Immune cell contribution

WAT consists of two compartments, the adipocytes that store TAG and the stromal vascular fraction which contains immune cells. During obesity, immune cells (mainly macrophages preceded by t-lymphocytes^{(Reference Xu, Barnes and Yang32)}) infiltrate the adipose tissue or undergo expansion^{(Reference Weisberg, Leibel and Anthony33)}. Classical (cluster of differentiation (CD)14⁺⁺CD16⁻) monocytes account for about 80 % of the circulating population and have high C-C chemokine receptor (CCR) 2 receptor expression^{(Reference Considine R34)}. CCR2, and its ligand monocyte chemoattractant protein-1 (MCP-1), play an important role in the recruitment of inflammatory macrophages into adipose tissue^{(Reference Kamei, Tobe and Suzuki35–Reference Gautier, Jakubzick and Randolph39)}, although this is not the only factor initiating obesity-associated macrophage recruitment (as discussed extensively elsewhere^{(Reference Inouye, Shi and Howard40–Reference Bai and Sun44)}). Monocyte migration into adipose tissue is induced by chemokines such as MCP-1 (also known as C–C motif ligand 2) and regulated on activation normal, T cell expressed and secreted (RANTES; also known as C–C motif ligand 5), which are upregulated in obese adipose tissue^{(Reference Weisberg, Leibel and Anthony33,Reference Lee and Lee45–Reference Keophiphath, Rouault and Divoux47 )}, and then differentiate into macrophages^{(Reference Sun, Ji and Kersten48)}. Fractalkine (also called C–X3–C motif ligand 1) and its receptor (C–X3–C chemokine receptor 1) have also been implicated in the recruitment of both monocytes and t-lymphocytes. Fractalkine is expressed on macrophages^{(Reference Zeyda, Gollinger and Kriehuber49)} and is upregulated in obese adipose tissue^{(Reference Shah, Lu and Hinkle50)}. Adipose tissue macrophages in lean tissue have a more alternatively activated (M2) anti-inflammatory phenotype, whereas macrophages in diet-induced obese tissue have a more classically activated (M1) pro-inflammatory phenotype^{(Reference Lumeng, Bodzin and Saltiel46)} and are commonly found in crown-like structures around dying adipocytes^{(Reference Lumeng, Bodzin and Saltiel46)}. Adipose tissue macrophages are however likely part of the spectrum from M1 to M2 polarisation, rather than two distinct populations^{(Reference Mosser and Edwards51)}. The change in number/function of these cells with obesity alters the WAT inflammatory cell populations and impact upon WAT inflammation and systemic insulin sensitivity (Fig. 1)^{(Reference Chawla, Nguyen and Sharon Goh52)}.

Gut microbiota contribution

Overnutrition^{(Reference Amar, Burcelin and Ruidavets53)} and HFD consumption^{(Reference Pendyala, Walker and Holt54)} cause metabolic endotoxemia as a result of lipopolysaccharide (LPS) from gram-negative gut bacteria translocating into the circulation^{(Reference Pendyala, Walker and Holt54,Reference Cani, Amar and Iglesias55 )}. The increased absorption of LPS is thought to occur due to impairments in gut barrier function^{(Reference Cani, Possemiers and Van De Wiele56)} as well as it being incorporated into chylomicrons during dietary fat absorption^{(Reference Ghoshal, Witta and Zhong57,Reference Laugerette, Vors and Peretti58 )}. Impairments in gut barrier function have also been associated with the development of low-grade inflammation^{(Reference Creely, McTernan and Kusminski59)} as a result of gut-derived LPS and SCFA activating TLR4 and nucleotide-binding oligomerisation domain-containing protein 1 receptors^{(Reference Sun, Ji and Kersten48)}. LPS binds to LPS-binding protein (LBP) and then transfers to CD14, which exists in membrane bound (mCD14) or circulating soluble (sCD14) states^{(Reference Schumann60)}. Subsequently, the LPS–LBP complex binds to mCD14 receptors on the surfaces of innate immune cells, including monocytes and macrophages, to initiate TLR4 signalling^{(Reference Schumann60,Reference Wright, Ramos and Tobias61 )}. LPS in plasma attaches to sCD14 or LBP which are located on HDL^{(Reference Berbée, Havekes and Rensen62,Reference Wurfel63 )}. In adipocytes, increased LPS concentrations have been shown to increase TLR4 activation and increase TNF-α and IL-6 secretion^{(Reference Song, Kim and Yoon64)}. Further human intervention studies are required in this area to understand how dietary patterns and alterations in the gut microbiome contribute to metabolic-inflammation^{(Reference Arora and Bäckhed65,Reference Thursby and Juge66 )}.

SFA

SFA, especially long-chain SFA, are thought to promote a pro-inflammatory environment in WAT (Fig. 2). In adipocytes treated with palmitic acid (PA; a common long-chain SFA), NF-κB binding and TNF-α secretion were increased, whereas IL-10 production was decreased^{(Reference Bradley, Fisher and Maratos-Flier67)}. PA has also been shown to prime the NLRP3 inflammasome via TLR4/NF-κB signalling in bone marrow-derived macrophages (BMDM)^{(Reference Reynolds, Mcgillicuddy and Harford68)} leading to increased IL-1β production. Palmitate, but not lauric acid, has also been shown to activate the NF-κB pathway and increase IL-6 and TNF-α expression in adipocytes^{(Reference Ajuwon and Spurlock69)}. The translocation of NF-κB to the nucleus necessary to up-regulate the production of pro-inflammatory cytokines is dependent on inhibitory factor κB (IκB) phosphorylation by the upstream regulator inhibitor of NF-κB kinase (IKK); this is initiated by either TNF-α or TLR4 activation (e.g. with LPS stimulation)^{(Reference Baker, Hayden and Ghosh70)}. BMDM were sensitive to priming by both PA and LPS, and secreted higher levels of cleaved IL-1β in response to ATP stimulus^{(Reference Reynolds, Mcgillicuddy and Harford68)}. In BMDM and dendritic cells, the SFA component of the diet, and not the obese phenotype alone, was responsible for increased IL-1β secretion^{(Reference Reynolds, Mcgillicuddy and Harford68)}. However, the stimulation of TLR4 by SFA remains ambiguous with the suggestion that TLR4 may not be a receptor for palmitate^{(Reference Lancaster, Langley and Berglund71)}. Erridge et al.^{(Reference Erridge and Samani72)} investigated the effects of common SFA (including lauric acid, myristic acid, PA and stearic acid) on TLR4 signalling in a broad range of cell types including macrophages and adipocytes and found that LPS stimulation of TLR4 may account for the activation commonly attributed to SFA treatment. However, TLR4 does mediate palmitate-induced inflammation indirectly through the priming of macrophages and modification of macrophage lipid metabolism^{(Reference Lancaster, Langley and Berglund71)}.

Increases in plasma LPS concentrations have been attributed to altered gut microbiota and increased gut permeability in response to increased dietary SFA^{(Reference Hersoug, Møller and Loft73)}. Both LPS and PA promote M1 polarisation of macrophages^{(Reference Saberi, Woods and de Luca74,Reference Suganami, Tanimoto-Koyama and Nishida75 )}, which leads to a more pro-inflammatory macrophage phenotype. In addition, stearic acid and PA have been shown to stimulate MCP-1 expression via the TLR4/NF-κB pathway^{(Reference Schaeffler, Gross and Buettner76)}; this enables increased recruitment of monocytes to the adipose tissue and macrophage polarisation from an M2 to an M1 inflammatory phenotype.

The synthesis of the lipid-derivative, ceramide, is dependent on the quantity of long-chain SFA in the diet^{(Reference Merrill77)}. Pro-inflammatory cytokines and SFA can upregulate genes involved in ceramide biosynthesis^{(Reference Holland, Bikman and Wang78)}. Ceramides can initiate assembly of the NLRP3 inflammasome^{(Reference Ralston, Lyons and Kennedy4,Reference Lyons, Kennedy and Roche79 )}, which enables the cleavage of pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. The NLRP3 inflammasome is also activated by SFA through the production of reactive oxygen species^{(Reference Wen, Gris and Lei11,Reference Dostert, Pétrilli and Van Bruggen80 )}.

MUFA

In comparison with long-chain SFA, MUFA are thought to promote a more anti-inflammatory WAT environment. In adipocytes treated with oleic acid, TNF-α secretion and NF-κB binding were unaltered, which is in contrast to the pro-inflammatory effect of PA described above^{(Reference Bradley, Fisher and Maratos-Flier67)}. In obese mice, a MUFA- compared to a SFA-rich diet, improved insulin sensitivity through increased phosphorylation of protein kinase B, increased GLUT4 gene expression, reduced priming of IL-1β and increased AMP activated protein kinase (AMPK) activation^{(Reference Finucane, Lyons and Murphy81)}. The MUFA palmitoleate has also been shown to maintain AMPK phosphorylation compared to the SFA palmitate in BMDM derived from mice^{(Reference Chan, Pillon and Sivaloganathan82)}. AMPK activation reduces NLRP3 activation^{(Reference Wen, Gris and Lei11)} and inhibits NF-κB signalling^{(Reference Salminen, Hyttinen and Kaarniranta83)}. Therefore, maintenance of AMPK activity may help to mediate the anti-inflammatory effect of MUFA (Fig. 2)^{(Reference Finucane, Lyons and Murphy81,Reference Chan, Pillon and Sivaloganathan82 )}.

In BMDM of chow fed mice, palmitoleate was also reported to increase anti-inflammatory related genes and oxidative metabolism, which are indicative of M2 macrophage polarisation^{(Reference Chan, Pillon and Sivaloganathan82)}. In BMDM derived from HFD fed mice, palmitoleate incubation reduced the pro-inflammatory gene expression profile suggesting macrophage polarisation from a more M1 to M2 phenotype^{(Reference Chan, Pillon and Sivaloganathan82)}. Moreover, in mice fed an SFA-rich diet that were then transferred to a MUFA-rich diet, the negative effects of the prior SFA-rich diet were not completely reversed^{(Reference Finucane, Lyons and Murphy81)}. Furthermore, the co-incubation of BMDM with PA and palmitoleic acid, reduced the SFA-induced increase in M1 macrophage polarisation and NF-κB signalling by preventing inhibitory factor κBα (IκBα) degradation and NF-κB translocation to the nucleus^{(Reference Chan, Pillon and Sivaloganathan82)}. Collectively, these findings indicate that MUFA can at least impede some of the negative effects of SFA.

n-3 PUFA

The n-3 PUFA EPA and DHA appear to have anti-inflammatory and insulin-sensitising effects in vitro (Fig. 2). In human monocyte-derived macrophages, EPA and DHA reduced TNF-α, IL-1β and IL-6 expression through downregulation of LPS-induced NF-κB binding^{(Reference Weldon, Mullen and Loscher84)}. In addition, in macrophages pre-treated with DHA and then stimulated with LPS, NF-κB activation and TNF-α secretion were reduced^{(Reference Oliver, McGillicuddy and Harford85)}. DHA but not EPA increased IL-10 secretion and reduced M1 macrophage polarisation^{(Reference Oliver, McGillicuddy and Harford85)}. In adipocytes, incubation with both EPA and DHA (complexed to albumin) increased adiponectin secretion compared to a control (albumin alone)^{(Reference Oster, Tishinsky and Yuan86)}. DHA increased adiponectin secretion to a greater extent than EPA and only DHA enhanced PPARγ and adiponectin gene expression compared to the control^{(Reference Oster, Tishinsky and Yuan86)}. Adiponectin is known to be upregulated, in part, through PPARγ activation^{(Reference Phillips and Kung87)}. Long-chain n-3 PUFA can act through PPARγ^{(Reference Oster, Tishinsky and Yuan86,Reference Grimm, Mayer and Mayser88 )}, which inhibits NF-κB signalling through NF-κB and inhibitory factor κBα^{(Reference Pascual and Glass89,Reference Delerive, De Bosscher and Vanden Berghe90 )}. These PUFA act through the receptor G-protein coupled receptor (GPR120), inhibiting NF-κB signalling and reducing its pro-inflammatory and insulin desensitising effects^{(Reference Oh, Talukdar and Bae91)}. They can also promote the M2 polarisation of macrophages^{(Reference Sun, Ji and Kersten48,Reference Odegaard, Ricardo-Gonzalez and Goforth92 )}. In addition, in trans-well co-cultured macrophages from mice fed a HFD, and contact co-cultures with macrophages from mice fed a low-fat diet, fish oil enrichment showed reduced NLRP3 activation, reduced IL-6 and TNF-α secretion and reduced expression of M1 macrophage polarisation genes^{(Reference De Boer, Monk and Liddle93)}.

Hyperenergetic interventions

WAT inflammatory responses to overnutrition (i.e. hyperenergetic feeding) can provide early insight into the development of obesity and cardiometabolic disorder progression. Four out of six studies (3–56-d) reported no effect of a hyperenergetic, HFD on markers of WAT inflammation (Table 1)^{(Reference Tam, Viardot and Clément94–Reference Chen, Liu and Thompson97)}. Specifically, following a 3-d period of overfeeding (+5230 kJ requirements/d; 45 %E total fat), no change in WAT gene expression of macrophage markers or MCP-1 but increased HOMA-IR (a marker of systemic IR) was reported, relative to baseline^{(Reference Chen, Liu and Thompson97)}. In this study, no further details of the diet were provided^{(Reference Chen, Liu and Thompson97)}. In the study of Tam et al.^{(Reference Tam, Viardot and Clément94)}, healthy individuals completed a 28-d overfeed (+5230 kJ/d; 45 %E total fat); this was achieved by asking participants to supplement their habitual diet with high-fat snacks (crisps, chocolate, cheesecake and a dairy dessert containing a liquid oil-based supplement^{(Reference Samocha-Bonet, Campbell L and Viardot98)}). No change in WAT gene expression of macrophage markers, MCP-1 or IL-10 was reported, relative to baseline^{(Reference Tam, Viardot and Clément94)}. These authors also reported no change in the number of circulating monocytes or the absolute number of WAT macrophages. However, a change in macrophage polarisation may have occurred, as indicated by the increased CD40/CD206 ratio following the intervention^{(Reference Tam, Viardot and Clément94)}. In agreement with Tam et al.^{(Reference Tam, Viardot and Clément94)}, following 56-d overfeeding (140 %E requirements/d; 44 %E total fat) no change in gene expression of macrophage markers, MCP-1, NF-κB or adiponectin was reported, relative to baseline^{(Reference Tam, Covington and Bajpeyi95)}. A strength of this study was the controlled nature of the intervention; all meals were prepared by the research team and consumed under supervision, ensuring dietary adherence. However, the foods used in this intervention were not described^{(Reference Tam, Covington and Bajpeyi95)}. Following 14 and 56 d overfeeding (+3180 kJ/d; 48 %E total fat), which involved adding high-fat snacks (cheese, butter, almonds) to the habitual diet, Alligier and colleagues^{(Reference Alligier, Meugnier and Debard96)} also reported no change in expression of WAT genes related to inflammation. However, increases in LBP gene expression were reported at 14 and 56 d^{(Reference Alligier, Meugnier and Debard96)}. This provides some support for the potential of an inflammatory response as LBP is known to transfer LPS to mCD14 on monocytes and initiate TLR4 signalling^{(Reference Schumann60)}. At 14 and 56 d, HOMA-IR was increased suggesting increased systemic IR following the intervention. No evidence of macrophage infiltration was observed following the 56-d overfeeding period.

Table 1. Summary of hyperenergetic human studies examining the effect of a dietary intervention differing in fat quantity or quality on fasted subcutaneous white adipose tissue (WAT) inflammatory responses

OL, open-label; SA, single-arm; NR, not reported; CHO carbohydrate; CD, cluster of differentiation; MCP-1, monocyte chemoattractant protein-1; HOMA-IR, homeostatic model of insulin resistance; CRP, C-reactive protein; R, randomised; P, parallel; OW, overweight; NOD, nucleotide-binding oligomerisation domain, LBP, lipopolysaccharide-binding protein; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; TC, total cholesterol; DB, double-blind; PPARγC1A, PPAR γ coactivator 1 α; y, years; %E, percentage total energy; ↓, significant decease; ↑, significant increase; ↔, no change.

* Diet composition data are presented as dietary intervention targets, unless otherwise stated.

† Results are significant to P < 0⋅05.

‡ All WAT outcomes for gene expression, unless otherwise stated.

§ Percentage of overfeed energy.

|| DNA methylation WAT outcomes.

¶ Diet composition data taken from Rosqvist et al.^{(Reference Rosqvist, Iggman and Kullberg122)}.

** Diet composition data are taken from dietary intake records.

†† Data reported as g/d.

The remaining two studies reported increased WAT inflammatory responses to a hyperenergetic intervention (Table 1). Perfilyev et al.^{(Reference Perfilyev, Dahlman and Gillberg99)} employed a 49-d overfeeding intervention (+3138 kJ/d), which was achieved by supplementing the habitual diet with high-caloric muffins containing refined palm or sunflower oil for an SFA- and n-6 PUFA-rich intervention, respectively. Mean DNA methylation of adiponectin increased in WAT following the SFA-rich diet, whereas the methylation of MCP-1, IL-6 and insulin receptor was increased following the n-6 PUFA-rich diet^{(Reference Perfilyev, Dahlman and Gillberg99)}. These authors also pooled data from both intervention arms. In response to the overall effect of overfeeding, increased DNA methylation of anti-inflammatory cytokine adiponectin and PPARγ coactivator 1 α (PPARγC1A), and the pro-inflammatory cytokine TNF-α were observed. A shorter hyperenergetic intervention (21-d; +4184 kJ/d) was employed by Luukkonen and colleagues^{(Reference Luukkonen, Sädevirta and Zhou100)}, where the habitual diet of overweight participants was supplemented with SFA- (coconut oil, butter and blue cheese), MUFA- (olive oil, pesto, pecan nuts and butter) or carbohydrate (CHO)-rich foods (orange juice, sugar-sweetened beverage and candy)^{(Reference Luukkonen, Sädevirta and Zhou100)}. The authors reported increased HOMA-IR, ceramides and LBP:sCD14 ratio following the SFA-rich diet. Ceramides are known to increase WAT NLRP3 inflammasome assembly^{(Reference Ralston, Lyons and Kennedy4,Reference Lyons, Kennedy and Roche79 )} and LBP is known to play a role in TRL4 signalling. In WAT, the SFA- but not the MUFA-rich diet increased expression of genes related to nucleotide-binding oligomerisation domain-containing receptor signalling and leucocyte transendothelial migration. It is possible that the more ‘at risk’ population (overweight/obese participants) recruited by Luukkonen et al.^{(Reference Luukkonen, Sädevirta and Zhou100)} demonstrated an enhanced inflammatory response to the overfeeding protocol. This is in contrast to the findings from the above-mentioned studies, where leaner cohorts were studied^{(Reference Tam, Viardot and Clément94,Reference Tam, Covington and Bajpeyi95,Reference Chen, Liu and Thompson97 )}. In more ‘at risk’ populations (obese and diabetic participants) levels of metabolic inflexibility have been reported^{(Reference Storlien, Oakes and Kelley101)}. It has also been suggested that lean and obese individuals have differential WAT gene expression responses to energy surplus^{(Reference Shea, French and Bishop102)}. Whilst Luukkonen et al.^{(Reference Luukkonen, Sädevirta and Zhou100)} reported increased expression of WAT genes related to inflammation following overfeeding, changes in WAT gene expression of inflammatory markers were not typically observed following interventions of 3–56-d^{(Reference Tam, Viardot and Clément94–Reference Chen, Liu and Thompson97)}. However, increased HOMA-IR was reported in a number of these studies^{(Reference Alligier, Meugnier and Debard96,Reference Chen, Liu and Thompson97,Reference Luukkonen, Sädevirta and Zhou100 )}, suggesting that WAT inflammation may occur subsequent to weight gain and IR^{(Reference Tam, Viardot and Clément94–Reference Chen, Liu and Thompson97)}.

To date, only a limited number of human intervention studies have been conducted in this area. Dietary adherence was assessed subjectively in some of these hyperenergetic studies through weekly contact with a research dietitian^{(Reference Tam, Viardot and Clément94,Reference Luukkonen, Sädevirta and Zhou100 )}, supervised meal consumption^{(Reference Tam, Viardot and Clément94)} and by asking participants to complete daily food checklists^{(Reference Chen, Liu and Thompson97)} or 5-d dietary records^{(Reference Alligier, Meugnier and Debard96)}. In two of the studies, adherence to the diets was assessed objectively by measurement of the fatty acid composition of WAT TAG^{(Reference Perfilyev, Dahlman and Gillberg99)} (a biomarker which reflects long-term dietary fatty acid intake^{(Reference Hodson, Skeaff and Fielding103)}) and plasma cholesterol esters^{(Reference Perfilyev, Dahlman and Gillberg99)} or plasma very LDL TAG^{(Reference Luukkonen, Sädevirta and Zhou100)} (circulating biomarkers which can be influenced by recent dietary fatty acid intake^{(Reference Hodson, Skeaff and Fielding103)}). Firm conclusions are hard to draw due to methodological differences, including study designs, duration, total fat and fatty acid composition of the diets, foods included in the intervention and participant characteristics. Further work is warranted to investigate the early WAT inflammatory response to overfeeding. More severe HFD interventions (approximately 150 % estimated energy requirements, approximately 65 %E total fat), which are known to alter glycaemic control following a 7-d intervention^{(Reference Parry, Smith and Corbett104–Reference Parry, Turner and Woods106)}, provide a good starting point for future work.

Isoenergetic interventions

Four studies have been identified that investigated the effect of a chronic, isoenergetic dietary intervention differing in fatty acid quality on fasted WAT inflammation (Table 2). van Dijk and colleagues^{(Reference van Dijk, Van Feskens and Bos107)} compared the WAT gene expression profile of overweight participants following a 56 d SFA- or MUFA-rich intervention. The assessment of plasma NEFA and WAT fatty acid composition provided objective evidence of dietary adherence^{(Reference van Dijk, Van Feskens and Bos107)}. In response to the SFA-rich intervention, these authors reported an increased expression of WAT pro-inflammatory genes involved in inflammation and immune function (including TLR, NF-κB, IL-6, T-cell receptor and P38 mitogen-activated protein kinase (MAPK) signalling) and decreased expression of WAT anti-inflammatory genes (including adiponectin and PPARγ). Following the MUFA-rich intervention, a decreased WAT gene expression of macrophage markers was reported. Moreover, WAT genes that were upregulated following the SFA-rich intervention were either unchanged or down-regulated (TLR, T-cell receptor) or upregulated to a much lesser extent (NF-κB, IL-6, P38 MAPK) following the MUFA-rich intervention. Pre-intervention WAT samples were collected when participants were consuming their habitual diet, before beginning a 14 d SFA-rich run-in diet prior to the intervention. Thus, it is possible that the SFA-rich nature of the run-in diet may have dampened an anti-inflammatory effect of the MUFA-rich intervention, as shown previously in a dietary intervention with mice^{(Reference Finucane, Lyons and Murphy81)}. It is also important to note that in a comment on this work^{(Reference Dahlman108)}, the results reported by van Dijk et al.^{(Reference van Dijk, Van Feskens and Bos107)} were suggested to exaggerate the effect of fatty acid composition on WAT gene expression responses as the authors did not make any adjustments for multiple analysis for their microarray data. However, findings indicate that the substitution of dietary SFA with MUFA could help to mitigate WAT inflammation^{(Reference van Dijk, Van Feskens and Bos107)}. This is in agreement with cross-sectional data, where metabolic syndrome patients that were high-SFA consumers, but not high-MUFA consumers, presented with increased gene expression of caspase-1 and pycard-1 (part of the NLRP3 inflammasome)^{(Reference Finucane, Lyons and Murphy81)}.

Table 2. Summary of isoenergetic human studies examining the effect of a dietary/supplemental intervention differing in fat quantity or quality on fasted subcutaneous white adipose tissue (WAT) inflammatory responses

OL, open-label; R, randomised; P, parallel; NR, not reported; CHO, carbohydrate; OB, obese; CD, cluster of differentiation; MCP-1, monocyte chemoattractant protein-1; CCL3, C–C motif chemokine ligand 3; CRP, C-reactive protein; TC, total cholesterol; LDL-C, LDL-cholesterol; HDL-C, HDL-cholesterol; SB, single-blind; OW, overweight; RANTES, regulated on activation normal, T cell expressed and secreted; PC, placebo-controlled; TNFRSF1A, TNF receptor superfamily member 1A; RELA/p65, NF-κB p65 subunit; TLR, toll-like receptor; IL1RN, IL 1 receptor antagonist; sTNFR, soluble TNF receptor; y, years; %E, percentage total energy; ↓, significant decease; ↑, significant increase; ↔, no change.

* Diet composition data are presented as dietary intervention targets, unless otherwise stated.

† Results are significant to P < 0⋅05.

‡ WAT outcomes for gene expression.

§ WAT biopsies collected post-intervention only.

|| Additional diet composition data taken from Bos et al.^{(Reference Bos, de Vries and Feskens123)}.

¶ Diet composition data are taken from dietary intake records.

** Data reported as g/d.

Three isoenergetic studies investigated the impact of an n-3 PUFA-rich intervention on WAT inflammation^{(Reference de Mello, Dahlman and Lankinen109–Reference Kratz, Kuzma and Hagman111)}. De Mello et al.^{(Reference de Mello, Dahlman and Lankinen109)} compared WAT gene expression following an 84-d intervention of differing n-3 PUFA quantities (camelina sativa oil, lean fish, fatty fish or control condition). No change in WAT gene expression of MCP-1, IL-1β, IL-6, IL-10, TNF-α, TNF receptor superfamily member 1A (TNFRSF1A), TLR2 or TLR4 was reported for all conditions, relative to baseline. A strength of this study was the comparison between different food sources of n-3 PUFA including fish and vegetable oil. The interventions were achieved by informing participants how to make dietary choices to achieve the desired intake of macronutrients. For the control group, participants were asked to minimise intake of fish to one meal per week and maintain habitual fat intake by replacing some fish meals with lean meat or skin-free chicken. This reduced participant burden compared to a fully supervised dietary intervention. Kratz et al.^{(Reference Kratz, Kuzma and Hagman111)} also employed a long-term intervention (98 d) but all foods were provided by the research team. These authors investigated the effect of an n-3 PUFA-rich diet compared to a control diet on WAT inflammation in overweight/obese participants, although this was a secondary aim of the investigation. Rapeseed and flaxseed oil were used for the n-3 PUFA intervention and high-oleic safflower and sunflower oils were used for the control intervention; total fat %E remained similar between interventions. Following both the control and n-3 PUFA-rich diet, systemic C-reactive protein (CRP) was increased but IL-6 and MCP-1 remained unchanged. WAT gene expression of TNF-α, IL-6, CD14, MCP-1, adiponectin, CD206 and CD284 were unchanged following both interventions. Itariu et al.^{(Reference Itariu, Zeyda and Hochbrugger110)} employed a shorter intervention of 56 d and assigned morbidly obese participants to either an n-3 PUFA (3⋅36 g EPA/DHA; achieved in 4 capsules/d) or control SFA (5 g butter fat/d) supplement condition (matched for caloric intake) prior to undergoing elective bariatric surgery. Systemic CRP and adiponectin remained unchanged pre- to post-intervention for both conditions, however IL-6 was reduced following the n-3 PUFA intervention. In WAT, these authors reported no difference in gene expression of adiponectin, IL-6, CD68 or CD163 in the n-3 PUFA group compared to the control group post-intervention. A decreased gene expression of MCP-1, C-C motif ligand 3 and CD40 was also reported in the n-3 PUFA group compared to the control group. As acknowledged by the authors, it was not feasible to examine change-from-baseline gene expression inflammatory responses in WAT as only post-intervention WAT biopsies were collected^{(Reference Itariu, Zeyda and Hochbrugger110)}. Baseline characteristics (including age, sex, BMI, blood pressure, HOMA-IR) were however comparable between participants randomly assigned to the n-3 PUFA or control group.

The ambivalent nature of the results from studies investigating PUFA-rich interventions may, in part, be due to differences in study design, participant cohorts recruited and the duration and composition of the dietary or supplemental intervention. All studies were conducted in ‘at risk’ populations (i.e. overweight/obese or pre-diabetic) and therefore responses in lean, healthy individuals also require investigation. An objective measure of compliance was employed in two of these studies, as assessed by fatty profile of plasma phospholipids^{(Reference de Mello, Dahlman and Lankinen109,Reference Itariu, Zeyda and Hochbrugger110 )} and cholesterol esters^{(Reference de Mello, Dahlman and Lankinen109)}, compared to twice-weekly reviews of dietary records and weighing of returned foods or supplements^{(Reference Kratz, Kuzma and Hagman111)}. Although there is strong in vitro evidence for the anti-inflammatory effects of n-3 PUFA, differences in doses achievable in cell or animal models compared to the physiologically achievable dose in vivo in human participants may account for the difficulty in translating these findings to man. Overall, the effect of n-3 PUFA on WAT inflammation remains unclear^{(Reference van Dijk, Van Feskens and Bos107,Reference de Mello, Dahlman and Lankinen109–Reference Kratz, Kuzma and Hagman111 )}. Further well-controlled intervention studies are therefore required to confirm the effect of n-3 PUFA on WAT inflammation.

Acute studies

It is also important to consider the WAT inflammatory response to feeding since we spend most of the waking day in a postprandial (fed), rather than a fasted state^{(Reference Williams112)}. WAT may be a key mediator in the promotion of systemic low-grade inflammation, an early component of the postprandial pro-atherogenic phenotype^{(Reference Magné, Mariotti and Fischer113,Reference Krauzová, Kračmerová and Rossmeislová114 )}. Few studies to date have investigated the effect of a single high-fat meal on WAT inflammatory responses (Table 3); this includes studies comparing the macronutrient content or fatty acid quality of a meal.

Table 3. Summary of acute human studies examining the effect of meal differing in fat quantity or quality on postprandial subcutaneous white adipose tissue (WAT) inflammatory responses

WAT, white adipose tissue; R, randomised; P, parallel; PC, placebo-controlled; NR, not reported; CHO, carbohydrate; MCP-1, monocyte chemoattractant protein-1; CD, cluster of differentiation; SA, single-arm; OW, overweight; OB, obese; IRS2, insulin receptor substrate 2; IL1RA, IL 1 receptor antagonist; IκBα, inhibitory factor κBα; IκBβ, inhibitory factor κBβ; CO, crossover; T2D, type-2 diabetes; TNFRSF1A, TNF receptor superfamily member 1A; CRP, C-reactive protein; y, years; %E, percentage total energy; ↓, significant decease; ↑, significant increase; ↔, no change.

* Diet composition data are presented as dietary intervention targets.

† Results are significant to P < 0⋅05.

‡ WAT outcomes for gene expression.

§ This study reported results on an acute response to a chronic (12-week) dietary intervention.

Travers et al.^{(Reference Travers, Motta and Betts115)} compared the WAT inflammatory response to a single mixed meal (54 % total fat) in lean, overweight and obese participants. The meal provided energy equivalent to about 65 % of each participant's RMR and consisted of brioche, strawberry jam, margarine, a milkshake and decaffeinated tea. Increased WAT gene expression of IL-6 and MCP-1 and a decrease in IRS-2 were reported 6 h post-meal consumption. These results were independent of adiposity. This may suggest that a postprandial inflammatory response is a normal response to feeding or an apparently normalised response. As suggested by the authors, normalisation of the response may be due to reduced responsiveness of WAT to the mixed meal components, insulin or similar net exposure per g WAT (as adjustments for adipose tissue mass were made in the analysis of this study). In addition, Dordevic et al.^{(Reference Dordevic, Pendergast and Morgan116)} compared WAT inflammatory responses to three different beverages: high-CHO, high-fat and placebo (water) beverage meal. WAT gene expression of MCP-1, IL-6, TNF-α and CD68 were increased at 2 and 4 h following all beverages. Dordevic and colleagues^{(Reference Dordevic, Pendergast and Morgan116)} collected three WAT samples from a single incision; they altered the needle inclination for the second and third biopsy sample. As an increased WAT inflammatory response was reported following all meals, it is likely that the sampling technique confounded the results.

Meneses et al.^{(Reference Meneses, Camargo and Perez-Martinez117)} compared postprandial responses to differing qualities of fatty acids in metabolic syndrome patients from the LIPGENE study. Firstly, participants completed a 12-week intervention (low-fat, high-complex CHO (high-CHO); low-fat, high-complex CHO + 1⋅24 g/d n-3 PUFA (high-CHO + PUFA); high-SFA; high-MUFA) before the postprandial response to a high-fat meal was investigated. The fatty acid composition of the meal was reflective of the prior dietary intervention although total fat intake remained equal for all meals (65 %E). These authors reported increased systemic IL-6 and WAT gene expression of p65 (part of the NF-κB complex) 4 h following the high-CHO and high-CHO + PUFA meal, but not following the high-MUFA or high-SFA meal. Gene expression of inhibitory factor κBα, MCP-1 and IL-1β was increased 4 h following all meals. However, no change in systemic MCP-1 was reported following all meals^{(Reference Meneses, Camargo and Perez-Martinez117)}. It is also important to note that this work may have been confounded by the fact that the test meal was administered following a 12-week dietary intervention. Pietraszek et al.^{(Reference Pietraszek, Gregersen and Hermansen118)} compared an SFA-rich meal (49 %E medium-chain SFA, primarily lauric acid; 30 %E long-chain SFA, primarily myristic acid) to a MUFA-rich meal (72 %E MUFA, primarily oleic and palmitoleic acid) in healthy first-degree relatives of patients with T2D (relatives) and healthy controls. The meals consisted of white bread and soup made with macadamia nut oil or coconut oil for the MUFA- and SFA-rich meals, respectively. Systemic CRP was unchanged and IL-6 was increased following the SFA- and MUFA-rich meal. For IL-6 there was no difference in response between relatives and healthy controls. In WAT, gene expression of IL-1β, IL-6 and TNF-α were upregulated at 3⋅5 h following the SFA-rich meal in controls but not relatives. In response to the MUFA-rich meal, increased WAT gene expression of MCP-1, IL-1β, IL-6 and TNF-α was observed in relatives at 3⋅5 h postprandially, while adiponectin and TNFRSF1A were upregulated in the WAT of the controls. The findings of Pietraszek et al.^{(Reference Pietraszek, Gregersen and Hermansen118)} suggest that healthy participants and relatives who are at increased risk of developing T2D and CVD, have differential WAT but not systemic responses.

Overall, research investigating the postprandial WAT inflammatory response is limited^{(Reference Travers, Motta and Betts115–Reference Pietraszek, Gregersen and Hermansen118)} and only two studies examined the effect of a high-fat meal varying in fatty acid quality^{(Reference Meneses, Camargo and Perez-Martinez117,Reference Pietraszek, Gregersen and Hermansen118 )}. Furthermore, one of these studies examined the postprandial response following a chronic dietary intervention varying in fat quantity and quality^{(Reference Meneses, Camargo and Perez-Martinez117)}. Therefore, it is not currently possible to draw firm conclusions regarding the impact of fatty acid quality on postprandial WAT inflammatory responses. Further randomised controlled trials are warranted to determine whether fatty acid quality (SFA v. unsaturated fatty acids) can differentially affect WAT inflammatory responses as this could have important implications for cardiometabolic disease risk reduction. Additionally, different participant cohorts could be examined since healthy controls and more ‘at risk’ populations (i.e. relatives of patients with T2D) may have differential WAT responses. In addition, sampling timepoints employed in previous postprandial studies have been inconsistent (ranging from 2–6 h) and limited to one biopsy postprandially^{(Reference Travers, Motta and Betts115,Reference Meneses, Camargo and Perez-Martinez117,Reference Pietraszek, Gregersen and Hermansen118 )}, except in the study conducted by Dordevic et al.^{(Reference Dordevic, Pendergast and Morgan116)}. However, the sampling technique employed in the latter study^{(Reference Dordevic, Pendergast and Morgan116)} likely confounded the results. The time-course of the WAT postprandial inflammatory response to fatty acid ingestion remains unknown. Future work is required to investigate postprandial WAT inflammatory responses (through repeated biopsy collection). However, it is imperative the sampling technique employed does not elicit a local inflammatory response^{(Reference Guerra, Gómez-Cabrera and Ponce-González119)}.