Does dietary fat affect inflammatory markers in overweight and obese individuals?—a review of randomized controlled trials from 2010 to 2016
Telle-Hansen et al. Genes & Nutrition
Does dietary fat affect inflammatory markers in overweight and obese individuals?-a review of randomized controlled trials from 2010 to 2016
Vibeke H. Telle-Hansen 3
Jacob J. Christensen 0 2
Stine M. Ulven 0
Kirsten B. Holven 0 1
0 Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo , Postbox 1046, Blindern, 0317 Oslo , Norway
1 Norwegian National Advisory Unit on Familial Hypercholesterolemia, Oslo University Hospital Rikshospitalet , P.O. box 4950, Nydalen, 0424 Oslo , Norway
2 The Lipid Clinic, Oslo University Hospital Rikshospitalet , P.P. box 4950, Nydalen, 0424 Oslo , Norway
3 Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences , Postbox 4, St. Olavsplass, 0130 Oslo , Norway
Background: Obesity, a major cause of death and disability, is increasing worldwide. Obesity is characterized by a chronic, low-grade inflammatory state which is suggested to play a critical role in the development of obesity-related diseases like cardiovascular diseases and type 2 diabetes. In fact, in the hours following consumption of a meal, a transient increase in inflammatory markers occurs, a response that is exaggerated in obese subjects. Dietary composition, including content of dietary fatty acids, may affect this inflammatory response both acutely and chronically, and thereby be predictive of progression of disease. The aim of the review was to summarize the literature from 2010 to 2016 regarding the effects of dietary fat intake on levels of inflammatory markers in overweight and obesity in human randomized controlled trials. Methods and results: We performed a literature search in MEDLINE, EMBASE, and PubMed databases. The literature search included human randomized controlled trials, both postprandial and long-term interventions, from January 2010 to September 2016. In total, 37 articles were included. Interventions with dairy products, vegetable oils, or nuts showed minor effects on inflammatory markers. The most consistent inflammatory-mediating effects were found in intervention with whole diets, which suggests that many components of the diet reduce inflammation synergistically. Furthermore, interventions with weight reduction and different fatty acids did not clearly show beneficial effects on inflammatory markers. Conclusion: Most interventions showed either no or minor effects of dietary fat intake on inflammatory markers in overweight and obese subjects. To progress our understanding on how diet and dietary components affect our health, mechanistic studies are required. Hence, future studies should include whole diets and characterization of obese phenotypes at a molecular level, including omics data and gut microbiota.
Overweight; Obese; Inflammation; Metabolic; Dietary fat; Fatty acids; CRP; IL-6; TNFα; RCT
Obesity and inflammation
The prevalence of obesity is increasing worldwide. The
number of affected individuals is nearly doubled between
1980 and 2008 [
], and estimates show that by 2030,
prevalence will increase by 65 million in the USA and 11
million in the UK [
]. Obesity, defined as a body mass
index (BMI) of 30 kg/m2 or higher, is independently
associated with increased mortality and is an important
risk factor for metabolic diseases, such as cardiovascular
diseases (CVD) and type 2 diabetes (T2D) [
can be considered a consequence of prolonged
imbalance between energy intake and expenditure, driven by a
complex interplay between genes, diet, and other
environmental factors [
]. Interestingly, the chronic
lowgrade inflammatory state of obesity [
] is suggested to
play a critical role in the development of obesity-related
metabolic dysfunction . Adipose tissue contains
adipocytes and infiltrated macrophages, both of which
release a spectrum of similar inflammatory mediators,
including acute-phase proteins (like PAI-1), cytokines
(like IL-6, TNFα), and chemokines (like MCP1).
Consequently, circulating levels of inflammatory markers are
elevated in human obese subjects and associate with
obesity-related parameters [
Dietary fat and inflammation
Lifestyle factors, such as diet and exercise, play an
important role in the development and progression of obesity and
its comorbidities. Specific dietary factors, such as dietary
fat, may modulate inflammation and thereby risk of disease
in humans [
]. Dietary fat is composed of different fatty
acids, like saturated fatty acids (SFA) and trans fatty acids,
monounsaturated fatty acids (MUFA), polyunsaturated
fatty acids (PUFA) of both omega (n) 6- and n3-family, and
conjugated linoleic acid (CLA). The inflammation-specific
modulatory effect of dietary fat may for example act via the
eicosanoid metabolism or as regulators of membrane and
cytosolic signaling through activation of gene expression.
Dietary fat can also directly regulate gene expression
by acting as ligand for transcription factors, such
as the peroxisome proliferator-activated receptors
(PPAR) and liver X receptors (LXR). Importantly, the
inflammatory response differs depending on the type
of fatty acid. Generally, while SFA and trans fat are
considered pro-inflammatory, the PUFA and especially
the long-chain (LC) n3 fatty acids are considered
antiinflammatory. Being a precursor of pro-inflammatory
eicosanoids, n6 PUFA have been suggested to mediate
pro-inflammatory effects and thereby increase the risk
of chronic diseases in humans [
]. However, despite the
general acceptance that n6 PUFA are pro-inflammatory,
several studies show that humans with the highest
intake or plasma level of n6 PUFA have the lowest
inflammatory status and hence do not support a
proinflammatory effect [
In the hours following the consumption of a meal, a
transient increase in circulating inflammatory markers
], which potentially contributes to endothelial
dysfunction and vascular disease [
]. The post-prandial
inflammatory reaction appears to be triggered mainly by
triglycerides and SFA, in addition to total energy and
glucose content of the meal [
]. Interestingly, this
post-prandial inflammatory response is exaggerated in
obese subjects [
]. Persistent increased post-prandial
exposure produces a state of chronic low-grade
inflammation, characterized by increased systemic levels of
pro-inflammatory cytokines (TNFα, IL-1β, and IL-6) and
], which is a critical player in the
development of many lifestyle diseases.
Research on diet-related health effects has traditionally
examined single nutrients. Although successful, this
approach has largely changed towards the examination of
food, diets, or dietary patterns. Humans do not eat single
nutrients; they eat meals with complex mixtures of
different nutrients. In addition, many nutrients have
synergistic or interactive effects. Previous studies have shown
that healthy dietary patterns, characterized by increased
PUFA intake in place of SFA, are associated with
decreased chronic low-grade inflammation, in particular
decreased level of TNFα and IL-6 [
Obesity-related inflammation is mainly mediated by
the increased fat mass in the obese state; however, it
may be modulated by chronic or acute exposure to
dietary fat. Calder and coworkers performed a
comprehensive review of dietary factors and inflammation in 2011,
including both dietary patterns and dietary components
(whole grains, fruits, vegetables, nuts, soya, coffee, tea,
cocoa, fiber, milk peptides, vitamin E, vitamin C, fatty
acids, carbohydrates, iron, vitamin D, phytochemicals,
gut microbiota, prebiotics, and probiotics) [
conclude that a healthy dietary pattern, like the
Mediterranean diet, is associated with decreased low-grade
inflammation in both healthy and obese individuals.
They further conclude that important protective factors
in the diet are whole grains, fiber, fruits, vegetables, fish,
PUFA, and especially n-3 PUFA, vitamin C, vitamin E,
and carotenoids. Dietary factors that are inconclusive or
have no effect on inflammation include nuts, tea, coffee,
cocoa, flavonoids, alcohol, milk peptides, vitamin D,
probiotics, and prebiotics, while oxidized lipids, SFA, and
trans fatty acids promote inflammation [
]. The aim of
the present review was to summarize the latest research
findings (2010–2016) in the area of dietary fat and
inflammatory markers in overweight and obesity in human
randomized controlled trials.
To identify relevant studies, we performed a literature
search in MEDLINE, EMBASE, and PubMed. The
search was performed in September 2016 and was
limited to publications from January 2010 to September
2016. Only original articles and randomized intervention
trials in overweight and obese humans were included.
Furthermore, only studies with information about intake
of total fat, SFA, MUFA, and PUFA, or with total fatty
acid profile in the foods or whole diet were included.
Inflammatory markers included in this article were defined
as pro-inflammatory cytokines, acute-phase proteins,
and adhesion molecules and chemokines (CRP, TNFα,
IL-6, ICAM, VCAM, and MCP1). In addition, altered
proteome and mRNA transcripts of such markers were
included. We included studies which clearly or possibly
fulfilled the following criteria: overweight/obese subjects,
intervention with fatty acids, and at least one
inflammatory marker measured. Moreover, we excluded studies
that clearly fulfilled at least one of the following criteria:
not original study (for example editorial, review or
conference paper), animal study, or lack of inclusion criteria
measurements (as defined previously). Duplicate articles
were removed. In total, 37 articles were reviewed in full
text and included in the present article. Figure 1 shows
the flow chart of the study selection.
Results and discussion
Dietary fat and inflammatory markers
In the present review, we discuss the effects of dietary fatty
acid intake on markers of inflammation in overweight and
obese subjects, as documented by post-prandial and
shortand long-term intervention trials (parallel and cross-over
design; 3 weeks to 1 year) (Tables 1 and 2).
Dairy products include a vast amount of different
products, consisting of many different nutrients, bioactive
compounds and bacteria. During the last years, several
studies have been conducted to improve our knowledge
of the possible health effects of milk and dairy products.
Drouin-Chartier and coworkers investigated the effect of
intake of milk (3.2 servings of 2% fat milk/day)
compared with no servings of milk/day in a randomized
cross-over study where each period lasted for 6 weeks
]. No difference was seen in levels of CRP, VCAM,
ICAM, and E-selectin after the treatment in any of the
groups (Table 1). The authors concluded that short-term
milk intake has no observable favorable or deleterious
effects on cardio-metabolic risk factors [
Furthermore, fermented dairy products have been shown to
have cardio-protective effects [
]. Using a cross-over
design, Nestel et al. investigated the effects of full-fat
fermented (cheese and yogurt), full-fat non-fermented
(butter and cream) and low-fat (milk and yogurt) dairy
products in obese subjects [
]. Each of the three
interventions lasted for 3 weeks. The low-fat products had
half the amount of total fat and a quarter amount of
SFA than the full-fat products, while MUFA and PUFA
content were similar in all groups. They did not find any
changes in the inflammatory markers CRP, TNFα,
Fig. 1 Flow chart of the study selection
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The symbols reflect statistical significant increase (↑) or decrease (↓) between groups, or no change (↔) between groups
ICAM, VCAM, IL-1β, and MIP-1a except for increased
levels of IL-6 in the full-fat non-fermented group,
compared to the other groups. Moreover, Van Meijl and
Mensink investigated the effects of low-fat dairy
products on low-grade systemic inflammation and
endothelial function in overweight and obese subjects [
Subjects were randomly allocated to consume 500 mL
low-fat (1.0%) milk and 150 g low-fat (1.5%) yogurt or
600 mL of fruit juice and 43 g fruit biscuits
(corresponding to three biscuits). Each study period was 8 weeks.
Daily intake of dairy products compared to fruit juice
did not change fasting plasma concentration of CRP [
or TNFα, IL-6, ICAM, VCAM, MCP1, or sTNFR1 [
However, sTNFR2 was increased after dairy compared to
control food intake [
] (Table 1).
Considerable public interest has been focused on
minimally processed products, mainly because they are
believed to contain more natural ingredients, nutrients
and bioactive molecules, and thereby appear healthier.
In this respect, trans fatty acids occur naturally in fats
from ruminants, and fats produced using certain
industrial processes, and are known to have negative
cardiometabolic effects. However, CLA, a natural trans fatty
acid, has been examined for possible beneficial health
effects in several studies [
]. Venkatramanan et al.
investigated the effect of milk enriched with natural CLA
or enriched with synthetic CLA, compared to untreated
milk, in a randomized three-phase cross-over
singleblind trial . Each dietary phase lasted for 8 weeks.
The amount of total fat was similar in the study
products (approx. 4.0%) but the level and type of CLA
differed; however, there was no difference in any of the
measured inflammatory markers between the three
dietary groups [
]. In another study, they compared buns
with butter made of milk from grazing versus
conventional fed cows [
]. The fatty acid profile in both the
butter and buns were similar. After 12 weeks of
intervention, there were no differences in inflammatory
markers between the groups [
] (Table 1).
The six studies included in this review compare quite
different dairy products. Two of the studies found minor
differences in inflammatory markers. Whereas the
fullfat and non-fermented products slightly increased
inflammation, only a limited amount of inflammatory
markers changed in each study. Therefore, from the
studies included in the present review, it seems that
intake of dairy products have no favorable or deleterious
effects on inflammation (CRP, TNFα, ICAM, VCAM,
IL1β, sTNFR1, and MIP-1α) in overweight and obese
subjects. Nevertheless, dairy products may have beneficial
effects by lowering CRP levels in obese subjects [
captured in studies included in the present review, and
the effect may be related to non-lipid content of the
dairy products, such as matrix effects or dairy peptides.
In the present review, the focus was fat intake, and
therefore no studies specifically investigating matrix
effects or dairy peptides were included, which may explain
the lack of beneficial effects.
Nuts are high-energy, nutrient-dense foods that are rich
in PUFA and other bioactive components, including
fiber, antioxidants, vitamins, and minerals [
suggests that nut consumption may have beneficial
effects on oxidative stress, inflammation, and vascular
]. Importantly, epidemiological studies show a
negative correlation between nut intake and risk of CVD
] and recently, the PREDIMED study found 30%
reduction in CVD after intake of a Mediterranean diet
enriched with mixed nuts (walnuts, almonds, and
hazelnuts) in a high-risk CVD group [
Five studies that investigated the inflammatory effects
of nuts in overweight and obese subjects were included
in this review (Table 1). When investigating the effect of
the American Heart Association (AHA) dietary
guidelines with or without enrichment of 30 g raw mixed nuts
(15 g walnuts, 7.5 g almonds, and 7.5 g hazelnuts) on
inflammatory markers for 12 weeks, Lopez-Uriarte et al.
did not find any changes in VCAM and ICAM between
the groups [
]. However, VCAM was reduced within
the nut group. In the same study, Casas-Agustench and
coworkers investigated the effect on CRP, MCP1, IL-18,
and IL-6 [
]. A moderate weight loss was observed in
both groups. MCP1 and IL-18 levels decreased after
both diets, with no differences between the groups. The
level of IL-6 was reduced in the nut group only;
however, the significance disappeared after adjusting for
weight loss. Interestingly, no differences were seen for
plasma levels of CRP, neither within nor between the
]. Furthermore, Bakhtiary et al. did a 12-week
randomized controlled study among elderly women with
metabolic syndrome (MetS). Studying the effect of intake
of soy nuts or textured soy protein, they found no
significant differences in CRP between the groups [
another study, the effects of high oleic peanuts on
cardio-metabolic measures and CRP in healthy,
overweight adults were examined; however, no clear effects
were found [
]. Finally, Tey and coworkers compared
the effects on inflammatory markers with consumption
of either 0, 30, or 60 g of hazelnuts per day for 12 weeks
]. They found no effect on any of the inflammatory
markers examined (CRP, IL-6, ICAM, and VCAM).
Despite the high-fat content of nuts, including PUFA,
intake of nuts do not seem to modulate markers of
inflammation in overweight or obese individuals, which is
in accordance with previous review [
]. Even though two
of the five included studies found lower inflammatory
markers in the nut groups (IL-6, VCAM), the effects
disappeared when adjusting for weight loss or compared to
the control group.
Vegetable oils are rich in PUFA, the main constituent
being n6 fatty acids. Even though n6 fatty acids are
widely considered pro-inflammatory while n3 fatty acids
are considered anti-inflammatory, the evidence
supporting the former is contradictory and inconclusive [
addition, there is strong evidence that n6 fatty acids
promote health by reducing LDL cholesterol and thereby
the risk of CVD [
]. Our group previously
showed no change in CRP among overweight and obese
subjects after 12 weeks of intervention with food items
where alpha-linolenic acid rich triglyceride oil was
substituted with alpha-linolenic acid rich diacylglycerol
oil  (Table 1). In a randomized, parallel single-blind
study, Gagliardi and coworkers investigated the effects
of daily servings of butter, no-trans-fat margarine or
plant sterol margarine on biomarkers of inflammation
and endothelial dysfunction [
]. No significant
difference between the groups was found on the
concentration of inflammatory and endothelial dysfunction
markers. Moreover, Bjermo et al. investigated the effects
of a high-PUFA diet (vegetable oil) or high-SFA diet
(mainly butter) on liver fat, systemic inflammation, and
metabolic disorders in a randomized study lasting for
10 weeks (the HEPFAT study) [
]. Compared to the
SFA group, liver fat, IL1Ra, and sTNFR2 were lower in
the PUFA group at the end of the study. In contrast, no
group difference was found for plasma levels of CRP,
IL1β, IL-6, and IL-10 [
]. Moreover, in an 8-week
randomized single-blind parallel intervention study, Lee and
coworkers compared the effect of three PUFA-based
supplements, corn oil, a botanical oil, or fish oil. None
of the supplements changed the level of CRP within or
between groups [
]. In an 8-week single-blind,
randomized trial, Rozati et al. investigated the effects of extra
virgin olive oil, compared with corn oil, soybean oil, and
butter, on quantity and functionality of a number of
lymphocyte subsets [
]. In general, there were no
antiinflammatory effects of olive oil intake; however, the
authors suggested that the increased T cell proliferation in
the olive oil group might reflect immune-modulatory
effects of olive oil consumption [
Masson and Mensink [
], Esser and coworkers [
and van Dijk et al. [
] all studied the difference in
postprandial response after intake of SFA or PUFA in
overweight subjects. Masson and Mensink compared a
butter meal (14 E% SFA) and a margarine meal (8.7 E%
PUFA of which 8.0 E% was linoleic acid). Compared
with the SFA meal, the PUFA meal decreased IL-6,
TNFα, sTNFR1 and sTNFR2, and sVCAM [
et al. and Van Dijk et al. reported data from the same
study, where three different high-fat milkshake meals
consisting of palm oil, high oleic sunflower oil, or n3
PUFA (DHA) [SFA-meal (51 E% SFA), MUFA-meal (79
E% MUFA) and PUFA-meal (38 E% PUFA)] were
compared in both obese and lean subjects [
with MetS  and lean, obese, and obese-diabetic
] were included in the studies. In the work by
Esser et al., all groups displayed a post-prandial increase
in many of the measured inflammatory markers,
including IL-8, sICAM-3, sICAM-1, sVCAM-1, and a decrease
in IL-6. In contrast, and despite clear differences in
post-prandial triglyceride response and higher baseline
values of CRP in obese subjects, they found no global
differences between the groups on inflammatory
]. Still, SFA consumption was associated with
higher plasma P-selectin concentration 2 h post-prandial
compared with MUFA and n3 PUFA, and lymphocyte
CD11a and CD11b expression decreased in lean
participants but did not change in obese subjects [
Dijk et al. found that plasma concentrations of IL-1β
varied both according to the type of fat and groups [
In addition, the TNFα level was lower after the
intervention in lean compared with obese and obese diabetic
]. Palmolein, derived from dry fractionation
of palm oil, is a rich source of both SFA (42%) and
MUFA (47%), in addition to some PUFA (12%), and is
widely used for both frying and replacement of trans fat.
In a post-prandial study with isocaloric high protein,
high-fat meals prepared with either palmolein or olive
oil, Stonehouse and coworkers observed no differences
on endothelial function 1–5 h after intake of a high
protein meal consisting of 40 g of either olive oil or
palmolein in overweight and obese men [
]. Finally, in
another post-prandial, cross-over study in 30 obese
males and females, investigating the inflammatory effects
of a high-carbohydrate diet, high-MUFA diet (high oleic
sunflower oil), high-PUFA diet (sunflower oil), or a
highSFA diet (palm oil), the researchers found no differences
between groups with regards to CRP, TNFα, and IL-6 [
Although tissue biopsies are often limited in human
studies, blood samples are easily accessible. Peripheral
blood mononuclear cells (PBMC) are a subset of the
white blood cells that include monocytes and
lymphocytes. The PBMC, as part of the immune system, are
exposed to many of the same environmental factors as
metabolic tissues and provide a model for human
metabolic regulation and inflammation on, for example, gene
expression level [
]. In addition to the circulating
inflammatory markers, Van Dijk et al. also measured the
effect of high SFA (palm oil), high MUFA (high oleic
sunflower oil), and high n3 PUFA (DHA) on gene
expression in PBMC . Intake of high-fat MUFA and n3
PUFA shakes compared to SFA shakes, induced higher
increase in the expression of MCP1 and IL-8 mRNA
levels in PBMC [
] (Table 1).
In the present review, 3 of 10 studies with vegetable
oils found some beneficial effects on inflammation
]. Except for some contradictory effects observed at
gene expression level in the study by Van Dijk et al. ,
none of the studies found convincing evidence of
increasing circulating inflammatory markers after intake of
vegetable oils. Hence, vegetable oils do not seem to have
detrimental inflammatory effects in overweight and
obese subjects, and might even have some beneficial
effects. These findings correlate with different studies
showing reduced risk of CVD and cholesterol after
intake of n6 fatty acids. Ulven et al. obtained 11%
reduction in LDL cholesterol when replacing 5% of the energy
from SFA with PUFA, mainly linoleic acid, with no effect
on inflammatory markers in normal weight individuals
]. Farvid and coworkers have shown that by replacing
5% of the energy from SFA with linoleic acid, gives a
13% reduction in risk of coronary artery disease (CAD)
mortality and 9% in cardiac events [
]. In the
PREDIMED study, a 13% reduction in risk of stroke, heart
infarction and cardiovascular mortality was obtained
with a diet high in linoleic acid [
]. In addition,
epidemiological studies show similar results [
Humans eat mixed diets, not single nutrients.
Consequently, researchers have shifted focus to examine the
health effects of complex diets and dietary patterns
instead of the classic reductionist approach. The
Mediterranean diet has long been related to improved health,
while a westernized diet has the opposite effect.
Similarly, a healthy Nordic diet associate with lower
mortality and improve cardiovascular risk factors [
Uusitupa and De Mello have investigated the effects of a
healthy Nordic diet on inflammatory markers in obese
individuals with MetS  or impaired glucose
], respectively. In those studies, a healthy Nordic
diet included whole grain (of which ≥ 50% rye, barley,
and oat), cereals, fruits, vegetables and berries, rapeseed
oil, margarine, low-fat dairy products, fish, white meat,
and avoidance of sugar-sweetened beverages. The
control diet included refined cereal products (of which ≥
90% as wheat) and butter, less fruits and vegetables and
no berries, and less than one meal of fish per week.
There were no limits of dairy products, meat and
sugarsweetened beverages. Uusitupa et al. found decreased
levels of IL1Ra with the healthy diet compared with the
control diet. In addition, there was an association
between intake of saturated fats and IL1Ra [
] (Table 1).
De Mello et al. found decreased levels of E-selectin in
the healthy diet group compared with the control diet
group, and CRP levels decreased both within the healthy
diet and whole grain enriched diet (WGED), but there
were no difference when compared with control diet
]. Furthermore, Camhi et al. examined CRP changes
in subjects with MetS enrolled in a lifestyle intervention
trial with factorial design (the DEER trial) [
Subjects were randomly assigned to a control group, an
exercise group, a diet group (NCEP-II guidelines), or a diet
and exercise group. CRP was reduced in the two latter
groups, but in women only. In men and in women and
men combined, however, CRP was unchanged. In
addition, in that study, there was no effect of exercise on
CRP levels . Finally, in a fully controlled study with
14 overweight and obese, dyslipidemic women, CRP
levels decreased after 3 weeks with a high-PUFA diet
compared to a high-SFA diet [
] (Table 1).
Measuring the effects of single nutrients or foods
might be difficult due to sensitivity of the analyses, as
well as the fact that many nutrients are correlated in
dietary patterns. In the present review, three of the four
studies decreased levels of CRP or other inflammatory
markers after intervention with mixed diets, in addition
to some within group effects. The NCEP-based diet, a
Nordic diet, and a high-PUFA diet all showed beneficial
effects on inflammation, as evidenced by decreased CRP,
E-selectin, and IL1Ra. This finding indicates that a
change in whole diet is more effective with regard to
inflammation compared to change of single components
of the diet. This may be explained by the accumulation
of many small effects and the synergy of single nutrients,
or that compliance is easier for participants when given
a whole diet instead of single nutrients or foods, thereby
also contributing to decreasing confounding factors and
practical obstacles. Several studies have shown beneficial
health effects of exchanging SFA with PUFA, and in the
review by Calder et al., they suggest that Mediterranean
diet, characterized by high intake of PUFA, may lead to
decreased chronic low-grade inflammation [
]. Hence, it
is conceivable that a healthy fatty acid composition (high
PUFA and low SFA) as part of a healthy dietary pattern
may be of importance in reducing systemic low-grade
inflammation when overweight or obese.
The LIPGENE study
In the pan-European LIPGENE study, researchers
investigated whether high-SFA diet (HSFA), high-MUFA diet
(HMUFA), or low-fat, high-complex carbohydrate diets
supplemented with either sunflower oil (LFHCC-SFO)
or long chain (LC) n3 fatty acids (LFHCC-LC n3) for
12 weeks affected CRP [
], IL-6, TNFα, ICAM, or
] in subjects with MetS (Table 1). No
dietspecific effects were found. In contrast, after 12 weeks of
intervention, a post-prandial fat challenge was
performed, and ICAM [
] was reduced with the HMUFA
diet compared with the LFHCC-LC n3 and HSFA diets,
while MCP1 [
] were reduced with both HMUFA and
LFHCC-LC n3 diets compared to HSFA diet. In
contrast, in later analyses, Meneses and coworkers did not
find any changes in IL-6 or MCP1 after the
postprandial fat challenge [
Dietary fatty acids may affect health via several
mechanisms, for example by influencing the activity of
transcription factors involved in metabolic regulation and
inflammation, like NF-κB and PPARγ [
]. Changes in
adipose tissue gene expression was studied in the
LIPGENE study, and it was shown that the mRNA level of
p65 (sub-unit of the NF-κB transcription factor) was
induced by a HSFA challenge meal, but with no apparent
difference between the four different test meals .
Post hoc statistical analyses, however, showed that the
p65 gene expression level was increased after intake of
LFHCC-SFO and LFHCC-LC n3 diets. In addition, the
post-prandial (4 h) IκBa gene expression in PBMC was
increased after HSFA compared with LFHCC-LC n3
]. In contrast, fasting IκBa gene expression level
was increased after 12 weeks of intervention and
postprandial (0 h) with the LFHCC-LC n3 diet compared
with HSFA and MUFA diets. Furthermore, post-prandial
PBMC TNFα and MMP-9 mRNA levels were reduced
after intake of the HMUFA compared with the HSFA
diet. After the HMUFA post-prandial fat challenge, the
mRNA level of TNFα and metalloproteinase-9 (MMP-9)
were downregulated in PBMC compared with the HSFA
fat challenge [
]. Moreover, the post-prandial effect on
the PBMC proteome (nuclear and cytoplasmic) was also
examined in the LIPGENE study by Rangel-Zuniga et al.
] and Camargo et al. [
]. The PBMC proteome
(nuclear and cytoplasmic) displayed changes in
proinflammatory proteins after intake of HMUFA (F2,
TLN1, GSN, CAPZ) and LFHCC-LC n3 diets (FGB,
FGG, VCL, ACTB, CAPZA1, and MACF1) [
Pathways analysis showed that inflammatory response
protein was differently expressed 4 h after intake of four
different meals with different fat quality. In particular,
pathway analysis showed that the top function associated
with protein differently expressed after intake of a HSFA
meal was inflammatory response (HLA-C, THBS1, and
PSME1 were upregulated, and PLEC, FGB, and HSPA1A
were downregulated) [
] (Table 1).
Inflammatory markers, both circulating and mRNA
levels (TNFα, ICAM, MCP1, p65, and MMP-9), were
investigated in the LIPGENE study, in which four of the
seven studies investigated gene expression and or
proteome effects. Taken together, the results from the
LIPGENE study suggest that a high-MUFA diet, and to a
lesser extent a LFHCC diet, have some anti-inflammatory
effects compared with high-SFA diet. However, only two
of the studies showed effects on circulating inflammatory
markers, both investigating effect after a fat challenge; the
other studies showed no effect, and it is therefore difficult
to draw firm conclusions.
Fatty acids in weight reduction studies
Diet-induced weight reduction effectively improves
obesity-related metabolic aberrations and low-grade
inflammation. However, the importance of dietary fat in
the rising prevalence of overweight and obesity is
unknown. While some studies show no association
between dietary fat intake and body weight, other studies
do find an association [
]. However, during the past
years, several studies have confirmed that total energy
intake, rather than macronutrients distribution per se, is
the more important determinant of weight reduction
and maintenance [
]. Therefore, it is of high
interest to elucidate if different fatty acids, as part of a
dietinduced weight reduction, will affect the low-grade
inflammatory status observed in overweight and obesity.
Tovar and coworkers [
] investigated the
cardiometabolic protective effect of an 8-week multifunctional
diet (MFD; including food items such as
low-glycemicimpact meals, antioxidant-rich foods, oily fish, viscous
dietary fibers, soybean and whole barley, kernel products,
almonds, and plant stanols) in overweight and obese
subjects, compared with a control diet where none of the
abovementioned functional food items were included.
Some of the food items were included in the control diet
was provided such as white wheat bread, dark wheat
bread, parboiled rice, cornflakes, champignon spread,
prawn spread, powdered pastry cream, fruit preserves, and
mango chutney. Both diets were designed according to
the Nordic nutrition recommendations. Both diets
resulted in a weight loss of approximately 2%. There was no
difference between the diets in levels of CRP between the
groups (Table 2). Silver et al. tested the effect of a
16week, high-fat diet-based weight reduction
]. The high-fat diets were supplemented with
either 9 g/d of stearate (18:0), oleate (18:1), linoleate
(18:2), or placebo, and a panel of inflammatory
markers was measured. All four groups each lost 5 kg
weight, which accounted for most of the observed
effects on the inflammatory markers (IL-1a, IL-1β,
IL12, IL-17, IFNγ, TNFα, and TNFβ). Using linear
mixed models, adjusting for weight change and
compared with the control group, the authors showed
that the main effects of 18:0 was a drastic reduction
of IFNγ, and the main effects of 18:1 was a small
increase in IL-1β, IL-6, IL-10, IL-12, and TNFα.
Surprisingly, there were no main effects of 18:2 [
a 12-week weight reduction trial, De Luis et al.
investigated the effects of a PUFA or MUFA diet, as well
as interaction with GLP-1 variants, on CRP [
found no differences in CRP with either the dietary
interventions or the genetic variants. Su et al.
investigated the effect of n3 supplementation on
inflammatory markers in the context of a 12-week weight
]. Women with MetS were randomly
assigned to one of four interventions: energy
restriction, energy restriction with meal replacement, energy
restriction with fish oil, or energy restriction with
meal replacement and fish oil. Although they found a
small additive effect of n3 supplementation, the
authors concluded that the weight reduction was a more
important determinant of changes in inflammatory
markers than fish oil intake [
]. Moreover, the effect
of low-fat versus low-carbohydrate diets on
inflammation was investigated in 103 males and females for
12 weeks [
]. The low-fat diet group ingested less
than 30 E% from fat (with < 7 E% from SFA) and 55
E% from carbohydrates, while the low-carbohydrate
diet group had less than 40 g per day of digestible
carbohydrates (total carbohydrates minus fiber).
Compared to the low-fat diet, intervention with the
lowcarbohydrate diet decreased CRP levels [
] (Table 2).
Weight reduction per se will have positive
cardiometabolic effects, including reduced inflammation [
However, only one of the weight reduction studies
included in this review found a beneficial effect on CRP
between groups with different dietary fat composition.
Moreover, one of the studies found that a high fat diet
supplemented with oleate compared to placebo
increased several inflammatory markers despite a weight
]. The present review do not focus on
weight reduction and inflammatory response, but rather
fat quality and inflammatory response, which might
explain the discrepancy between the present review
compared with previous studies [
]. The limitation in time,
giving a limited amount of studies in the present review
may also influence the results.
Obesity is associated with pathological changes in
adipose tissue morphology, including infiltration of immune
cells, and obese individuals have higher circulating levels
of inflammatory markers than lean individuals [
Associations between intake or status of various fatty acids
and inflammatory markers have been examined in
human studies and there is a general agreement that
increasing dietary SFA intake, especially in overweight
and obese individuals, is associated with raised
inflammatory markers . In the present review comprising
studies between January 2010 and September 2016, we
only found minor effects of dietary fat on inflammatory
markers in overweight and obese subjects. The most
consistent effects were found after intervention with
whole diets. Dairy products, vegetable oils and fatty
acids in dietary weight reduction studies only showed
minor effects, while nuts did not seem to have any
effects on inflammatory markers. Due to small effects,
large inter-individual differences and insensitive methods,
dietary health effects are difficult to measure. This might
explain why we do not find any effects after intervention
with single nutrients or foods in the present review.
However, nutrients in whole diets may have synergistic effects,
and thereby be able to affect the inflammatory system
with more beneficial effects. To measure diet-induced
changes, it may be necessary to temporarily disrupt the
body’s homeostasis, which may be done with dietary
challenge tests. The extent of the disruption and the speed
of recovery to homeostasis may be considered as health
Only two of the studies investigating the effect of
mixed diets found differences between subgroups among
the intervention groups. In the study by De Mello et al.,
the CRP level was significantly reduced after the WEGD
diet compared with the control diet, but only when
excluding statin users [
]. Similar, CRP level was reduced
between the diet- and diet/exercise group compared
with the control group, but only in women with MetS
]. Due to the small effect sizes expected from dietary
interventions, medications that influence inflammation
may camouflage a real effect. In addition, different effect
sizes between men and women are commonly registered.
This is maybe due to physiological or pathophysiological
differences between the sexes, or differences in
compliance and motivation. Finally, subtle differences in
baseline level of inflammation may appear as differences in
response to diet. Responses to dietary challenges
postprandial may be more informative than measurement of
fasting homeostatic measures. In the present review,
nine articles included post-prandial measures, in which
five found changes in inflammatory response. Hence, a
dietary challenge apparently showed a more consistent
response. However, four articles were from the LIPGENE
study, therefore making it difficult to conclude if studies
including a challenge are more efficient in differentiating
the response elicited by diet.
Investigating the transcriptomic profile in different
cells can improve our understanding of the metabolic
regulation and provide insights into the mechanisms of
metabolic disease. Investigating metabolic responses of
food and nutrients optimally involve tissue biopsies.
However, invasive biopsy procedures are a limiting factor
in human studies, while blood samples are easily
accessible. Diet-induced changes in concentration of circulating
inflammatory markers compared to tissue concentrations
may be undetectable, but the PBMC gene expression
measurements may be more sensitive than plasma proteins to
alterations in circulating nutrients. Also, PBMC are
hypothesized to be a relevant substitute for investigating
metabolic regulation in tissues and are frequently used as
an indirect measure, particularly of gene regulation
]. Svahn et al. compared the transcriptome
effect of dietary fat in different organs. In contrast to
the hypothesis stated above, they found that dietary
fatty acids affected the transcriptome in distinct
manners in different organs , demonstrating the
complexity of diet-gene interactions and the interpretation
of dietary intervention studies. The present review did
not find obvious effects of dietary fat on gene
expression or proteomic related to inflammation; however,
few studies investigating gene expression or proteome
Obese individuals represent a heterogeneous group with
different phenotypes. Interestingly, a subgroup of obese
individuals has been described as “metabolically healthy
obese” (MHO). In contrast to at-risk obese (ARO), the
MHO phenotype is defined by a favorable cardio-metabolic
profile, despite the same amount of body fat, including a
more favorable inflammatory profile, less visceral fat, less
infiltration of macrophages into adipose tissue, and smaller
adipocyte cell size [
]. The studies included in the
present review have not presented data of differentiated
effects in different obese phenotypes. It has been estimated
that 18–44% of all obese may be categorized as MHO 
and because the effect sizes may be small, it may be difficult
to detect dietary effects on inflammation when investigating
all obese as one group. During the past years, increasing
focus has been given to the relation between gut microbiota
and health. Several studies have confirmed a direct
implication of gut microbiota in obesity progression [
] and gut
microbiota is established as a determining factor in
obesityrelated inflammation [
]. Gut microbiota are affected by
several factors, including dietary factors like fat quality and
quantity and fiber. The present review investigates
inflammatory-modulating effects of mainly dietary fat
quality, and to some degree quantity. However, the proportion
of fat versus other dietary components, like fiber or the
composition of gut microbiota, is not included in any
of the studies.
In the present article, only a restricted part of the
scientific field has been reviewed. Our literature search was
limited to randomized controlled trials with fatty acids
in overweight and obese subjects, published between
2010 and 2016 that included measurement of
inflammatory markers. In addition, we have categorized the
included studies according to type of dietary
intervention. Hence, some of the studies may be relevant in
more than one category, which may have affected the
conclusion. Taken together, in the present review we find
minor changes in inflammation after modulating fat
intake in overweight and obese subjects. Even though
randomized controlled trials are superior when studying
cause-and-effect, they do not necessarily have a
mechanistic approach. To progress our understanding on how
diet and dietary components affect our health,
mechanistic studies are required. Hence, future studies should
include whole diets and characterization of obese
phenotypes at a molecular level, including omics data and gut
microbiota to help us understand the role of diet on
lowgrade inflammation in overweight and obese subjects.
ARO: At risk obese; BMI: Body mass index; CAD: Coronary artery disease;
CRP: C-reactive protein; CVD: Cardiovascular disease; E%: Energy %;
ICAM: Intercellular adhesion molecule; MCP-1: Monocyte chemoattractant
protein-1; MetS: Metabolic syndrome; MHO: Metabolically healthy obese;
MMP-9: Matrix metalloproteinase-9; MUFA: Monounsaturated fatty acid; n3/
n6: Omega-3/omega-6; PBMC: Peripheral blood mononuclear cells;
PUFA: Polyunsaturated fatty acid; RCT: Randomized controlled trial;
SFA: Saturated fatty acid; T2D: Type 2 diabetes; TNFa: Tumor necrosis factor
alpha; VCAM: Vascular cell adhesion protein
VHTH, JJC, SMU and KBH conceived, designed, and revised the manuscript.
VHTH and JJC did the literature search. All authors read and approved the
Dr. Telle-Hansen has received grants from Mills DA, although not related to
the contents of this manuscript. Dr. Ulven has received grants from Mills DA,
TINE DA, and Olympic Seafood; none of which is related to the contents of
this manuscript. Dr. Holven has received research grants and/or personal fees
from Tine DA, Mills DA, Olympic Seafood, Amgen, Sanofi and Pronova; none
of which are related to the contents of this manuscript. Christensen has no
financial relationships relevant to disclose.
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