Table Of ContentCOMMENTARY
Adipocyte1:3,173–176;July/August/September2012;G2012LandesBioscience
Of mice and men
Factors abrogating the antiobesity effect of omega-3 fatty acids
Lise Madsen1,2 and Karsten Kristiansen1
1DepartmentofBiology;UniversityofCopenhagen;Copenhagen,Denmark;2NationalInstituteofNutritionandSeafoodResearch;Bergen,Norway
The ability of n-3 long chain poly- a large prospective cohort study, Nurses’
unsaturatedfattyacids(PUFAs)to Health Study cohort,12 reported that
prevent high fat diet-induced obesity in higher intake of fish and n-3 PUFAs
rodentsis welldocumented.Evidence for was associated with higher prevalence of
a similar effect in humans is, however, obesity, another US prospective cohort
limited. Intervention studies in humans study, The Health Professional Follow-up
are inconclusive and epidemiological study, showed that men who consumed
studies are dichotomous. Our recent fish were less likely to be obese.13 The
finding that sucrose and other high latterfindingissupportedbysmallercross-
glycemic index carbohydrates abrogate sectional studies where the level of plasma
the antiobesity effect of n-3 PUFAs n-3 fatty acids, used as a biomarker for
might, at least in part, provide an intakeoffish,wasinverselycorrelatedwith
explanation to the apparent discrepancy bodymassindex(BMI)andwaistcircum-
between human and rodent intervention fences.14 Similarly, an inverse relationship
studies, and the lack of effect in some has been reported in obese patients
human trials. In addition to the amount between abdominal obesity and amount
and type of carbohydrates, the levels of of n-3 PUFA in adipose tissue samples15
n-6 PUFAs, linoleic acid in particular, in andbetweentheamountofn-3PUFAsin
Keywords: obesity, fish oil, PUFA,
the background diet might influence the subcutaneous adipose tissue and reduced
carbohydrates, linoleic acid,
antiobesogenic effect of n-3 PUFAs. adipocyte size.16
persistent organic pollutants
Lastly, it is plausible that the quantity Although a few human intervention
Submitted: 04/09/12 ofpersistentorganicpollutantsinfishoil, trials, where weight loss, BMI and/or
and seafood rich in n-3 PUFAs, might waist circumstances were reported end-
Revised: 05/07/12
have an influence on the outcome of points, have shown promising results,
Accepted: 05/08/12
the trials. other similar trials have failed, and taken
http://dx.doi.org/10.4161/adip.20689 together the human intervention trials are
Correspondenceto:LiseMadsen inconclusive. A systematic review of the
orKarstenKristiansen; Alargenumberofstudieshavedocumented subject was published fairly recently by
Email:[email protected]@bio.ku.dk theability offishoil toattenuate,1-9 and in Buckley andHowe,17and therefore onlya
at least one case, totally prevent10 high fat few studies will be mentioned here. The
Commentaryto:HaoQ,LillefosseHH,FjæreE, diet-induced obesity in rodents. Moreover, positive and quite convincing results from
MyrmelLS,MidtbøLK,JarlsbyRH,etal.High-
atleastonestudyhasdemonstratedthatn-3 at least two trials published in 2007
glycemicindexcarbohydratesabrogatethe
PUFAs are able to reduce the amount of are worth mentioning though. First,
antiobesityeffectoffishoilinmice.AmJPhysiol
EndocrinolMetab2012;302:E1097–112;PMID: body fat in mice already made obese by a Thorsdottir et al.18 demonstrated that
22338077;http://dx.doi.org/10.1152/ajpendo. high fat diet.11 In view of the promising 1.5 g of n-3 PUFA per day during
00524.2011 rodent studies one would expect fish oil eight weeks of caloric restriction signific-
and
andseafoodenrichedinn-3PUFAstobea antly increased weight loss in young
AlvheimAR,MaldeMK,Osei-HyiamanD,Hong
useful, effective and safe tool to reduce overweight men. This was, however, not
LinY,PawloskyRJ,MadsenL,etal.Dietary
linoleicacidelevatesendogenous2-AGand obesityalsoinhumans. seen in women. Second, Kabir et al.
anandamideandinducesobesity.Obesity(Silver Epidemiological associations between reported that 3 g of n-3 PUFA per day
Spring)2012;Inpress;PMID:22334255;http://dx. intake of n-3 PUFAs and obesity develop- reduced total fat mass and the diameterof
doi.org/10.1038/oby.2012.38
ment are, however, inconclusive. Whereas subcutaneous adipocytes in a two month
www.landesbioscience.com Adipocyte 173
randomized controlled trial with type 2 is also highly variable. For instance, the PUFAs. The levels of LA and high
diabetic women.19 However, Krebs et al. average amount to meet this 50% in the glycemic index carbohydrates might be of
did not observe an increased weight loss Philippines,DenmarkandUS,is133,578 particular importance, as the background
when5goffishoilwascombinedwithan and 2,178 mg per day, respectively.23 In levels of LA will determine the amount of
energyrestricteddietinoverweighthyper- this respect it is worth noting that we n-3 PUFAs required replacing AA in PL,
insulinemic women.20 Moreover, a meta- found a strong positive correlation and high glycemic index carbohydrates
analysis from 2009, aimed to investigate between obesity development and con- may reduce the antiobesogenic effect. It is
the effect of n-3 PUFAs on glycemic sumption of LA and soybean oil.6 Also, likely that the success and failure of
control in type 2 diabetic patients, con- intake of sugar was positively correlated different clinical trials using similar doses
cluded that there was no significant effect with obesity, whereas changes in total of n-3 PUFAs have been influenced by
on body weight.21 Several possible expla- energy consumptionwerenot.6Moreover, different background diets. The dose of
nations for the apparent discrepancy intake of calories from poultry, a major n-3 PUFAs used in clinical trials is
between rodent and humans trials and source of LA in the US diet,22 correlated generally relatively low, less than 3 g per
the lack of consensus in human interven- withobesitydevelopment,unlikeintakeof day, and this might be far too low if
tion studies, mostly related to study grains, beef, fish and seafood, eggs, dairy the background diet contains high levels
design, exist and these are discussed in or vegetables.6 In this context, it is worth of LA.26
the previously mentioned review by mentioningthatthewomenintheNurses’ A third aspect for consideration is the
Buckley and Howe.17 Here, we discuss Health Study cohort, who frequently source of n-3 PUFAs and the levels of
the findings in three recent rodent studies consumedfishandwerelikelytobeobese, persistent organic pollutants (POPs) in
that provide insight into how interaction also had a high intake of poultry.12 these.IncollaborationwithDr.Ruzzinwe
between nutrients may, at least in part, A second aspect regarding background have recently demonstrated that whereas
explain the discrepancies and inconsist- diets, when studying the effect of n-3 inclusionofpurifiedsalmonoilattenuated
encies observed in human studies. PUFAs, is the amount and type of obesity in Wistar rats, inclusion of crude
An important aspect concerning the carbohydrates. Our recent finding that salmon oil exaggerated obesity develop-
outcome of human trials concerns the sucrose24 and other high glycemic index ment.27 Moreover, we have shown that
levels of dietary n-6 PUFAs, linoleic acid carbohydrates25 abrogate the antiobesity chronic consumption of Atlantic salmon
(LA)inparticular,inthebackgrounddiet. effect of n-3 PUFAs in mice, demonstrate withahighlevelofPOPscausedobesityin
The estimated per capita consumption of that the antiobesogenic potential of n-3 mice.28 When the levels of POPs in the
soybean oil, containing about 50% LA, PUFAsisdependentonthemacronutrient salmonwerereduced,obesitydevelopment
has increased more than 1,000-fold from composition of the background diet. We in the mice decreased concomitantly.28
1909 to 1999 in the US; today represent- demonstrated that increasing the sucrose: POP exposure has been associated to
ing7.21energypercent(e%)ofthediet.22 proteinratiointhebackgrounddiet,dose- development of type 2 diabetes,29-33
A recent study performed in collaboration dependently abrogated the antiobesity whereas the correlation between POP
withDrAlvheimandDrHibbelndemon- effect of fish oil.25 In fact, when the exposureandobesitypersehasbeenmore
strated that increasing the dietary levels of sucrose amount was high, a diet enriched difficult to establish. However, a recent
LA from 1 to 8 e%, thereby reflecting the in n-3 PUFAs was as obesogenic as a diet Danish cohort study demonstrated a
increase during the 20th century, elevated enriched in n-6 PUFAs.24 A diet contain- positive correlation between BMI and the
the level of arachidonic acid (AA)-phos- ing35e%sucrosemightsurelybeoflittle concentration of certain POPs, such as
pholipids and promoted obesity in mice.6 human relevance. However, we recently dichlorodiphenyltrichloroethane (DDT),
By adding 1 e% n-3 PUFAs to the 8 e% demonstrated that inclusion of high in adipose tissue.34 A major problem
LA diet, EPA and DHA replaced AA in glycemic index carbohydrates, such as linking POPs with obesity development
tissue phospholipids, and obesity devel- amylopectin, also abrogated the antiobe- is that plasma levels of POPs are not
opment was attenuated.6 The conversion sity effect of fish oil.25 Today, grains and reliable predictors of POP exposure.34
of LA to AA, allows competition between sugarrepresentthemajorenergysourcesin Further,sincePOPsaccumulateinadipose
AA and the n-3 PUFAs, EPA and DHA, the US diet, representing approximately tissue, measurements of POP concentra-
for incorporation into the phospholipids. 22 and 17 e%, respectively.22 If the tions in plasma and adipose tissue are
Thus, intake of LA will influence the sucrose:protein ratio, and/or the amount strongly affected by the increased mass of
omega-3 index (red blood cell EPA + of high glycemic index carbohydrates adipose tissue in obese individuals result-
DHA as a percentage of total red blood influence on the antiobesogenic effect of ing in a “dilution” of POPs. Thus, a
cell lipids).23 It is important to note that n-3 PUFAs also in humans, both the type negative correlation between concentra-
there is a large variability not only in and level of carbohydrates in the back- tionsof polychloridinated biphenyl(PCB)
intake of n-3 PUFAs but also in LA ground diets will affect the outcome of congeners in plasma and BMI has been
between different countries, and thus, the the trials. reported in two separate studies.35,36 In
omega-3 index is highly variable.23 Together, these two reports illustrate one of these studies,35 intake of fish, fatty
Accordingly, the amount of n-3 PUFAs theimportanceofacontrolledbackground fish in particular, was associated with the
requiredtomeet50%n-3PUFAsintissue diet when studying the effect of n-3 measured levels of adipose tissue POP
174 Adipocyte Volume1Issue3
concentrations.POPsaccumulateinlipid- tissue weights without a concomitant oil, whereas an increased adipose tissue
rich food, and fatty fish thus represent a reduction on body weight.1,5,7,37,38 Thus, mass was still observed in the female
sourceofbothPOPsandn-3PUFAs.The a decrease in body weight in humans mice.41 This points to a role of the LDL
levels of POPs in farmed fish depend on might not necessarily be expected. receptor for an intriguing gender depend-
the composition of the fish feed, whereas Moreover, two often ignored rodent ent difference in fat partitioning and
contamination in feral fish is determined studies have reported an increased adipose collectively these studies also point to
by factors including fat content, prey and tissuemassinrodentsfedn-3PUFAs.Fish leptin as a key player in the action of n-3
geographic location. Thus, even though a oil is actually reported to increase adipose PUFAs. Thus, reduced leptin sensitivity,
direct causal link between human obesity tissue mass in db/db mice when included as often observed in obese subjects, might
and POP exposure remains to be estab- in a high fat diet39 and inclusion of 6% reduce n-3 PUFA action.
lished, it seems warranted to consider menhaden fish oil doubled the amount of Collectively, the levels of LA as well as
possible exposure to POPs in human adipose tissue mass in female LDL the amount and type of carbohydrates in
intervention trials where fish or seafood receptor deficient mice, while still pre- the background diet might influence the
is used as a source of n-3 PUFAs. venting hepatic steatosis.40 Interestingly, antiobesogeniceffectofn-3PUFAsalsoin
Concerning the apparent discrepancy nooveralleffectonadiposetissuemasswas humans. Furthermore, the actual content
betweenrodentsandhumansontheeffect observed in a study where both male and of EPA and DHA varies in different
of n-3 PUFAs in body weight and obesity female mice were fed a high fat diet studies, and in combination this may
itshouldbementionedthatseveralrodent supplemented with fish oil in comparison provide an explanation for the apparent
studies have reported an effect on adipose to a high fat diet supplemented with olive lack of effect in some human trials.
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