic acid concentrations in women,

which implies increased D6- and D5-desaturase activities

(Ottosson et al. 1984). This is consistent with the obser-vation

that women taking 30–35 mg ethynyloestradiol/d

in a contraceptive pill, which represents an increase in oes-trogen

exposure compared with the menstrual cycle, had

2·5-fold greater conversion of a-[13C]LNA to DHA than

those who did not take synthetic oestrogens (Burdge &

Wootton, 2002). One additional important implication of

our findings and those of Pawlosky et al. (2003a) is that

the conversion of docosapentaenoic acid (DPA) to DHA,

which uniquely requires both D6-desaturase activity and

peroxisomal b-oxidation, is also modified by gender.

This suggests that DHA synthesis may be regulated inde-pendently

from the activity of earlier steps in the pathway.

There appears to be a reciprocal relationship between

partitioning of a-[13C]LNA towards b-oxidation, measured

as excretion of13CO2 on breath and C recycling into satu-rated

and monounsaturated fatty acids, and conversion to

eicosapentaenoic acid (EPA), DPA and DHA (Burdge &

Wootton, 2003). Women, who preferentially use carbo-hydrate

as an energy source ( et al. 1998), would

have a greater availability of a-LNA for conversion to

EPA, DPA and DHA. In men, who use fatty acids as an

energy source to a greater extent than women (

et al. 1998), less a-LNA would be available for conversion

to long-chain polyunsaturated fatty acids. Together with

greater fractional conversion of DPA, preferential parti-tioning

of fatty acids away from b-oxidation may further

increase the overall capacity of women for DHA synthesis.

Although there appear to be differences in the sensitivity

of the techniques used, these are not so great as to produce

differing conclusions about the effects of gender upon

a-LNA metabolism. In fact, when [13C]DHA enrichment

exceeded background abundance, we could readily detect

it (Burdge & Wootton, 2002). We suggest that conversion

below this level would be of questionable biological

importance. Kinetic analysis of the type described by

Pawlosky et al. (2003b) uses concentrations of labelled

fatty acids in plasma as an indirect measure of a-LNA

conversion, which is an intracellular process. Since such

models ignore partitioning of individual intermediates

between lipid pools and different metabolic fates (b-oxi-dation,

storage or further metabolic transformation), there

is a tendency towards underestimation of conversion and

limited precision.

The key question that remains to be addressed is the bio-logical

significance of differences in capacity for DHA

synthesis between men and women. It is possible that

maintenance of DHA concentrations in tissues in men

may depend on dietary sources or recycling to a greater

extent than in women. Capacity to up-regulate DHA syn-thesis

under hormonal control in women may be important

for satisfying fetal demands for DHA during pregnancy.

Plasma phospholipid DHA concentration increases in preg-nant

women: this may facilitate supply of DHA to the fetus

(Postle et al. 1995). Up-regulation of DHA synthesis due to

rising circulating oestrogen levels may be an important

source of DHA to support this increase in maternal

plasma DHA concentration. One potential implication is

that differences in capacity for DHA synthesis may con-tribute

to the 50 % variation in plasma DHA concentration

between women at term (Postle et al. 1995). If true, infants

born to mothers with a lower capacity for DHA synthesis

may be at greater risk of deficit in DHA assimilation. It

would then be important to characterise in detail factors

that determine capacity for DHA synthesis in women.

References

Burdge GC, AE & Wootton SA (2002) Eicosapentaenoic

and docosapentaenoic acids are the principal products of a-linolenic

acid metabolism in young men. Br J Nutr 88, 355–363.

Burdge GC & Wootton SA (2002) Conversion of a-linolenic acid

to eicosapentaenoic, docosapentaenoic and docosahexaenoic

acids in young women. Br J Nutr 88, 411–420.

Burdge GC & Wootton SA (2003) Conversion of a-linolenic acid to

palmitic, palmitoleic, stearic and oleic acids in men and women.

Prostaglandins Leukot Essent Fatty Acids 69, 283–290.

AE, JL, Stolinski M & Wootton SA (1998)

The effect of age and gender on the metabolic disposal of

1-13C palmitic acid. Eur J Clin Nutr 52, 22–28.

Ottosson UB, Lagrelius A, Rosing U & von Schoultz B (1984) Rela-tive

fatty acid composition of lecithin during postmenopausal

replacement therapy—a comparison between ethinyl estradiol

and estradiol valerate. Gynecol Obstet Invest 18, 296–302.

Pawlosky R, Hibbeln J, Lin Y & Salem N Jr (2003a) n-3 Fatty

acid metabolism in women. Br J Nutr 90, 993–994.

Pawlosky RJ, Hibbeln JR, Lin Y, et al. (2003b) Effects of

beef- and fish-based diets on the kinetics of n-3 fatty

acid metabolism in human subjects. Am J Clin Nutr 77,

565–572.

Postle AD, Al MDM, Burdge GC & Hornstra G (1995) The

composition of individual molecular species of plasma phos-

phatidylcholine

in human pregnancy. Early Hum Dev 43,

47–58.

Cheers, Alan Pater