Omega-3 fatty acid supplementation in horses

Abstract

Polyunsaturated omega-3 fatty acids (n-3 PUFA) are a family of essential fatty acids with many biological activities. These fatty acids are incorporated into cell membranes, changing their structural and functional characteristics. N-3 PUFA can act by modulating inflammatory responses at different levels. Omega-3 PUFA can be converted in the body to longer-chain n-3 PUFA at a limited rate and are differently converted in body systems. It appears that when specific longer-chain n-3 PUFA are desired these need to be supplemented directly in the diet. In different species some evidence indicates a potential effect on improving insulin sensitivity. Recently, a novel class of n-3 PUFA-derived anti-inflammatory mediators have been recognized, termed E-series and D-series resolvins, formed from EPA and DHA, respectively. N-3 PUFA derived resolvins and protectins are heavily involved in the resolution of inflammation. Supplementation with n-3 fatty acids in horses may help manage chronic inflammatory conditions such as osteoarthritis, equine metabolic syndrome, laminitis, and thereby help to improve longevity of sport horse.

Full text

Invited Review
Omega-3 fatty acid supplementation in horses
Tanja Hess1, Trinette Ross-Jones2
1 Colorado State University, Department of Animal Science, Fort Collins, CO, USA.
2 Department of Animal Science and Wildlife Management, Tarleton State University, Stephenville, TX, USA.
ABSTRACT - Polyunsaturated omega-3 fatty acids (n-3 PUFA) are a family of essential fatty acids with many biological
activities. These fatty acids are incorporated into cell membranes, changing their structural and functional characteristics.
N-3 PUFA can act by modulating inflammatory responses at different levels. Omega-3 PUFA can be converted in the body to
longer-chain n-3 PUFA at a limited rate and are differently converted in body systems. It appears that when specific longer-
chain n-3 PUFA are desired these need to be supplemented directly in the diet. In different species some evidence indicates
a potential effect on improving insulin sensitivity. Recently, a novel class of n-3 PUFA-derived anti-inflammatory mediators
have been recognized, termed E-series and D-series resolvins, formed from EPA and DHA, respectively. N-3 PUFA derived
resolvins and protectins are heavily involved in the resolution of inflammation. Supplementation with n-3 fatty acids in horses
may help manage chronic inflammatory conditions such as osteoarthritis, equine metabolic syndrome, laminitis, and thereby
help to improve longevity of sport horse.
Key Words: alpha linolenic acid, arachidonic acid inflammation, docosahexaenoic acid, eicosapentaenoic acid, linoleic acid
Revista Brasileira de Zootecnia
© 2014 Sociedade Brasileira de Zootecnia
ISSN 1806-9290
www.sbz.org.br
R. Bras. Zootec., 43(12):677-683, 2014
Received May 22, 2014 and accepted October 1, 2014.
Corresponding author: tanja.hess@colostate.edu
http://dx.doi.org/10.1590/S1516-35982014001200008
Copyright © 2014 Sociedade Brasileira de Zootecnia. This is an Open Access article
distributed under the terms of the Creative Commons Attribution Non-Commercial
License, which permits unrestricted non-commercial use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Dietary n-3 and n-6 long-chain polyunsaturated
fatty acids (PUFA)
Dietary fats are required to support absorption of
fat-soluble vitamins and provide the essential fatty acids
(NRC, 2007), linoleic acid (LA) and alpha-linolenic acid
(ALA). The long-chain fatty acid family of omega-6
(n-6) and omega-3 polyunsaturated fatty acids (PUFA) are
essential components of the diet and are necessary in daily
physiological functions as well as for fetal development and
neonatal growth. The ‘parent’ fatty acids are linoleic acid
(LA) for the n-6 family and alpha-linolenic acid (ALA) for
the n-3 family. These ‘parent’ fatty acids are considered
essential in mammalian diets; the lack of proper enzymes
prevents their endogenous synthesis. The derivatives of these
‘parents’ are likely of even greater importance; LA can be
elongated and converted to arachidonic acid (ARA), whose
primary role is to produce 20 carbon-signaling molecules
known as eicosanoids. Eicosanoids have short half-lives
and are localized close to their production site, influencing
events within and around the cells that produce them.
Arachidonic acid and other eicosanoid- producing fatty
acids must be present in tissue in order for these signaling
molecules to be effective. Eicosanoids are important in that
they regulate a variety of cellular functions, during both
physiological (normal) and inflammatory events. The most
well-known classes of eicosanoids are prostaglandins (PG),
thromboxanes (TX), leukotrienes (LT) and lipoxins (LX);
with PG and TX being synthesized via the cyclooxygenase
(COX) pathway and LT and LX being converted from
ARA by lipoxgenases (Figure 1). While all classes are vital
physiological components, prostaglandins are important
as they are utilized by all major organ systems including
reproductive, gastrointestinal and neurological. Of these
active eicosanoids, prostaglandin E2 is the primary PG,
synthesized exclusively from ARA, playing an important
role in the inflammatory response. In terms of joint
health and the development of osteoarthritis, PGE2 has
been implicated as therapeutic target as it is elevated
in early stages of the disease and contributes to down-
stream production of degradative cartilage enzymes
(McIlwraith, 2005).
Long-chain derivatives of ALA, specifically
eicosapentaenoic acid (EPA), n-3 docosapentanoic acid
(DPA) and docosahexaenoic acid (DHA) (Figure 2), have
as equally important roles as ARA in cellular function and
physiologic homeostasis. While all ALA derivatives can be
converted to produce eicosanoids, EPA is the most widely
recognized n-3 PUFA that is a source for anti-inflammatory

678 Hess and Ross-Jones
R. Bras. Zootec., 43(12):677-683, 2014
PG, TX, LT and LX (Figure 1). However, research results
indicate that n-3 DPA and DHA also play vital roles in
mediating the inflammatory response in conjunction with
EPA (Kaur et al., 2011). Increased intake of EPA and DHA
in a dose-dependent manner has been shown to decrease
ARA amounts in cell membrane phospholipids involved in
inflammation (Calder, 2014). Furthermore, increased EPA
intake has been shown to inhibit ARA metabolism (Calder,
2014) and decrease the expression of the pro-inflammatory
gene COX-2 (Calder, 2014). One of the premier sources of
EPA and DHA is marine fish oil, also known as menhaden
oil. Eicosapentaenoic acid, though found in the largest
quantities in marine fish oil, originates from ALA (Figure 2),
which is encountered in high concentrations in plant fats.
Plant oils such as linseed, soybean and flaxseed oils are
all sources of ALA, therefore, when consumed, the animal
may be able to synthesize EPA, DPA and DHA from these
plant oils (Figure 2). Alpha-linolenic acid is converted
to EPA, DPA and DHA via a desaturation and elongation
pathway (Figure 2). The initial step, the addition of a
double bond to ALA by the ∆6-desaturase enzyme, is the
rate-limiting step in the pathway and contributes to the
reported low conversion efficiency of ALA to the longer-
chain PUFA (Calder, 2013). Both LA and ALA share a need
for ∆6-desaturase (Figure 2), and while the enzyme has a
higher affinity for ALA, in humans dietary fats contain a
higher percentage of LA, therefore competing for the same
enzyme ALA needs for conversion to its longer derivate
(Tu et al., 2010). In addition, ALA has been shown to have
the highest oxidation rate among all unsaturated fatty acids
in human tracer studies (Nettleton, 1991), contributing to
the low conversion of ALA to its longer derivate. A review
of studies investigating the efficiency of dietary ALA
conversion in humans reported the conversion of ALA to
EPA ranged from 8-10% with conversion efficiency being
as low at 4% for DHA (Williams and Burdge, 2006). Due to
evidence of a low conversion rate, it is recommended to supply
EPA and DHA directly in the diet (Arterburn et al., 2006).
A source of ALA in the equine diet is forage (hay or
pasture), which is the largest portion of equine diets. Many
horses are fed forage alone; however, performance horses
require additional energy-dense feeds such as grains or
oils due to their higher energy demands. Vegetable oils
are also a source of ALA, such as flaxseed and linseed
oil, which can be top-dressed onto feed. Linoleic acid is
very abundant in cereal grains such as corn and barley, and
makes up the majority of the fat in corn oil as well. Algae
produce the n-3 PUFA, EPA and DHA; therefore they are
present in fish because algae is an ordinary diet of fish. For
that reason, marine foods and fish oil are a good source of
EPA and DHA and may be consumed by humans and other
carnivores or omnivores. Additionally, they have been used
as supplements in equine diets. Horse studies indicated that
supplementation with ALA would not lead to increases in
circulating DHA (Hansen et al., 2002; Vineyard et al., 2010),
only increases in circulating EPA.
Inflammation and PUFA
Cellular activities involved in inflammatory responses
are designed to be harmful to pathogens; however, they
can cause damage to the host tissues (Calder, 2014).
Inflammation usually is self-limiting, and resolves rapidly
due to the activation of negative feed-back mechanisms like
secretion of anti-inflammatory cytokines or pro-resolving
lipid mediators, shedding of receptors for inflammation,
and activation of regulatory cells (Calder, 2014). Loss of
this regulatory process can result in excessive, inappropriate
or chronic inflammation that can cause damage to the
host organism (Calder, 2014). As part of these anti-
inflammatory and pro-resolving mediators, a novel class
Figure 1 - Eicosanoid formation from arachidonic acid (ARA) and
eicosapentaenoic acid (EPA).
ALA - α-linolenic acid; ARA - arachidonic acid; DGLA - dihomo-γ-linolenic acid;
DHA - docosahexaenoic acid; DPA - docosapentaenoic acid; EPA - eicosapentaenoic
acid; GLA - γ-linolenic acid; LA - linoleic acid.
Figure 2 - Biochemical pathway for the incorporation of n-3 and
n-6 fatty acids.
Source: Reprinted from Arterburn et al. (2006), with permission.

679
Omega-3 fatty acid supplementation in horses
R. Bras. Zootec., 43(12):677-683, 2014
of n-3 PUFA-derived anti-inflammatory mediators have
been recognized, termed E-series and D-series resolvins,
formed from EPA and DHA, respectively (Calder, 2009).
Protectins are another class of mediators produced from
DHA (Calder, 2014). While information is limited, it
appears n-3 PUFA-derived resolvins and protectins are
heavily involved in the resolution of inflammation (Kohli
and Levy, 2009). Protectins D1 are produced from DHA, and
known as protectins D1, owing to their protecting activity
in inflammatory and neural systems. Biological effects of
resolvins and protectins have been studied in cell culture
and animal models of inflammation and have been shown to
stimulate resolution and reduce magnitude of inflammatory
response in vivo (Serhan et al., 2008). Resolvin E1 reduces
inflammation in vivo and blocks human transendothelial
migration (Serhan et al., 2004). Resolvin E2 reduces
zymosan initiated neutrophil infiltration (Tjonahem et al.,
2006). Resolvin D1 has been shown to be a potent regulator
of mouse and human neutrophils (Serhan et al., 2004;
Sun et al., 2007). Resolvin E1 also has been shown to
initiate resolution of inflammation causing a decrease
in the number of neutrophils in exsudates sooner than
during spontaneous resolution. Resolvin E1 and resolvin
D1 prevented the infiltration of neutrophils into sites of
inflammation, and inhibited IL-1β production (Calder,
2014). Protectin D1 also blocked T cell migration in vivo,
reducing TNF-α (tumor necrosis factor alpha), IL-1β,
interferon-γ (IF-γ) secretion, and promoting T cell apoptosis
(Ariel et al., 2006). Protectin D1 shifted the onset of
resolution to an earlier time point in addition to shortening
the time to reduce the number of maximum neutrophils by
half (Serhan et al., 2008).
Other anti-inflammatory effects of n-3 PUFA from plant
and animal sources include a reduced cytokine production
in vitro (De Caterina et al., 1994) and in vivo (Meydani
et al., 1993; Grimm et al., 1994; McCann et al., 2000).
Sources of fatty acids in the diet
In humans, supplementation with long-chain n-3 PUFA
has been shown to improve inflammatory status, prevent
cardiovascular diseases (Calder, 2001), and reduce pain
and inflammation in patients with rheumatoid arthritis
(MacLean et al., 2004). In arthritic horses, supplementation
with EPA and DHA increased stride length (Woodward et al.,
2005) and reduced inflammatory markers (Manhart et al.,
2009). In horses, feeding Menhaden fish oil modulated
leucotriene synthesis influencing inflammatory conditions
(Hall et al., 2004).
Proposed mechanisms of EPA and DHA on
inflammation
Several mechanisms have been proposed regarding the
processes by which EPA and DHA act on the inflammatory
response in tissues. It is well established that these lipids act
on both a direct (by alteration of eicosanoid production via
cyclooxygenase and lipoxygenase pathways) and indirect
(modification of gene transcription) mechanism (Calder,
2006). Direct modification of prostaglandin and leukotriene
synthesis was outlined previously. Supplementation of n-3
PUFA in feeds will also exert an effect on the expression of
inflammatory genes (Renier et al., 1993; Curtis et al., 2000;
Wallace et al., 2001).
It is hypothesized that particular fatty acids, such as
EPA and/or DHA, may modify transcription factors in
the nucleus and thus influence cytokine and eicosanoid
production at the level of gene expression (Figure 3).
Another theory is that n-6 (i.e., ARA) and n-3 (i.e., EPA and
DHA) fatty acids modify protein synthesis of inflammatory
mediators via modification of cell surface receptors on lipid
rafts or within the cell by suppression of nuclear receptor
activation (Chapkin et al., 2009). Additional regulation
comes in the form of peroxisome proliferator-activated
receptors, which are key nuclear receptors that regulate
transcription of genes through ligand binding with a variety
Figure 3 - Summary of the anti-inflammatory actions of n-3
polyunsaturated fatty acids; modified from Calder (2013).
EPA - eicosapentaenoic acid; DHA - docosahexaenoic acid; ARA - arachidonic
acid; COX - cyclooxigenase; NFkB - nuclear factor kappa B; PPAR - peroxisome
proliferator activated receptor.
Solid red lines indicate inhibition.
Solid blue lines indicate sources of n-3 PUFA.
Solid green lines indicate inflammatory activation.

680 Hess and Ross-Jones
R. Bras. Zootec., 43(12):677-683, 2014
of lipophilic metabolites, having a high affinity for PUFA,
in particular DHA (Stulnig, 2003). Peroxisome proliferator-
activated receptors usually have three isoforms; α, β, γ and
are believed to be potent regulators of adipocyte function
as well as immune molecules such as lymphocytes and
macrophages (Marx et al., 2002) influencing downstream
transcription of inflammatory cytokines (Figure 3).
Insulin sensitivity and n-3 PUFA
Insulin resistance (decreased insulin sensitivity) in
horses has been linked to the development of laminitis,
osteochondrosis, and metabolic syndrome (Coffman and
Coles, 1983; Ralston, 1996; Treiber et al., 2006; Frank et al.,
2010) and is therefore considered a problem in the equine
industry. These diseases can result in a loss of function and
performance of the horse. Several factors may predispose
a horse to developing insulin resistance, such as diet, age,
breed/genetics and obesity (Jeffcot et al., 1986; Treiber et al.,
2006; Vick et al., 2007). Supplementation with certain
dietary components could increase insulin sensitivity in
animals that have insulin resistance, reducing the risk for
the development of diseases such as metabolic syndrome
and laminitis.
Dietary supplementation with n-3 PUFA has been shown
to increase insulin sensitivity in pigs and rats (Behme,
1996; Luo et al., 1996). Dietary EPA and DHA incorporate
into cell membranes increasing membrane fluidity due to
greater unsaturation of the membrane improving glucose
transport function (Lardinois et al., 1987; Zhao et al., 2008).
Incorporation of EPA and DHA in muscle cell membrane
has been shown to increase binding of insulin (Storlein et al.,
1991) and m-RNA expression of GLUT-4 transporters in
rats (Figueiras et al., 2010). Supplementation with EPA
and DHA has shown to improve insulin sensitivity in rats
(Storlein et al., 1991), pigs (Behme, 1996), and in humans
(Rasic-Milutinovic et al., 2007).
n-3 PUFA supplementation and exercise
Supplementation with EPA and DHA in horses has
also been shown to lower heart rate, plasma glycerol, free
fatty acids and cholesterol during an exercise test compared
to horses supplemented with corn oil (O’Connor et al.,
2004). In human trained athletes supplemented with fish
oil, heart rate and oxygen consumption was lower than
in subjects supplemented with olive oil (Peoples et al.,
2008). Incorporation of n-3 PUFA to muscle membranes
increased insulin sensitivity (Pan et al., 1995) and resulted
in increased ability of skeletal muscle to take up glucose.
Furthermore, studies have shown that lower proportions of
long-chain PUFA and higher proportions of saturated fatty
acids in skeletal muscle phospholipids are associated with
insulin resistance. Skeletal muscle characteristics (i.e., fatty
acid profile) have some genetic influence (Baur et al., 1999)
but diet and physical activity also influence skeletal muscle
fatty acid profile in rats, humans, and horses (Ayre et al.,
1996; Andersson et al., 2000; Hess et al., 2012).
Specific horse studies
Effects of two different dietary sources of n-3 PUFA on
incorporation into the plasma, red blood cell, and skeletal
muscle in horses (Hess et al., 2012)
In humans, the PUFA DHA and EPA need to be
supplemented in order for them to be incorporated into
tissues. There is limited conversion of ALA to DHA in
humans (Burdge et al., 2001; Arterburn et al., 2006). As
stated before, in horses, supplementation with ALA did not
lead to increases in circulating DHA (Hansen et al., 2002;
Vineyard et al., 2010), only EPA. Feeding of n-3 PUFA
to horses may increase circulating levels and increase
incorporation into muscle tissue. This could potentially
improve chronic inflammatoryconditions in horses; however,
the optimal type of fatty acid to be supplemented needed to
be investigated.
In a related study in our laboratory (Hess et al., 2012)
in order to compare different sources of dietary omega-3
fatty acid supplementations on plasma, red blood cell and
skeletal muscle fatty acid compositions in horses, three
(alfalfa/bromegrass) hay and barley diets were fed: one
was supplemented with an algae and fish oil containing
DHA and EPA (MARINE; Magnitude; JBS United,
Sheridan, IN); another group was supplemented with the
same amount of ALA in flaxseed (FLAX) as FLAX, and a
third group (control; CON) was fed hay and barley to make
all diets have the same calorie amount. Treatments were
supplemented for 90 d. Blood samples and muscle middle
gluteal biopsies were collected on d 0, 30, 60, and 90 of
supplementation.
Direct supplementation of EPA and DHA through a
marine source increased PUFA concentrations in the plasma,
red blood cell and muscle tissue of equines (Hess et al.,
2012). Although present in muscle tissue at baseline, EPA
and DHA increased in horses supplemented with a marine
source containing these specific fatty acids. In plasma and
red blood cells, EPA and DHA were below detection levels
in all groups and increased only in MARINE-supplemented
horses. Supplementation with dietary sources containing

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Omega-3 fatty acid supplementation in horses
R. Bras. Zootec., 43(12):677-683, 2014
EPA and DHA may be indicated when increased
incorporation of these n-3 fatty acids to muscle and red
blood cells is desired. Conversion of ALA from flaxseed
and forages to EPA and DHA occurs in the skeletal
muscle, as seen in this study (Hess et al., 2012) by
the detection of these fatty acids in equine muscles at
baseline. Supplementation with ALA through flaxseed
lead to higher incorporation of muscle n-3 DPA, a derivate
of EPA, compared to MARINE supplementation. Some
positive effects of n-3 DPA on inflammation have been
reported; however, the effects of such increases should
be evaluated in further studies addressing inflammatory
responses and compared to EPA and DHA in horses
(Hess et al., 2012). In this study, conversion of ALA to
EPA and DHA did not occur after supplementation with
extra ALA (above the control dietary n-3 PUFA level) from
FLAX.
Effects of n-3 PUFA supplementation on insulin sensitivity
in horses (Hess et al., 2013)
Dietary supplementation with n-3 PUFA has been
shown to increase insulin sensitivity as described above.
In order to test the hypothesis that supplementation with
n-3 PUFA would improve insulin sensitivity, the same
diets described for the previous study were fed to a group
of 21 adult mares to test glucose and insulin dynamics.
Specific tests to determine insulin sensitivity (frequent
sampling intravenous glucose tolerance tests) were
performed on days 0, 30, 60, and 90 of supplementation
(Hess at al., 2013).
No overall treatment effect was observed when
all mares within each treatment were compared among
themselves. However, when treatments were compared
among mares with the lowest quintile in insulin sensitivity
(Treiber et al., 2005) (11 mares) there was a trend (P = 0.08)
for a treatment effect, where MARINE (n = 5 and
FLAX (n = 3) horses had higher insulin sensitivity (SI =
1.18±0.16 in FLAX, and 1.05± 0.16 in MARINE compared
to 0.59±0.16 in CON, n = 3). Although a small number
of insulin resistant mares were compared, further studies
should be performed in a larger group of insulin resistant
horses. If proven effective, supplementation with omega-3
fatty acids could help to reduce problems associated with
insulin resistance in horses (Hess et al., 2013).
Evaluation of synovial fluid in horses fed two different sources
n-3 PUFA: a pilot study (Ross-Jones et al., 2014)
Elevating n-3 PUFA in mammalian diets may
downregulate inflammatory processes in the joint
(Proudman et al., 2008) and has been shown to have
symptom-modifying effects in inflammatory diseases
(Lau et al., 1993). One hypothesized mechanism is the
potential of long-chain n-3 PUFA to reduce the production
of potent inflammatory eicosanoids (Chapkin et al., 2009),
primarily PGE2. In order to test the effects of different
sources of n-3 PUFA on synovial fluid composition, the
diets described on the first study (Hess et al., 2012) were
supplemented for 90 days (Ross-Jones et al., 2014).
On day 90 of supplementation, approximately 3 mL
of synovial fluid were extracted from the right carpus of
each horse. Fluid was analyzed for fatty acid concentration
and PGE2 concentration. Synovial fluid samples from
the MARINE group exhibited EPA and DHA, whereas
the FLAX and CON groups did not express detectable
concentrations. Synovial prostaglandin E2 concentration in
the MARINE group tended to be lower compared to CON
horses (P<0.10).
Synovial fluid fatty acid levels for EPA and DHA
were significantly higher in the MARINE group
compared to either CON or FLAX groups, indicating
that direct supplementation of EPA and DHA is required
if higher fluid concentrations of those fatty acids are
desired (Ross-Jones et al., 2014). A small difference between
treatment and control in synovial fluid PGE2 concentration
in the current study may be due to all horses being healthy
and free of existing joint inflammation or disease. Inducing
experimental inflammation in healthy animals receiving
a dietary n-3 PUFA supplement may cause measurable
differences in eicosanoid levels.
Results indicated a possible inhibition of inflammatory
eicosanoid prostaglandin E2 production in equine synovial
fluid by oral supplementation of the polyunsaturated
fatty acids EPA and DHA. Further research is needed
to determine if oral n-3 PUFA supplementation can be
therapeutically advantageous in horses experiencing joint
inflammation.
Implications
Based on results from several studies, supplementation
with n-3 polyunsaturated fatty acids has the potential to
benefit humans and horses in diverse ways. Future studies
should address the effects of n-3 polyunsaturated fatty
acid supplementation on inflammation and specifically
in horses with chronic inflammatory diseases such as
laminitis, metabolic syndrome, pituitary pars intermedia
disease and osteoarthritis improving the horses’ health
and wellbeing.

682 Hess and Ross-Jones
R. Bras. Zootec., 43(12):677-683, 2014
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