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Background and Objectives:
The unique nutritional and functional properties of flaxseed
differentiate it from other cereal and oilseed crops. Interest in
flaxseed has focused on possible anticarcinogenic properties and its
role in reducing the risk of cardiovascular diseases. Much less
attention has been given to the use of flax products for prevention
and management of Type 2 diabetes mellitus. Although it has been
demonstrated that oils with a high n-3 to n-6 fatty acid content may
improve insulin action and reduce adiposity, the effects of flaxseed
oil are not well documented.
Both flaxseed oil and fish oil (also known as menhaden oil) are
dietary sources of omega-3 fatty acids. Flaxseed oil is a rich source
of α-linolenic acid (ALA, 18:3 n-3) while fish oil supplies the very
long chain fatty acids, EPA (20:5 n-3) and DHA (22:6 n-3). ALA in
flaxseed oil can be metabolized to EPA and DHA, but there are
questions about the efficiency of this process and whether the
metabolism of n-3 fatty acids may respond differently in the diabetic
state.
Previous studies investigating the relationship between n-3 fatty
acids and insulin resistance have focused on intake of fish or fish
oil. For example, habitual fish intake (and presumably intake of long
chain n-3 fatty acids) has been inversely associated with the
incidence of glucose intolerance and diabetes mellitus [Feskens et al
(1991) Diabetes Care 14: 935-941). Insulin resistance and obesity are
decreased when young growing animals are fed diets rich in n-3 fatty
acids (fish oil) compared to diets rich in n6 fatty acids [Malasanos
and Stacpoole (1991) Diabetes Care 14: 1160-79; Fickova et al (1998)
J. Nutr. 128: 512-519]. However, the effects of flaxseed oil [high
α-linolenic acid 18:3 n-3], on development of insulin resistance and
obesity, and glycemic control in diabetes have not been directly
compared with fish oil [high in EPA (20:5 n-3) and DHA (22:6 n-3)] or
diets rich in n-6 fatty acids.
The objectives of this project were:
- To compare the effects of diets with similar
polyunsaturated/saturated fatty acid ratios (P/S=2) containing
flaxseed oil, fish oil, or safflower oil on glycemic control,
development of insulin resistance and adipose tissue metabolism in
fa/fa Zucker rats, a model for the early stages of Type 2 diabetes.
- To determine the effects of diets containing flaxseed oil, fish
oil or safflower oil on fatty acid composition of adipose and muscle
tissue of fa/fa and lean Zucker rats.
Procedure and Project
Activities:
Weanling male fa/fa and lean Zucker rats were fed diets of 7% fat
(by weight) containing flaxseed oil (FXO group), menhaden oil (MO
group) or safflower oil (SO group) for 9 weeks. The percentage of
saturated (SAT), monounsaturated (MUFA) and polyunsaturated fatty acid
(PUFA) in the diets was held constant (26%/19%/55%) by using a mixture
of oils in each diet. The three diets had similar
polyunsaturated/saturated fatty acid ratios (P/S=2). The fa/fa Zucker
rats were used as a model for insulin resistance and obesity, the
early stages of Type 2 diabetes. Oral glucose tolerance was assessed
at 8.5 weeks. Body weight, fat pad weight, serum biochemistry and
pancreatic islets were assessed as indicators of obesity and insulin
resistance. Fatty acid composition of adipose and muscle
triglycerides and phospholipids was determined by thin layer
chromatography (TLC) and gas chromatography (GC).
Results and Discussion:
-
When the dietary percentage of SAT, MUFA and
PUFA and the P/S ratio was constant, varying the percentage and
source of n-3 fatty acids did not alter body weight, body fat,
oral glucose tolerance, or pancreatic islets in the normal or
insulin resistant states using a rodent model. In general, other
studies attributing a unique effect of n-3 fatty acids (and
specifically fish oil) on body weight, body fat and/or insulin
sensitivity have altered the dietary n-3 fatty acid composition
concomitant with altering the percentages of dietary SAT, MUFA and
PUFA, and the dietary P/S ratio. To confirm our interpretation of
the relative role of the P/S ratio versus n-3 composition, we need
to complete an experiment where the dietary n-3 composition is low
or high and the P/S ratio is varied (high and low). This is an
important issue to be clarified for human nutritional science, and
for the implications of dietary recommendations for diabetes
prevention and treatment, and for assessment of specific food
products or supplements, including those containing flaxseed oil
or other specialty oils.
-
ALA (18:3 n-3) in the diet containing flaxseed
oil (FXO group) was metabolized to EPA (20:5 n-3), DPA (22:5 n-3)
and DHA (22:6 n-3) which were preferentially incorporated into
adipose and muscle PL of rats. The fatty acid composition of
adipose and muscle tissue was investigated because these are major
organs for insulin-stimulated glucose uptake. Other investigators
have proposed that a greater proportion of n-3 fatty acids in
membranes may modulate insulin signaling and thus insulin
sensitivity. However, oral glucose tolerance was not altered by
diet in the present study. Despite the lack of changes related to
glycemic control, the greater proportion of n-3 fatty acids in PL
may have other beneficial effects, for example, altered substrate
availability for eicosanoid synthesis and reduced cardiovascular
risk.
-
Dietary ALA was effective for elevating the
percentages of very long chain n-3 fatty acids in adipose and
muscle tissues when compared to diets containing similar
percentages of SAT, MUFA and PUFA. In fact, the rats fed flaxseed
oil (FXO group) had a higher percentage of EPA and DPA in adipose
PL, and a higher percentage of DPA in muscle PL compared to the
rats fed fish oil (MO group). Although rats fed flaxseed oil (FXO
group) had 19% less EPA in muscle PL, 38% less DHA in muscle PL,
and 67% less DHA in adipose PL compared to rats fed fish oil (MO
group), the elevations in very long chain n-3 fatty acids were
significant compared to the rats fed the high n-6 diet. The rats
fed flaxseed oil (FXO group) had 27-fold more EPA in muscle PL,
2.1-fold more DHA in muscle PL, and 2.7-fold more DHA in adipose
PL compared to rats fed safflower oil (SO group). Thus, dietary
flaxseed oil consumption has a significant impact on elevating
very long chain n-3 fatty acids in adipose and muscle tissue.
-
The buildup of DPA in PL of flaxseed oil-fed
rats (FXO group) suggests that further metabolism to DHA was
inhibited and/or more DHA was oxidized or recycled to DPA. The
rats fed flaxseed oil (FXO group) had higher percentages of DPA in
adipose and muscle PL (10% and 226%, respectively) compared to the
rats fed fish oil (MO). Perhaps this is a protective response to
prevent adverse effects associated with tissue accumulation of DHA.
Further research is warranted to determine if this is an advantage
of flaxseed oil consumption compared to fish oil consumption.
-
The dietary treatments altered the n-6 fatty
acid composition in adipose and muscle, but this did not influence
parameters such as body weight, body fat, oral glucose tolerance
or pancreatic islets in the fa/fa and lean Zucker rats. Others
have proposed that a relative deficiency of arachidonic acid (20:4
n-6) may have negative consequences for insulin sensitivity. In
the present study, the flaxseed oil and fish oil groups (FXO and
MO) had ~57% less arachidonic acid in adipose and muscle PL, but
the oral glucose tolerance response was not altered. This finding
supports our interpretation that the dietary SAT, MUFA and PUFA
composition is more important than the changes in individual fatty
acids.
-
The fatty acid composition of adipose and muscle
TG and PL reflected the diet composition. Both adipose and muscle
TG contained significant proportions of ALA (16% and 13%,
respectively) compared to ALA in PL (~1.5%). From an animal
production and meat science perspective, the marbled fat in meat
(muscle TG) from other mammalian species would be expected to
contain significant amounts of ALA that would be available for
further metabolism by species higher in the food chain (e.g.
humans).
-
The PUFA/SAT ratio for muscle PL was constant
across the dietary groups, but the n6 and n3 fatty acid
composition was altered by the dietary treatments. One of the
most prominent changes was the proportion of DHA in muscle PL:
11.4% in FXO vs. 18.3% in MO vs. 5.4% in SO rats. This amount of
DHA would be expected to alter cellular function and signaling.
-
The insulin-resistant obese state modulates the
tissue fatty acid composition, including the composition of very
long chain n-3 fatty acids. The fa/fa rats had a lower percentage
of total n-3 fatty acids in TG and adipose PL compared to lean
rats. The fa/fa rats had a lower percentage of EPA and DHA in
adipose TG and PL compared to lean rats. The DHA percentage was
elevated in adipose and muscle PL and muscle TG of fa/fa rats,
suggesting an inhibition of further metabolism to DHA and/or more
oxidation of DHA to DPA. These findings are important because
they indicate that fatty acid metabolism and accumulation are
altered in the insulin-resistant obese state. Given the
increasing prevalence of obesity and Type 2 diabetes in the
population and the various roles of n-3 fatty acids in metabolism,
it will be important to further our understanding of the
interactions of n-3 fatty acid metabolism and function in the
insulin-resistant obese state.
The research in this project has contributed to our understanding
of omega-3 fatty acid metabolism, including the metabolism of
α-linolenic acid (ALA) in flaxseed oil to very long chain omega-3
fatty acids (EPA, DPA and DHA), and alterations in fatty acid
metabolism in the insulin-resistant obese state, using a rodent
model. The project findings support the use of flaxseed oil as a
dietary source of omega-3 fatty acids, however, further research is
required to clarify the interactions of omega-3 fatty acids with
glycemic control and management of obesity and Type 2 diabetes.
Acknowledgements:
This project was made possible due to funding from the Governments
of Manitoba and Canada through the Canada-Manitoba Agri-Food Research
and Development Initiative (ARDI). Other sources of funding were from
the Flax Council of Canada (Project R99-06) and a NSERC Postgraduate
Scholarship (M. Gillam) and NSERC Undergraduate Summer Research Awards
(A. Noto, M. Zirk). The contributions of M. Gillam, A. Noto, M. Zirk,
J. Zahradka, M. Latta and the staff of the Animal Holding Facility are
gratefully acknowledged.
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