Modulation of Peroxisome Proliferator-Activated Receptor gamma

Review pubs.acs.org/JAFC

Modulation of Peroxisome Proliferator-Activated Receptor gamma (PPAR γ) by Conjugated Fatty Acid in Obesity and Inflammatory Bowel Disease Gaofeng Yuan,† Xiaoe Chen,† and Duo Li*,§,⊗,# †

Zhejiang Provincial Key Laboratory of Health Risk Factors for Seafood, Zhejiang Ocean University, Zhoushan 316022, China Department of Food Science and Nutrition, ⊗Zhejiang Key Laboratory for Agro-Food Processing, and #Zhejiang R&D Center for Food Technology and Equipment, Zhejiang University, Hangzhou 310058, China

§

ABSTRACT: Conjugated fatty acids including conjugated linoleic acid (CLA) and conjugated linolenic acid (CLNA) have drawn significant attention for their variety of biologically beneficial effects. Evidence suggested that CLA and CLNA could play physiological roles by regulating the expression and activity of PPAR γ. This review summarizes the current understanding of evidence of the role of CLA (cis-9,trans-11 CLA and trans-10,cis-12 CLA) and CLNA (punicic acid and α-eleostearic acid) in modulating the expression or activity of PPAR γ that could in turn be employed as complementary treatment for obesity and inflammatory bowel disease. KEYWORDS: conjugated linoleic acid, conjugated linolenic acid, obesity, inflammation, PPAR γ, adipogenesis, lipogenesis

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INTRODUCTION “Conjugated fatty acids” (CFAs) is the general term for positional and geometric isomers of polyunsaturated fatty acids with conjugated double bonds. The CFAs occur as diene, triene, and tetraene in which the most common conjugated polyenoic acids are octadecanoic and octatrienoic acids, termed conjugated linoleic acids (CLAs) and conjugated linolenic acids (CLNAs), respectively. CFAs have drawn significant attention for their variety of biologically beneficial effects. The health-promoting effects of CFAs were intensively investigated, among which CLA was best characterized and reported in detail.1 CLA is composed of a series of positional and geometric conjugated isomers of linoleic acid. Although a number of CLA isomers have been indentified in food, the primary research focus is on the two main isomers, cis-9,trans-11 CLA and trans-10,cis-12 CLA.2 CLA occurs naturally in many foods but mainly in dairy products and ruminant meats (Table 1). cis-9,trans-11 CLA is the principal dietary form of CLA, accounting for 90% of total CLA isomers found in natural sources.3 With the U.S. approval of CLA as generally recognized as safe (GRAS) for use in certain types of foods in 2008, the consumption of CLA, which may be associated with dietary supplements or foods, is expected to increase.4 It is reported that CLA has favorable physiological effects, such as antiatherosclerosis, antiobesity, antitumor, and antihypertension.4 CLNA occurs naturally in plant seeds, and considerable amounts of CLNA were found in several plant seeds (Table 1). Five CLNA isomers occur as major seed oils of several plants: αeleostearic acid (cis-9,trans-11,trans-13 18:3, α-ESA) from tung (Aleurites fordii), bitter ground (Momordica charantia), and snake gourd seed (Trichosanthes anguina); punicic acid (cis-9,trans11,cis-13 18:3, PUA) from pomegranate (Punica granatum) and trichosanthes (Trichosanthes kirilowii); α-calendic acid (trans8,trans-10,cis-12 18:3) from pot marigold (Calendula officinalis); jacaric acid (cis-8,trans-10,cis-12 18:3) from jacaranda (Jacaranda © XXXX American Chemical Society

minosifolia); and catalpic acid (trans-9,trans-11,cis-13 18:3) from catalpa (Catalpa ovata). It was reported recently that CLNAs exhibit several health benefits including anticarcinogenic activity, lipid metabolism regulation, and anti-inflammatory, antiobesity, and antioxidant activities, which led to increased interest in CLNAs.1 It has been reported that CFAs including CLA and CLNA could play their physiological role by regulating the expression and activity of peroxisome proliferator-activated receptor gamma (PPAR γ). Therefore, the aim of the present review was to systematically summarize and discuss the current evidence of the role of CLA (cis-9,trans-11 CLA and trans-10,cis-12 CLA) and CLNA (PUA and α-ESA) in modulating the PPAR γ expression or activity that could in turn be employed as a complementary treatment for obesity and inflammatory bowel disease (IBD).

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PPAR γ REGULATION AND THEIR MECHANISMS OF ACTION PPARs, with three existing isoforms (PPAR α, PPAR β/δ, and PPAR γ), belong to the nuclear receptors subfamily.20 PPARs consist of distinct functional domains including an N-terminal transactivation domain (AF1), a highly conserved DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) that contains a ligand-dependent transactivation function.21 By forming obligate heterodimers with retinoid X receptor (RXR), binding to PPAR-responsive regulatory elements (PPREs), and recruiting coactivator protein complexes to regulate expression of target genes positively, the PPARs control the expression of networks of genes involved in adipogenesis, lipid metabolism, inflammation, and maintenance of metabolic homeostasis.22,23 Received: October 19, 2014 Revised: December 29, 2014 Accepted: January 29, 2015

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DOI: 10.1021/jf505050c J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry Table 1. Content of Conjugated Fatty Acid in Food Sources isomer CLA (mainly cis-9,trans-11)

food source ruminant meats dairy products

plant oils seafood fish punicic acid

pomegranate seed

trichosanthes seed α-eleostearic acid

tung seed bitter gourd seed

snake gourd seed

concentration

comments

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0.27−0.56% 0.11−1.20% 0.17−0.7% 0.34−0.80% 0.4−1.7% 0.53−2.59% 0.4−0.84% 0.19−0.73% 0.09−0.37% 0.29−0.60% 0.516−0.986% 0.128−0.976% approx 0.5−7 mg/g cheese 0.432−1.021% nondetected to 0.933% 0.01−0.70% nondetected 0.03−0.06% 0.01−0.09%

U.S. foods German foods U.S. foods U.S. foods German foods Italian dairy products Brazilian dairy products U.K. cheese U.K. non-cheese dairy products U.K. meat products Italian and French commercial cheeses cow’s, sheep’s, and goat’s milk yogurts from Greece Canadian cheeses cheeses from Italian Spanish plain fermented milks U.S. foods German foods U.S. foods German foods

3 5 3 6 5 7 8 9 9 9 10 11 12 13 14 3 5 3 5

5.277−73.55% 76.1% 82.99% 32.27%

Israel China Japan China

15 16 17 18

67.69% 56.24% 54.1% 50.1−60.0% 48.48% 47.7%

Japan Japan China India Japan India

17 17 16 19 17 19

also exerts nongenomic actions, which are too rapid to involve gene expression modulation.34 The transcriptional activity of PPAR γ could be mediated by agonist and antagonist. Fatty acids and prostanoids, as the endogenous ligands for PPAR γ, can bind and activate PPAR γ.35,36 However, they are weak agonists compared to the strong synthetic thiazolidinedione agonists with robust insulin-sensitizing activities.37 The transcriptional activity of PPAR γ is also regulated by post-translational modifications including phosphorylation, sumoylation, and ubiquitination, providing additional possibilities for fine-tuning.34

Alternative splicing and differential promoter usage results in two isoforms of PPAR γ, PPAR γ1 and PPAR γ2, differing for the additional 28 amino acids in the N terminus present in PPAR γ2 and not in PPAR γ1.24,25 PPAR γ1 is expressed generally in multiple tissues, including the lower intestine, macrophages, and white adipose tissue (WAT), whereas PPAR γ2 expression is almost exclusively restricted to WAT.21 PPAR γ is a master regulator of adipogenesis as well as a potent modulator of insulin sensitivity, lipogenesis, and adipocyte survival and function.26−28 Moreover, PPAR γ has been considered as a molecular target for cancer chemoprevention29−31 and has been shown to be involved also in the regulation of genes contributing to hypertension and atherosclerosis.32 PPAR γ could exert pleiotropic effects by ligand-dependent transactivation of specific genes. Following ligand binding, the conformation of PPAR γ is changed and then causes the release of histone deacetylase corepressors, thus enabling PPAR γ to heterodimerize with RXR. RNA polymerase II and coactivators with histone acetyl transferase activity are then recruited to this complex, which binds to PPREs in the promoter region of the respective target genes, leading to chromatin remodeling and ultimately to increased transcription. On the other hand, PPAR γ can also down-regulate the expression of its target genes by interfering with other proteins and transcription factors such as nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) through a transrepression mechanism.31,33 In addition to their transactivating and transrepressional activity, the PPAR family

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MODULATION OF PPAR γ BY CLA IN OBESITY The prevalence of obesity and its associated comorbidities has grown to epidemic proportions worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely.38 Since Park et al. (1997) demonstrated that CLA modulated body fat in mice, interest in CLA as a weight loss treatment has increased.39 The antiobesity activity of CLA has been extensively studied, and multiple animal studies and some human studies have confirmed that supplementation with a CLA mixture (i.e., equal concentrations of the trans-10,cis-12 CLA and cis-9,trans-11 CLA isomers) or the trans-10,cis-12 CLA isomer alone decreases body fat mass.4,40 Of the two major isomers of CLA, the trans10,cis-12 CLA isomer is specifically responsible for the antiobesity effects41−44 and mechanisms involved in its impact on energy metabolism, adipogenesis, inflammation, lipid B


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Journal of Agricultural and Food Chemistry metabolism, and apoptosis.43 In the present review, the regulation of adipogenesis, lipogenesis, and inflammation through modulation of PPAR γ by trans-10,cis-12 CLA (Figures 1 and 2) is discussed.

Figure 2. Proposed mechanism of action of CLA-mediated inflammation by modulation of PPAR γ. The trans-10,cis-12 CLA activates the specific cell surface receptors, including G protein coupled receptor, G protein receptor, or protein tyrosine kinases, and consequently stimulates the translocation of PLC to the plasma membrane, thereby generating DAG and IP3 from PIP2. DGKs convert DAG into PA and, together with IP3, stimulate calcium release from ER. Increased intracellular calcium accumulation activates calcium-sensitive kinases, such as CaMKII, which promotes ROS production and MAPK activation. MAPK subsequently activates inflammatory signaling, NFκB, and AP-1. These inflammatory signals lead to a rise of secretion of inflammatory proteins, such as IL-6, IL-8, and MCP-1 and antagonize PPAR γ abundance and activity, thereby suppressing the expression of PPAR γ target genes and lipogenesis.

Figure 1. Proposed mechanism of action of CLA in adipogenesis and lipogenesis by modulation of PPAR γ. trans-10,cis-12 CLA reduced adipogenesis and lipogenesis by (1) regulating the expression PPAR γ and its target genes and (2) modulating the transactivating activity of PPAR γ, thereby reducing the expression of PPAR γ target genes. Ligand-dependent PPAR γ transactivating activity is antagonized by trans-10,cis-12 CLA, possibly via PPAR γ phosphorylation by ERK and AMPK. There is cross-regulation between SIRT1, AMPK, and PPAR γ. The transactivating activity of PPAR γ is attenuated by SIRT1 via binding directly or indirectly to PPAR γ. SIRT1 and AMPK activity are stimulated by one another and repressed by PPAR γ via a nontranscriptional mechanism.

decreased substantially after trans-10,cis-12 CLA treatment in mature in vitro differentiated primary human adipocytes51,70 or in mature 3T3-L1 adipocytes.57 On the other hand, direct effects of CLA isomers on the PPAR γ expression were investigated by using a luciferase reporter assay system in a number of studies. These studies found that the cis-9,trans-11 CLA isomer was a PPAR γ agonist, whereas the trans-10,cis-12 CLA isomer appeared to be a partial antagonist or weak agonist.58,64,71,72 However, Brown et al. showed that treatment with either cis9,trans-11 CLA or trans-10,cis-12 CLA led to a slight decrease in luciferase activity by using 3T3-L1 cells transiently transfected with a luciferase reporter construct containing a PPRE, suggesting that these two isomers may antagonize PPAR γ activity in adipocytes.58 There is no clear consensus regarding the activation or antagonism of PPAR γ by trans-10,cis-12 CLA, indicating that the way in which trans-10,cis-12 CLA affects PPAR γ expression is still unclear. The inhibitory effect in PPAR γ-induced gene expression could be due to reduced PPAR γ expression or post-translational inhibition of PPAR γ activity per se.43 Reduced PPAR γ activity could inhibit the expression of PPAR γ because PPAR γ directly or indirectly induces its own expression. Therefore, it is difficult to determine the levels at which inhibition occurs.43 CLA and the Activity of PPAR γ. PPAR γ activity can be modulated directly and indirectly at different levels (Figure 1). Several mechanisms are involved in the regulation of PPAR γ activity by supplementation with trans-10,cis-12 CLA. Phosphorylation, which can be mediated by the mitogen-activated protein

Regulation of Adipogenesis and Lipogenesis through PPAR γ by CLA. PPAR γ was originally described as a factor induced during adipocyte differentiation and function as a master regulator of adipocyte differentiation and metabolism.26,45−47 Adipogenesis has been studied extensively in vitro, in particular using the murine 3T3-L1 preadipocyte cell line.28,48−50 The regulation of adipogenesis through PPAR γ by CLA also has been investigated by using the 3T3-L1 preadipocyte cell line. CLA suppresses preadipocyte differentiation in animal51−56 and human preadipocytes57,58 by attenuating the expression and activity of adipogenic transcription factors such as PPAR γ and CAAT/enhancer binding protein α (C/EBP α). PPAR γ is best known for its role in regulating adipogenic and lipogenic pathways59 and is also crucial for controlling gene networks involved in lipid metabolism and glucose homeostasis, including adipocyte fatty acid binding protein (aP2),60 insulindependent glucose transporter 4 (GLUT4),61 lipoprotein lipase (LPL),62 and the fatty acid translocase (CD-36/FAT).63 trans10,cis-12 CLA has been shown to reduce triglyceride (TG) accumulation in adipocyte cell culture models42,52,53,64 and in the mouse65 by attenuating the expression and activity of PPAR γ and its target genes such as LPL, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD). CLA and the Expression of PPAR γ and Its Target Genes. The expression of PPAR γ was decreased after trans-10,cis-12 CLA supplementation in rodents.66−69 The expression and activity of PPAR γ and PPAR γ target genes and lipid content were also C


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Journal of Agricultural and Food Chemistry kinase (MAPK) pathway,73,74 is the most investigated posttranslational regulatory mechanism of PPAR γ.21 The Ser82 in PPAR γ1 and Ser112 in PPAR γ2 in the mouse and the corresponding serines 84 and 114 in the human PPAR γ isoforms have been described to be phosphorylated by all MAPKs (extracellular signal-related kinase, ERK; cJun-NH2-terminal kinase, JNK, and p38), resulting in the inhibition of both liganddependent and -independent transactivation activity of the receptor.21,34 Phosphorylation of PPAR γ may decrease its activity via ubiquitination and proteasome degradation.75 Kennedy et al. demonstrated that 24 h of treatment with trans10,cis-12 CLA increased PPAR γ phosphorylation and ERK 1/2 phosphorylation without significantly decreasing its protein levels, suggesting that the down-regulation of PPAR γ target genes is due to decreased transactivating activity in primary cultures of human adipocytes.70 These suggested that trans10,cis-12 CLA antagonizes ligand-dependent PPAR γ transactivating activity, possibly via PPAR γ phosphorylation by ERK.70 A similar inhibitory effect on PPAR γ transactivating activity has been found for AMP-activated protein kinase (AMPK) via the phosphorylation of specific sites of PPAR γ.76 AMPK was directly or indirectly responsible for the increased phosphorylation at Ser112 of PPAR γ in trans-10,cis-12 CLA treated adipocytes.77 The activity of PPAR γ could also be modulated by sirtuin 1 (SIRT1). SIRT1, a histone/protein deacetylase, is particularly involved in regulating cell energy metabolism, cell stress, and cell fate.78 SIRT1 could directly bind directly or indirectly to PPAR γ to repress PPAR γ transactivating activity, inhibit adipogenesis, and promote fat loss in adipocytes.79 After treatment with trans10,cis-12 CLA, cross-regulation between SIRT1, AMPK, and PPAR γ occurred in 3T3-L1 adipocytes.77 SIRT1 stimulated AMPK activity and attenuated PPAR γ activity, whereas AMPK stimulated SIRT1 activity and attenuated PPAR γ activity in trans-10,cis-12 CLA treated 3T3-L1 adipocytes. That PPAR γ has a repressive effect on the activities of AMPK and SIRT1, which is consistent with the opposing roles of PPAR γ in stimulating lipid biosynthesis and the catabolic energy-generating roles of AMPK and SIRT1.51,80 PPAR γ achieved these inhibitory effects via a nontranscriptional mechanism because PPAR γ affected the activity levels of SIRT1 and AMPK without changing the total amounts of these proteins in the response to trans-10,cis-12 CLA. Besides the well-known transactivating and transrepressional activity of PPAR γ, these results suggested an emerging role for PPAR γ in regulating nongenomic processes.34,81 Regulation of Obesity-Related Inflammation through PPAR γ by CLA. CLA and Obesity-Related Inflammation. To date there is no clear consensus regarding anti-inflammatory effects of CLA. It is likely that the effects of CLA on inflammation of adipose tissue are isomer-dependent. cis-9,trans-11 CLA reduces adipose tissue inflammation in ob/ob mice,82 whereas trans-10,cis-12 CLA reduces adiposity without improving or worsening insulin resistance and adipose tissue inflammation in hamsters and mice.67,83 Obesity is characterized by a chronic low-grade inflammation, primarily due to an imbalance between production/secretion of pro-inflammatory cytokines versus anti-inflammatory cytokines.84 Adipose tissue is not simply an energy reservoir, thermal regulator, or protective padding for important organs but also a metabolically active endocrine organ.85 Adipose tissue has the ability to produce a number of pro-inflammatory adipokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), inter-

leukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and resistin.86,87 Adipose tissue can also produce anti-inflammatory cytokines such as adiponectin and interleukin-10 (IL-10).87 These proinflammatory adipokines produced by adipose tissue can cause insulin resistance, thereby suppressing lipid synthesis and increasing lipolysis in adipocytes.43 The expression of PPAR γ and its target genes could be directly down-regulated by trans-10,cis-12 CLA supplementation. In contrast, PPAR γ and its target genes also could be indirectly inhibited by cytokines induced by trans-10,cis-12 CLA.62,84−86 ERK57 and NF-κB67,88 in adipocytes could be activated by trans10,cis-12 CLA supplementation and, consequently, these signaling pathways increased the expression or secretion of cytokines, for example, IL-6 and IL-857,67,68,70,88 and TNF-α and IL-1β,89 which are known to antagonize PPAR γ target gene expression and insulin sensitivity.69,90−92 trans-10,cis-12 CLA supplementation increased PGF 2α secretion in human adipocytes in vitro.93 trans-10,cis-12 CLA treatment also increased the levels of inflammatory prostaglandins (PGs) and C-reactive protein in humans in vivo.94 Supplementation with an oil mixture with trans-10,cis-12 CLA (5.5 g/day for 16 weeks) exhibited higher levels of C-reactive protein in serum and 8-iso-PGF 2α in urine of healthy postmenopausal women, compared with cis-9,trans-11 CLA.94 Inflammatory PGs such as PGF 2α have been reported to block adipogenesis through activation of MAPK, resulting in inhibitory phosphorylation of PPAR γ in 3T3-L1 preadipocytes.95 PGF 2α has also been demonstrated to inhibit adipogenesis through normoxic activation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway during 3T3-L1 preadipocyte differentiation under normal oxygen conditions.96 HIF-1 decreases the expression of PPAR γ and C/EBP α via the increased expression of the DEC1 transcriptional repressor.97 In addition, PGF 2α could inhibit adipogenesis by activating pro-inflammatory transcription factors that can antagonize PPAR γ.43 CLA and Inflammatory Signaling Cascade. The inflammatory signaling cascade is also involved in CLA-reduced adiposity (Figure 2). trans-10,cis-12 CLA mediated suppression of adipogenesis and lipogenesis and adipocyte delipidation were dependent on inflammatory signaling57,88,98 and linked to endoplasmic reticulum (ER) release of calcium and increased intracellular calcium ([Ca2+] i) accumulation.99 Up-regulation of inflammatory pathways by trans-10,cis-12 CLA increased the activities of NF-κB, AP-1, and MAPK,57,88,98 which led to inhibition of PPAR γ abundance and activity,58,70,100 reduction of glucose and fatty acid uptake, and de novo lipogenesis.42,57,58 The molecular mechanisms by which NF-κB inhibits PPAR γ activity are not completely understood. However, unlike suppression of the PPAR γ transactivating activity by MAPKinduced growth factor signaling through phosphorylation of PPAR γ, NF-κB blocked PPAR γ binding to DNA by forming a complex with PPAR γ and its AF-1-specific coactivator PGC-2 in the bone marrow stromal cell line ST2.90 Up to now, the upstream signals activated by trans-10,cis-12 CLA that initiate this inflammatory signaling cascade were investigated by a number of studies.99,101−103 One possible upstream mediator of trans-10,cis-12 CLA induced inflammation is [Ca2+] i, which is a vital second messenger for the activation of proteins involved in adipocyte proliferation, differentiation, and metabolism.101 trans-10,cis-12 CLA increased [Ca2+] i levels, leading to the production of reactive oxygen species (ROS), NFκB, JNK, ERK1/2, and, ultimately, the induction of inflammatory D


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Journal of Agricultural and Food Chemistry Table 2. Effect of Conjugated Fatty Acids on Inflammatory Bowel Diseasea isomer (purity) CLA CLA mixture (cis-9,trans-11/trans-9,cis-11, 12.36%; trans-11,trans-10,cis-12/cis-10,trans-12, 13.30%; trans-9,trans-11, 13.32%; other CLA isomers, 12.99%)

50:50 mixture of cis-9,trans-11 and trans-10,cis-12 CLA isomers


model (1) pigs challenged with Brachyspira hyodysenteria (2) pigs immunized with proteinasedigested Brachyspira hyodysenteria bacteria early weaned pigs with DSS-induced colitis

dose and duration

↓ enlargement of the colonic mucosa ↓ mucosal damage

124

2.21 wt % diet, 42 days

↓ onset of IBD ↓ colitis severe ↓ growth suppression ↓ disease activity

117

1 wt % diet, 42 days


female BALB/c mice with DSSinduced colitis

100 mg/kg/day, 7 days

50:50 mixture of cis-9,trans-11, and trans-10,cis-12 CLA isomers

C57BL/6 mice treated with azoxymethane and then challenged with 2% DSS


(1) 50:50 mixture of cis-9,trans-11, trans-10,cis-12 CLA isomers

C57BL6 mice with DSS inducedcolitis


50:50 mixture of cis-9,trans-11, and trans-10,cis-12 CLA isomers (capsules, 77.7%) CLNA PUA-enriched PSO (ND) pure PUA PUA-enriched PSO (71%)

PUA-enriched PSO (71%) PUA-enriched PSO (ND)

α-ESA-enriched BGO (ND)

0.0072 g VSL#3, 24 days

↓ tissue damage ↓ colitis ↓ colon shortening ↓ disease activity index ↓ disease activity ↓ colitis ↓ adenocarcinoma formation ↓ disease activity ↓ colitis ↓ colonic bacterial diversity ↓ macrophage accumulation ↓ disease activity ↑ quality of life of patients

patients with mild to moderate Crohn’s disease

6 g/day CLA, 12 weeks

male Wistar rats with TNBS-induced colitis male Wistar rats with TNBS-induced colitis IL-10−/− model mice with spontaneous pan-enteritis

2 wt % diet, 10 days 400 μg/day, 10 days 1 wt % diet, 42 days

C57BL/6J mice with DSS-induced colitis neonatal Sprague−Dawley rats with induced NEC

1 wt % diet, 42 days 1.5 wt % diet, 96 h ↓ incidence of NEC from 61 to 26% ↓ necrotizing colitis severity not mentioned, ↓ disease activity 42 days ↓ IBD-related disease phenotypes

C57BL/6J mice with DSS-induced colitis

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1.33 wt % diet, 72 days

(1) C57BL/6J mice with DSSinduced colitis (2) C57BL/6J mice with CD4+CD45RBhi transfer colitis

(2) VSL#3

effects

↓ ulceration status and tissue damage ↓ ulceration status and tissue damage ↓ lymphoplasmacytic infiltration ↓ enlargement of the colonic mucosa ↓ experimental IBD

116

127 125

126

128

106 106 155

155 156

160

PSO, pomegranate seed oil; BGO, bitter melon seed oil; PUA, punicic acid; α-ESA, α-eleostearic acid; IBD, inflammatory bowel disease; NEC, necrotizing enterocolitis; ND, not determined. Δ change; ↓ decrease. a

genes and PGs and insulin resistance in human adipocytes.99 Possible upstream signals of trans-10,cis-12 CLA mediated increased [Ca2+] i and inflammation included phospholipase C (PLC)102 and diacylglycerol kinases (DGKs).103 PLC, as an upstream enzyme that produces diacylglycerol (DAG), a substrate for DGK, and inositol-3-phosphate (IP3), an inducer of calcium release from the ER, was found to play an important role in trans-10,cis-12 CLA mediated activation of [Ca2+] i accumulation, inflammatory signaling, delipidation, and insulin resistance in human primary adipocytes.102 DGKs are a family of kinases that phosphorylate DAG, resulting in the conversion of DAG into phosphatidic acid (PA). DAG and PA acted as second messengers that activated an array of target proteins, resulting in significant changes in cellular signaling.104 DGKs, particularly DGK η, may also be involved in the regulation of trans-10,cis-12

CLA mediated inflammatory signaling, insulin resistance, and delipidation in primary human adipocytes.103 On the basis of the studies by Shen et al. and Martinez et al., the mechanism of CLAmediated inflammation and PPAR γ activity could be proposed (Figure 2).102,103 trans-10,cis-12 CLA may activate the specific cell surface receptors, including G protein coupled receptor, G protein receptor, or protein tyrosine kinases, and consequently stimulate the translocation of PLC to the plasma membrane, thereby generating DAG and IP3 from PIP2. DGKs convert DAG into PA and, together with IP3, stimulate calcium release from ER. Increased intracellular calcium accumulation activates calcium-sensitive kinases, such as CaMKII, which promotes ROS production and MAPK activation. MAPK subsequently activates inflammatory signaling, NF-κB and AP-1. These inflammatory signals lead to a rise of secretion of inflammatory proteins, such as E


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Journal of Agricultural and Food Chemistry IL-6, IL-8, and MCP-1, and antagonizes PPAR γ abundance and activity, thereby suppressing insulin-stimulated glucose uptake and lipogenesis.102,103

peripheral blood T cells to produce pro-inflammatory cytokines, decreased disease onset, and increased the quality of life of patients with mild to moderate Crohn’s disease.128 The protective effect of CLA against IBD could be mediated though PPAR γ activation.116,124 Dietary CLA supplementation suppressed colonic inflammation and up-regulated colonic PPAR γ expression in pigs with bacterial-induced colitis.124 Activation of colonic PPAR γ by CLA mediated protection from experimental IBD in mice with a targeted deletion of PPAR γ in immune and epithelial cells.116 Furthermore, dietary CLA ameliorated disease activity, decreased colitis, and prevented adenocarcinoma formation in the PPAR γ-expressing floxed mice but not in the tissue-specific PPAR γ-null mice, suggesting that CLA ameliorates colitis and prevents tumor formation in part through a PPAR γ-dependent mechanism.125 Indeed, besides induction of PPAR γ in vivo, other studies confirmed the increase of PPAR γ expression and activity in adipocytes,129 skeletal muscle,130 and macrophages131,132 with CLA or CLA-rich diets. In contrast to the reduction in PPAR γ expression by trans-10,cis12 CLA, treatment with cis-9,trans-11 CLA or mixtures of cis9,trans-11 CLA and trans10,cis-12 CLA activated the expression of PPAR γ. This may be due to cell-type specificity of the response to CLA or isomer specificity because the trans-10,cis-12 CLA was able to reduce PPAR γ expression in adipocytes, but the cis-9,trans-11 CLA failed to show the same suppressive effect on PPAR γ activity.133 Trefoil peptides (TFF) were found to be involved into CLAmediated DSS-induced colitis.127 TFFs are small proteaseresistant proteins characterized by a conserved cysteine-rich domain and comprise the gastric peptide (TFF1), the spasmolytic peptide (TFF2), and the intestinal trefoil factor (TFF3).134 TFFs could be involved in IBD pathogenesis, and they could be a potential treatment option.135 The colonic levels of TFF3 was increased after dietary supplementation of CLAenriched diet, and the activation of TFF3 by CLA is mediated by PPAR γ, suggesting that the DSS-induced injury in mice is ameliorated by CLA through the colonic activation of PPAR γ, which in turn will increase the levels of TFF3.127 Interestingly, VSL#3 probiotic bacteria produce CLA locally in the gut and were shown to suppress colitis by targeting macrophage PPAR γ.126 VSL#3 is a multistrain, high-potency probiotic preparation composed of four strains of lactobacilli (Lactobacillus casei, Lactobacillus plantarum, Lactobacillus bulgaricus, and Lactobacillus acidophilus), three strains of bifidobacteria (Bifidobacterium longum, Bifidobacterium breve, and Bifidobacterium infantis), and Streptococcus thermophilus. VSL#3 has been demonstrated to ameliorate colitis,126 prevent colitis-associated colorectal cancer in animal models of colitis,136,137 and induce remission in patients with ulcerative colitis.138,139 VSL#3 treatment could produce cis-9,trans-11 CLA in vivo,126,140 and a high concentration of cis-9,trans-11 CLA was found only in the mouse colon, but without systemic distribution in blood.126 The loss of PPAR γ in myeloid cells abrogated the protective effect of VSL#3 and CLA in mice with DSS colitis, suggesting that PPAR γ possibly plays a vital role in VSL#3 and CLA amelioration of the colitis in mice. VSL#3 could suppress intestinal inflammation by altering colonic microbial diversity and enhancing microbial CLA production locally that in turn activates PPAR γ.126 The CLAproducing probiotics may offer an alternative approach to conventional therapy in IBD by altering the intestinal microflora and enhancing CLA concentration; further exploration of the role of these bacteria in preventing human IBD is encouraged.

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MODULATION OF PPAR γ BY CLA IN IBD Inflammatory disorders including IBD, rheumatoid arthritis, atherosclerosis, metabolic syndrome, and ischemia/reperfusion injury are recognized as a major health problemd worldwide.105 One common characteristic of these diseases is excessive production of pro-inflammatory mediators such as TNF-α, GM-CSF, IL-1, IL-6, IL-8, leukotriene B4, and PAF; the presence of highly activated inflammatory cells such as neutrophils, monocytes, and macrophages; and excessive production of ROS.106 IBD is characterized by inflammation of the gastrointestinal tract and the most common IBD including ulcerative colitis and Crohn’s disease and some atypical forms such as collagenous colitis and intractable colitis. Conventional therapies for IBD patients are represented by salicylates, steroids, immunosuppressants, and anti-TNF-α drugs. However, conventional therapies showed variable response rates and potential side effects. IBD patients tend not to adhere to conventional pharmacological therapy, mainly due to the fear of long-term side effects.107 Thus, exploring novel therapeutic and preventive approaches for IBD is important and increasingly interesting.108,109 PPARs are the receptors for endogenous lipid molecules representing promising new targets for the treatment and prevention of inflammatory disorders such as IBD. The colon is a major tissue that expresses PPAR γ in epithelial cells and, to a lesser degree, in macrophages and lymphocytes. PPAR γ plays a role in the regulation of intestinal inflammation. Animal studies suggested that PPAR γ ligands have beneficial effects in different models of experimental colitis, with possible implications in the therapy of IBD.109 Synthetic PPAR γ ligands such as troglitazone and rosiglitazone, have been proven effective in rodent models of IBD,110,111 and their therapeutic efficacy is being tested in IBD clinical trials.112,113 However, the universal application of rosiglitazone or rosiglitazone for the management and treatment of IBD is unlikely due to the reported serious side effects such as weight gain, increased bone fracture, fluid retention, and heart failure.114 Interestingly, the use of dietary supplements such as CLA, CLNA, and probiotics (VSL#3) has proved beneficial on animal models of intestinal inflammation through the activation of PPAR γ.115 CLA has potent immunomodulatory effects in a wide range of inflammatory-based disorders including IBD,116,117 atherosclerosis,118,119 and diabetes.120,121 The potent immunomodulatory effect of CLA is exhibited in an isomer-specific manner. Evidence suggested that cis-9,trans-11 CLA is responsible for the antiinflammatory effect attributed to CLA, whereas trans-10,cis-12 CLA appears to be responsible for antiadipogenic effects.122 The anti-inflammatory potential of cis-9,trans-11 CLA has been demonstrated in animal models of IBD and human study. For animal studies of IBD, two main standardized methods are used to produce an experimental animal model of IBD: (1) oral administration of dextran sulfate sodium (DSS) in drinking water; (2) intracolonic administration of trinitrobenzenesulfonic acid (TNBS).123 A number of studies showed that CLA ameliorates experimental IBD in mice and pigs (Table 2).116,117,124−127 CLA also was shown to ameliorate the IBD in humans. In this open-label study, oral CLA administration (6 g/ day, 50:50 mixture of the cis-9,trans-11,trans-10,cis-12 CLA isomers) was well tolerated and suppressed the ability of F


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Journal of Agricultural and Food Chemistry Table 3. Effect of the Conjugated Linolenic Acid on Obesitya isomer (purity)

model

dose and duration

conjugated linolenic acid mixtures (49.1%) PUA-enriched PSO (ND)

male Sprague−Dawley rats male OLETF obese rats

1.0 wt % diet, 4 weeks 1.0 wt % diet, 2 weeks

PUA-enriched PSO (approximately 80%) genetically modified rapeseed oil containing PUA (2.5%) PUA-enriched PSO (64.79%)

male ICR CD-1 mice male ICR CD-1 mice

0.5 wt % diet, 4 weeks 0.25 wt % diet, 4 weeks

male CD-1 mice with high-fat feeding

61.79 mg/day PSO, 14 weeks

PUA-enriched PSO (ND)

male C57BL/6J mice with dietinduced obesity

1% PSO wt diet, 12 weeks

α-ESA-enriched BGO (50%)

male C57BL/6J mice with dietinduced obesity male C57BL/6J mice with dietinduced obesity male Golden Syrian hamsters

7.5 wt % diet, 5 weeks

α-ESA-enriched BGO (50%) PUA-enriched PSO (70%) or α-ESAenriched tung seed oil (70%) α-ESA-enriched BGO (54.1%) or PUAenriched PSO (76.1%) PUA-enriched PSO (ND)

a

male ICR mice male Wistar rats fed an obesogenic diet

2.5, 5, and 7.5 wt % diet, 11 weeks 1.22−1.27 wt % diet, 6 weeks 1 wt % diet, 6 weeks 0.5 wt % diet, 6 weeks

effects

ref

↓ perirenal and epididymal adipose tissue weight ↓ omental white adipose tissue weight (27%) no Δ abdominal white adipose tissue ↓ perirenal and epididymal adipose tissue weight ↓ perirenal and epididymal adipose tissue weight

141 142

↓ body weight ↓ weight gain ↓ body weight ↓ body fat mass ↓ 21% body fat

144

↓ 32, 35, and 65% of body fat

147

no Δ body weight

148

no Δ body weight no Δ perirenal or epididymal adipose tissues no Δ body weight no Δ white adipose tissue or interscapular brown adipose tissue weights

149

143 143

145 146

150

PSO, pomegranate seed oil; BGO, bitter melon seed oil; PUA, punicic acid; α-ESA, α-eleostearic acid; ND, not determined; change; ↓ decrease.

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MODULATION OF PPAR γ BY CLNA IN OBESITY The effect of CLNA isomers on body weight showed inconsistent outcomes in animal obesity models (Table 3). CLNA mixtures prepared by alkaline isomerization reduced perirenal adipose tissue weight to a larger extent when compared with linoleic acid, CLA, and α-linolenic acid in Sprague−Dawley rats.141 A PUA-enriched pomegranate seed oil (PSO) dietary supplement also reduced omental WAT weights, but not abdominal WAT weights in obese and hyperlipidemic OLETF rats.142 Supplementation with PSO or genetically modified rapeseed oil containing PUA decreased the weight of perirenal adipose tissue in ICR CD1 mice in a dose-dependent manner.143 Dietary supplementation with 61.79 mg/day of PSO significantly lowered the body weight and weight gain in mice with high-fat feeding, compared with the control.144 In another study, dietary supplementation with 1% of PSO ameliorated high-fat diet induced obesity and insulin resistance in mice, independent of changes in food intake or energy expenditure.145 Supplementation with α-ESA enriched bitter gourd seed oil (BGO) was shown to be more potent than soybean oil in attenuating high-fat diet induced body fat deposition in mice.146,147 In contrast, dietary supplementation with 1.22−1.27 or 1% of CLNA (α-ESA or PUA) for 6 weeks did not significantly change the body weight of hamsters or mice, respectively.148,149 A recent paper also showed that dietary supplementation of 0.5% of PUA did not lead to decreased fat accumulation in adipose tissue, liver, or skeletal muscle when rats were fed an obesogenic diet.150 The potential mechanism by which CLNA isomers exert the antiobesity effect is not clear. Because cis-9,trans-11 CLA has no antiadiposity activity,2,43 the antiadiposity potential of PUA and α-ESA cannot be attributed to CLA derived from α-ESA in vivo, because PUA and α-ESA are proved to be metabolized into cis9,trans-11 CLA, rather than trans-10,cis-12 CLA.151,152 PUA, αESA, and trans-10,cis-12 CLA might share a common metabolic or signaling pathway, leading to a qualitatively similar outcome in the WAT.147 Similarly to trans-10,cis-12 CLA, CLNAs might exert their antiadiposity effect by induction of the expression or secretion of cytokines and inhibition of adipogenesis and

preadipocyte differentiation through the regulation of PPAR γ.141,146,153,154 BGO and CLNA mixtures were shown to elevate the TNF-α level in C57BL/6J mice with diet-induced obesity and Sprague−Dawley rats,141,146 respectively, which are known to antagonize PPAR γ target gene expression.90 PSO was also shown to inhibit the adipogenesis and differentiation and decrease the protein level of PPAR γ in 3T3-L1 preadipocytes.153 Moreover, sustained activation of the ERK/MAPK signaling pathway, accompanied by PPAR γ phosphorylation, caused by αESA in the 3T3-L1 cell differentiation model might not only contribute to apoptosis but also have an inhibitory effect on adipogenesis.154

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MODULATION OF PPAR γ BY CLNA IN IBD PUA and IBD. Several in vivo studies assessed the antiinflammatory effects of PSO and PUA on IBD intestinal inflammation and the model of necrotizing enterocolitis (NEC) (Table 2). Oral administration of pure PUA (400 μg/ day) or 0.5 mL/day of PUA-enriched PSO for 10 days before TNBS injection in a colitis rat model ameliorated ulceration status and tissue damage, limiting neutrophil activation and lipid peroxidation.106 Supplementation with 1% of dietary PUA ameliorated spontaneous pan-enteritis in an IL-10−/− mouse model of IBD for 42 days and in mice with experimental IBD during a 7 day challenge with DSS.155 PSO has also been shown to be effective in a model of NEC. Oral administration with 1.5% of PSO decreased the incidence of NEC from 61 to 26% and the severity of necrotizing colitis, protecting the epithelial barrier and preserving the intestinal integrity in a neonatal model of NEC rats.156 These results suggested that PUA- or PUA-enriched PSO could ameliorate intestinal inflammation and damage. The underlying mechanisms by which PUA ameliorates experimental IBD are incompletely understood. Similarly to cis-9,trans-11 CLA, PUA was suggested as a potential PPAR γ agonist.155,157,158 PUA was shown to robustly bind and activate PPAR γ, therefore increasing PPAR γ-responsive gene expression and ameliorating diabetes and gut inflammation.159 PUA ameliorated spontaneous pan-enteritis in IL-10−/− mice and G


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Journal of Agricultural and Food Chemistry

reduces adipogenesis and lipogenesis in adipocytes and rodents by (1) regulating the expression PPAR and PPAR γ target genes and (2) modulating the transactivating activity of PPAR γ. Ligand-dependent PPAR γ transactivating activity is antagonized by trans-10,cis-12 CLA, possibly via PPAR γ phosphorylation by ERK and AMPK. The transactivating activity of PPAR γ could also be modulated by SIRT1 via binding directly or indirectly to PPAR γ in adipocyte. In addition, up-regulation of inflammatory signaling pathways by trans-10,cis-12 CLA increases the expression or secretion of cytokines and the activity of NF-κB, AP-1, and MAPK, which lead to inhibition of PPAR γ abundance and activity. Besides their antiobesity effect, CLAs also ameliorate experimental IBD through activation of PPAR γ. PUA and α-ESA are identified as natural agonists of PPAR γ and exert beneficial effects on animal models of intestinal inflammation through the activation of PPAR γ. In addition, PUA and α-ESA might exert their antiadiposity effect by induction of cytokine and inhibition of adipogenesis and preadipocyte differentiation through regulation of PPAR γ. Some issues remain to be resolved before CLAs and CLNAs can be recommended to humans with confidence to improve health and quality of life, particularly regarding mechanisms and safety concerns. More well-controlled clinical trials with defined subject characteristics, study duration, and doses and preparations on the safety and physiological effects are urgently needed. Moreover, further studies are necessary to identify the diversified molecular signaling pathways and the crosstalk among these signaling pathways mediated by CLAs and CLNAs to provide valuable information on the efficacy, specificity, and potential side effects of CLAs and CLNAs.

DSS colitis, up-regulated Foxp3 expression in T-cells, and suppressed TNF-α, but the loss of functional PPAR γ or δ impaired these anti-inflammatory effects. The deletion of PPAR γ in macrophages completely abrogated the amelioration effect of PUA on experimental colitis, whereas the deletion of PPAR δ or intestinal epithelial cell-specific PPAR γ decreased its antiinflammatory efficacy. These results strongly suggested that PUA ameliorates experimental IBD by regulating macrophage and Tcell function through PPAR γ- and δ-dependent mechanisms.155 α-ESA and IBD. α-ESA was also identified as a natural PPAR γ agonist by using complementary computational and experimental methods and found to be effective in ameliorating disease-associated phenotypes in mice with DSS colitis.160 Activation of PPAR γ by α-ESA could play an important role in amelioration of DSS-induced IBD. The anti-inflammatory actions of α-ESA may be both PPAR γ-dependent and -independent responses that ameliorated disease activity and intestinal lesions in mice with DSS colitis.160 Targeting PPAR γ represents a promising avenue for developing novel prophylactic and therapeutic interventions for IBD161,162 and obesity.163 Due to the side effects of full thiazolidinedione agonists of PPAR γ, there is a demand for naturally occurring PPAR γ modulators from edible items with minimum adverse effect and high tolerance to the human body.164 trans-10,cis-12 CLA has demonstrated antiobesity effects through regulation of expression and activity of PPAR γ, which is involved in reducing adipogenesis and lipogenesis and increasing inflammation. CLA (cis-9,trans-11 CLA or mixtures of cis-9,trans-11 and trans-10,cis-12 CLA) was also effective in ameliorating the experimental IBD though activation of PPAR γ. However, the safety of CLA is still of utmost concern and has been evaluated in numerous animal studies and human clinical trials.4 A minority of studies have reported ambiguous or deleterious effects of CLA supplementation with regard to liver functions, milk fat depression, insulin resistance, and oxidative markers.94,165−167 Although the safety of Clarinol and Tonalin TG 80, two oils with approximately 80% of the CLA 50:50 mixture of cis-9,trans-11 and trans-10,cis-12 isomers, has been established for the proposed uses and daily doses (3.75 g of Clarinol and 4.5 g of Tonalin TG 80 corresponding to approximately 3 and 3.5 g of CLA, respectively) for up to 6 months by the EFSA Panel on Dietetic Products, Nutrition and Allergies. However, the safety of CLA consumption for periods >6 months has not been established under the proposed conditions of use.168 These observations must be carefully considered, and further investigation is necessary before the widespread use of CLA as a functional food component. PUA and α-ESA, which were identified as natural agonists of PPAR γ, have proven beneficial effect on animal models of intestinal inflammation. PUA and α-ESA also exerted an antiadiposity effect through regulation of PPAR γ. Acute toxicological studies have demonstrated that PUA is safe in rats.169 Therefore, these plant-derived natural products are safer and may open the possibility to be used as functional foods and nutraceuticals. However, the exact mechanism by which PUA and α-ESA exert their physiological roles and human intervention studies are necessary to determine their beneficial effects on individuals with obesity or IBD. In summary, CLA (cis-9,trans-11 CLA and trans-10,cis-12 CLA) and CLNA (PUA and α-ESA) play an important role in modulating the expression or activity of PPAR γ and that could in turn be employed as complementary treatment for obesity and IBD. Available evidence suggested that trans-10, cis-12 CLA

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AUTHOR INFORMATION

Corresponding Author

*(D.L.) Mail: Department of Food Science and Nutrition, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. Phone: 86-571-8898 2024. Fax: 86-571-8898 2024. Email: [email protected]. Funding

The manuscript reports one of the studies funded by the Natural Science Foundation of Zhejiang Province (LY14C200004 and LY12C20007); G.Y. is the principal investigator. Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED AMPK AMP-activated protein kinase ACC acetyl-CoA carboxylase AP-1 activator protein-1 aP2 adipocyte fatty acid binding protein BGO nitter gourd seed oil CD-36/FAT fatty acid translocase C/EBP α CAAT/enhancer binding protein α CFA conjugated fatty acid CLA conjugated linoleic acid CLNA conjugated linolenic acid DAG diacylglycerol DGK diacylglycerol kinases DSS dextran sulfate sodium ER endoplasmic reticulum ERK extracellular signal-related kinase α-ESA α-eleostearic acid FAS fatty acid synthase H


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Journal of Agricultural and Food Chemistry GLUT4 HIF-1 IBD IL-1β IL-2 IL-6 IL-8 IL-10 IP3 JNK MAPK MCP-1 NEC NF-κB PUA PA PAI-1 PLC PGs PPRE PPAR PSO ROS SCD SIRT1 TNF-α TFF TFF1 TFF2 TFF3 TG TNBS [Ca2+] i

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insulin-dependent glucose transporter 4 hypoxia-inducible factor-1 inflammatory bowel disease interleukin-1 beta interleukin-2 interleukin-6 interleukin-8 interleukin-10 inositol-3-phosphate cJun-NH2-terminal kinase mitogen-activated protein kinase monocyte chemoattractant protein-1 necrotizing enterocolitis nuclear factor kappa B punicic acid phosphatidic acid plasminogen activator inhibitor-1 phospholipase C prostaglandins PPAR-responsive regulatory element peroxisome proliferator-activated receptor pomegranate seed oil reactive oxygen species stearoyl-CoA desaturase sirtuin 1 tumor necrosis factor-α trefoil peptides gastric peptide spasmolytic peptide intestinal trefoil factor triglyceride trinitrobenzenesulfonic acid intracellular calcium

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