Food Bioactives and Their Effects on Obesity-Accelerated

Jan 2, 2018 - Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan ..... phospho-liver kinase B1; p-PI3K, phosph...
1 downloads 6 Views 707KB Size
Subscriber access provided by READING UNIV

Perspective

Food bioactives and their effects on obesityaccelerated inflammatory bowel disease Yi-Shiou Chiou, Pei-Sheng Lee, and Min-Hsiung Pan J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b05854 • Publication Date (Web): 02 Jan 2018 Downloaded from http://pubs.acs.org on January 4, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Journal of Agricultural and Food Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 24

Journal of Agricultural and Food Chemistry

1

Food bioactives and their effects on obesity-accelerated inflammatory bowel

2

disease

3

Yi-Siou Chiou†, Pei-Sheng Lee†, and Min-Hsiung Panζ,† § ≠,

, , *

4 ζ

5 6

Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization; Hubei Collaborative Innovation Center for the

7 8

Characteristic Resources Exploitation of Dabie Mountains; Huanggang Normal University, Huanggang, Hubei, China †

9 10

Institute of Food Science and Technology, National Taiwan University, Taipei 10617, Taiwan

11 12

§

Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan

13 14



Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

15 16 17 18 19 20 21 22 23

*Please send all correspondence to: Dr. Min-Hsiung Pan Institute of Food Science and Technology, National Taiwan University, No. 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan. Tel. no. +886 2 33664133 Fax. no. +886-2-33661771 E-mail: [email protected]

24 25

1

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

26

ABSTRACT

27

Current views support the concept that obesity is linked to a worsening of the course

28

of inflammatory bowel diseases (IBD). Gut microbiota and adipose tissue

29

macrophage (ATM) are considered key mediators or contributors in

30

obesity-associated intestinal inflammation. Dietary components can have direct or

31

indirect effects on ‘normal’ or ‘healthy’ microbial composition and participate in

32

adiposity and metabolic status with gut inflammation. In this review, we highlight

33

food-derived bioactives that have a potential application in the prevention of

34

obesity-exacerbated IBD, targeting energy metabolism, M1 (classical activated)-M2

35

(alternatively activated) macrophage polarization, and gut microbiota.

36 37

KEYWORDS: IBD, ATM, obesity, Gut microbiota, bioactives

38 39

2

ACS Paragon Plus Environment

Page 2 of 24

Page 3 of 24

Journal of Agricultural and Food Chemistry

40

INTRODUCTION

41

The incidence of obesity has dramatically increased over the past decades in both

42

developed and developing countries. Due to its prevalence, obesity and related

43

metabolic complications such as dyslipidemia, insulin resistance, and steatohepatitis

44

have become global health issues. Obesity is a result of energy intake exceeding

45

energy expenditure over a prolonged period, causing abnormal fat accumulation. The

46

overnutrition-induced adipocyte hypertrophy and hyperplasia lead to activation and

47

recruitment of inflammatory cells into white adipose tissues (WATs) through

48

secreting cytokines and chemokines, promoting a state of low-grade systemic chronic

49

inflammation (1). Epidemiologic and experimental evidence has illustrated the

50

relationship between obesity and IBD.

51

One of the mechanisms responsible for IBD is chronic inflammation, which

52

drives immune responses that exert their effect through changes in microenvironments

53

such as gut microbiota and visceral adipose tissue (VAT). Most obese individuals

54

with a variety of metabolic disorders such as insulin resistance have stimulated

55

intestinal inflammation, which suggests that an alternatively activated macrophages

56

(M2) to classically activated macrophages (M1) transition of adipose tissue

57

macrophage (ATM) has a causative role in an obesity-associated proinflammatory

58

environment (2). It is currently believed that the gastrointestinal (GI) tract is the first 3

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

59

organ to be exposed to dietary components, which is considered a major linkage

60

exacerbating IBD symptoms in obese individuals (3). Therefore, specific dietary

61

factors clearly have a major impact on promotion or protection in obesity with

62

intestinal inflammation.

63

Despite all of the indications favoring a causative relationship between obesity

64

and IBD outcomes, our understanding of how dietary components are responsible for

65

the specific association between fat distribution and macrophage function at the

66

dysbiosis of gut microbiota in obesity-linked IBD is limited. This review consists of

67

three parts in which we discuss the current knowledge of the potential role of food

68

bioactives and their possible mechanistic links concerning: 1) food bioactives as a

69

master regulator of energy metabolism (Table 1), 2) M1-M2 macrophage polarization

70

balance (Table 2), and 3) alterations of gut microbial composition (Table 3).

71 72

ROLE OF FOOOD BIOACTIVES IN OBESITY-INDUCED INTESTINAL

73

INFLAMMATION

74

Imbalance between energy intake and expenditure ultimately results in fat deposition

75

and weight gain. Generally, obese individuals with an increasing waist circumference

76

and related metabolic complications are at an increased risk for developing IBD (1, 4).

77

Ulcerative colitis (UC) and Crohn's Disease (CD) are two diseases characterized by

78

chronic relapsing inflammation of the gastrointestinal tract. Increasing obesity-related 4

ACS Paragon Plus Environment

Page 4 of 24

Page 5 of 24

Journal of Agricultural and Food Chemistry

79

IBD incidence trends are associated with high-fat diets (HFD)/Western-style (HFW)

80

diets (5). The quantities and composition of consumed nutrients, especially fats and

81

carbohydrates, are important influencing factors on intestinal inflammation either

82

directly or indirectly by modifying the metabolic/immunological activity of the host

83

gut microbiota (5). It is already known that foods/diets are a source of not only

84

nutrients but also bioactive constituents such as polyphenols, which are naturally

85

present in a wide variety of fruits and vegetables. Growing evidence clearly

86

demonstrates that food bioactives are good factors for improving obesity and

87

inflammatory-related disorders (6, 7), and also have a positive influence on gut

88

microbiota composition and implications in human health (8). In this context, we

89

review possible mechanisms for potential roles of food-based bioactives and their

90

associated mechanisms in obesity-induced intestinal inflammation.

91

Activates energy metabolism

92

Owing to the essential role of adipose tissue (AT) in controlling energy

93

homeostasis including lipids and glucose metabolism, its alteration may trigger a

94

systemic low-grade inflammatory state in various tissues such as muscle and liver.

95

This contributes to the development of metabolic abnormalities like hepatic steatosis

96

and insulin resistance. Previous reports also indicated that metabolic syndrome (MetS)

97

is an important parameter in IBD patients (9), implying that the initial management of 5

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

98

MetS is partly responsible for the superior effects in preventing intestinal

99

inflammation. Evidence for recent studies demonstrated that the administration of

100

(-)-epigallocatechin-3-gallate (EGCG) (10), resveratrol (11), luteolin (12), and chrysin

101

(13) showed an improvement in hepatic and muscular steatosis, insulin resistance, and

102

glucose intolerance via reducing blood glucose and lipid absorption, and increasing

103

fecal lipids in HFD, high sucrose (HS), and HFW diet-induced obesity models. These

104

results also suggest that the beneficial effects of resveratrol and luteolin may be

105

mediated by simultaneously activating lipolysis, thereby reducing hepatic lipotoxicity

106

and de novo lipogenesis. Interestingly, luteolin treatment further increased the

107

elevated FA oxidation and tricarboxylic acid (TCA) cycle, which may contribute to

108

reduced adiposity. Additionally, dietary supplementation of EGCG resulted in

109

attenuation of hepatic and WAT lipogenesis due to its effect in reducing diet

110

digestibility and promoting FA oxidation and energy expenditure (14).

111

Traditionally, mammalian adipose tissues can be divided into two classes: white

112

adipose tissue (WAT) and brown adipose tissue (BAT). Unlike the functional

113

properties of WAT, BAT has been identified as an important site for energy

114

expenditure through efficient thermogenesis. Activation of brown adipocytes or the

115

browning of white adipocytes (termed beige or brite adipocytes), which are

116

characterized as uncoupling protein 1 (UCP-1)-expressing and mitochondrial-rich 6

ACS Paragon Plus Environment

Page 6 of 24

Page 7 of 24

Journal of Agricultural and Food Chemistry

117

adipocytes, contributes to whole body energy expenditure and therefore is also

118

another attractive weapon against diet-induced obesity (7). Studies on EGCG’s effects

119

on thermogenesis and induction of high mitochondrial density in BAT have shown an

120

upregulation in the expression of uncoupling proteins (UCPs) and an increase in the

121

markers of mitochondrial biogenesis such as peroxisome proliferator activated

122

receptor gamma coactivator 1-alpha (PGC-1α) (10). Recent studies also have revealed

123

that dietary farnesol (15) and chrysin (16) possess a development of beige adipocytes

124

in both inguinal adipose tissue (IAT) and epididymis adipose tissue (EAT). They also

125

enhance WAT browning as well as induce the brown-like phenotype, which certainly

126

limit adipogenesis and TG accumulation. We can believe the possibility that the

127

regulation of energy metabolism through consumption of food bioactives in obese

128

individuals might indicate the involvement of preventing the development of IBD.

129 130

Changes in M1–M2 macrophage polarization

131

Adipose endocrine function is multifaceted. It secretes a great number of hormones

132

and signaling molecules collectively called adipokines, which exert their biological

133

roles in the regulation of energy, glucose/lipid metabolism, inflammation, and insulin

134

sensitivity, immune responses, and host defense mechanisms (2).

135

As discussed in the previous sections, the circulating pro-inflammatory adipokines are 7

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

136

released by obese VAT mainly in the mesenteric fat, which is integral to the

137

inflammatory cascade involved in IBD (1). AT is recognized as a key endocrine organ

138

that consist of adipocytes, connective and nerve tissue, immune system cells (T and B

139

lymphocytes, macrophages), chondrocytes, osteocytes, and myocytes.

140

The obesity-associated state of chronic low-grade systemic inflammation termed

141

“metabolic inflammation” is a unique process driven by adipose tissue macrophages

142

(ATMs)-produced inflammatory response. ATMs from obese individuals are polarized

143

toward an M1 phenotype (pro-inflammatory) with upregulation of proinflammatory

144

cytokines such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor

145

alpha (TNF-α), and interleukin-6 (IL-6). Recently, diet supplementation with

146

quercetin (17), chrysin (13), apigenin (18), and naringenin (19) has been documented

147

to decrease obesity-induced systematic inflammation via preventing immune cell

148

infiltration (mast, myocytes, and macrophages) and favoring M2 (anti-inflammatory)

149

macrophage polarization. In addition, chrysin was also found to inhibit the biological

150

functions (antigen-presenting ability, phagocytic activity, and ROS production) of the

151

M1 macrophages. One of the most important sequela of AT inflammation is insulin

152

resistance (2). Studies from obesity-related inflammation in vitro have further showed

153

that food bioactives including quercetin (17), tangeretin (20), malvidin, peonidin (21),

154

and luteolin (22) enhanced the glucose uptake and blocked inflammation by 8

ACS Paragon Plus Environment

Page 8 of 24

Page 9 of 24

Journal of Agricultural and Food Chemistry

155

expressing glucose transporter 4 (GLUT4) and insulin receptor substrate (IRS) and

156

suppressing proinflammatory cytokines production, which is thought to improve

157

insulin sensitivity. This data strongly supports the fact that food-derived bioactives

158

have an ability to modulate macrophage M1-M2 status and could be a potential

159

strategy for dampening obesity-accelerated intestinal inflammation.

160 161

Alterations in gut microbiota

162

Gut microbiota are increasingly recognized as having pivotal roles in host energy

163

metabolism, lipid accumulation, and immunity by producing pharmacologically active

164

signaling molecules. Scientific efforts have been focused on understanding the

165

mechanistic basis of the crosstalk between dietary components and gut microbiota in

166

the incidence of IBD and obesity-related metabolic disorders, thus revealing the

167

importance of the gut-microbial–host-immune axis (23). For example,

168

microbial-derived short chain fatty acids (SCFAs) produced by fermentation of

169

dietary fibers have been shown to interact with G protein-coupled receptors (GPCRs),

170

affecting insulin sensitivity and thus regulating energy metabolism. Additionally,

171

SCFAs also have been shown to reduce inflammatory cytokine production by

172

inhibiting transcription factor nuclear factor kappa B (NFκB). However, HFD feeding

173

in mice induced a low-grade inflammatory status that is associated with a decrease in 9

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

174

the number of Bifidobacteria, which has been shown to decrease lipopolysaccharide

175

(LPS) levels and to improve mucosal barrier function. Such findings are important

176

because specific groups of bacteria may also provide beneficial effects on the

177

intestinal mucosa and protection against IBD by using supplements and foods with

178

probiotics and food ingredients-derived prebiotics (3, 24).

179

Bacteroidetes and Firmicutes are the dominant phyla in both mice and human

180

microbial populations (>90%). Several studies have found that a higher Firmicutes to

181

Bacteroidetes ratio positively correlated with the obese phenotype (24). Unlike obese

182

phenotypes, patients with IBD have an increased abundance of the ratio of

183

Bacteroidetes to Firmicutes (23). In vivo studies have provided evidence that EGCG

184

(25), resveratrol (26), and piceatannol (27) dietary supplements decreased lipid

185

accumulation in adipocytes and the liver that are likely mediated by mechanisms of

186

improving intestinal microbial balance and changing the composition of the colonic

187

microbiota. In addition, complex interactions between genetics and nutrition are also

188

involved in pathogenic mechanisms for IBD by the gut microbiome influencing

189

epigenetic changes and therefore effects on the immune system and the mucosal

190

barrier (28). In particular, EGCG supplementation may be partially derived from

191

antioxidative activities as well as epigenetic modifications observed on CpG

192

methylation (25) which alleviates conditions associated with obesity and metabolic 10

ACS Paragon Plus Environment

Page 10 of 24

Page 11 of 24

Journal of Agricultural and Food Chemistry

193

syndromes. These results support the emerging view that the gut microbiota

194

contributes to obesity and obesity-related IBD and suggest that consuming food

195

bioactives may cause alterations in the intestinal microbiome and epigenome interface

196

between the environment and genes, triggering a normal mucosal immune system and

197

maintaining genomic stabilities.

198 199

SUMMARY AND FUTURE DIRECTIONS

200

In this paper, we review the recent advances in dietary factors and intestinal

201

microbiota-host interaction in adiposity and dissect the plausible relationship

202

mechanisms between obesity and IBD, focusing on the key pathways of energy

203

metabolism, M1-M2 macrophage polarization, and gut microbiota alteration. We also

204

highlight the potential role of food-based bioactive compounds underpinning the

205

mechanisms linking obesity with intestinal inflammation that can be utilized to

206

outline directions for obesity-associated IBD prevention and therapeutic targets. We

207

assume from present results that food-derived bioactives may have the ability to

208

prevent obesity-exacerbated intestinal inflammation, which is partially associated

209

with the induction of energy metabolism, activation state of ATMs from an

210

M2-polarized state, and alteration of gut microbiota composition in diet-induced

211

obese individuals (Figure 1). However, further mechanistic studies of in vivo are

212

required to solidify the role of food-derived bioactives and directly test this 11

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

213

hypothesis.

214 215

Acknowledgment

216

This study was supported by the Ministry of Science and Technology

217

[105-2320-B-002-031-MY3, 105-2628-B-002-003-MY3].

218 219

Conflicts of interest

220

The authors declare no conflict of interest.

221 222

12

ACS Paragon Plus Environment

Page 12 of 24

Page 13 of 24

Journal of Agricultural and Food Chemistry

223 224 225 226 227 228 229 230

Reference 1. Yehuda-Shnaidman, E.; Schwartz, B. Mechanisms linking obesity, inflammation and altered metabolism to colon carcinogenesis. Obes. Rev. 2012, 13 (12), 1083-1095. 2. Makki, K.; Froguel, P.; Wolowczuk, I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN. Inflamm. 2013, 2013, 139239. doi: 10.1155/2013/139239

231

3. Lakhan, S. E.; Kirchgessner, A. Gut microbiota and sirtuins in obesity-related

232 233

inflammation and bowel dysfunction. J Transl. Med. 2011, 9, 202. doi: 10.1186/1479-5876-9-202

234 235 236 237 238 239 240 241 242 243 244 245

4. Harper, J. W.; Zisman, T. L. Interaction of obesity and inflammatory bowel disease. World J Gastroenterol. 2016, 22 (35), 7868-7881. 5. Rapozo, D. C.; Bernardazzi, C.; de Souza, H. S. Diet and microbiota in inflammatory bowel disease: The gut in disharmony. World J Gastroenterol. 2017, 23 (12), 2124-2140. 6. Hussain, T.; Tan, B.; Yin, Y.; Blachier, F.; Tossou, M. C.; Rahu, N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid. Med. Cell Longev. 2016, 2016, 7432797. Article ID 7432797 7. Azhar, Y.; Parmar, A.; Miller, C. N.; Samuels, J. S.; Rayalam, S. Phytochemicals as novel agents for the induction of browning in white adipose tissue. Nutr. Metab (Lond) 2016, 13, 89. doi: 10.1186/s12986-016-0150-6 8. Cardona, F.; ndres-Lacueva, C.; Tulipani, S.; Tinahones, F. J.; Queipo-Ortuno,

246

M. I. Benefits of polyphenols on gut microbiota and implications in

247

human health. J Nutr. Biochem. 2013, 24 (8), 1415-1422.

248 249 250 251 252 253 254

9. Yorulmaz, E.; Adali, G.; Yorulmaz, H.; Ulasoglu, C.; Tasan, G.; Tuncer, I. Metabolic syndrome frequency in inflammatory bowel diseases. Saudi. J Gastroenterol. 2011, 17 (6), 376-382. 10. Lee, M. S.; Shin, Y.; Jung, S.; Kim, Y. Effects of epigallocatechin-3-gallate on thermogenesis and mitochondrial biogenesis in brown adipose tissues of diet-induced obese mice. Food Nutr. Res. 2017, 61 (1), 1325307. doi: 10.1080/16546628.2017.1325307 13

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

255 256 257 258 259 260

11. Alberdi, G.; Rodriguez, V. M.; Miranda, J.; Macarulla, M. T.; Arias, N.; ndres-Lacueva, C.; Portillo, M. P. Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutr. Metab (Lond) 2011, 8 (1), 29. doi: 10.1186/1743-7075-8-29 12. Kwon, E. Y.; Jung, U. J.; Park, T.; Yun, J. W.; Choi, M. S. Luteolin attenuates hepatic steatosis and insulin resistance through the interplay between the

261 262

liver and adipose tissue in mice with diet-induced obesity. Diabetes 2015, 64 (5), 1658-1669.

263 264

13. Feng, X.; Qin, H.; Shi, Q.; Zhang, Y.; Zhou, F.; Wu, H.; Ding, S.; Niu, Z.; Lu, Y.; Shen, P. Chrysin attenuates inflammation by regulating M1/M2 status via

265 266 267 268

activating PPARgamma. Biochem. Pharmacol. 2014, 89 (4), 503-514. 14. Klaus, S.; Pultz, S.; Thone-Reineke, C.; Wolfram, S. Epigallocatechin gallate attenuates diet-induced obesity in mice by decreasing energy absorption and increasing fat oxidation. Int. J Obes. (Lond) 2005, 29 (6), 615-623.

269 270 271 272

15. Kim, H. L.; Jung, Y.; Park, J.; Youn, D. H.; Kang, J.; Lim, S.; Lee, B. S.; Jeong, M. Y.; Choe, S. K.; Park, R.; Ahn, K. S.; Um, J. Y. Farnesol Has an Anti-obesity Effect in High-Fat Diet-Induced Obese Mice and Induces the Development of Beige Adipocytes in Human Adipose Tissue

273 274

Derived-Mesenchymal Stem Cells. Front Pharmacol. 2017, 8, 654. doi: 10.3389/fphar.2017.00654

275

16. Choi, J. H.; Yun, J. W. Chrysin induces brown fat-like phenotype and enhances

276 277 278 279 280 281 282 283 284 285

lipid metabolism in 3T3-L1 adipocytes. Nutrition 2016, 32 (9), 1002-1010. 17. Dong, J.; Zhang, X.; Zhang, L.; Bian, H. X.; Xu, N.; Bao, B.; Liu, J. Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKalpha1/SIRT1. J Lipid Res. 2014, 55 (3), 363-374. 18. Feng, X.; Weng, D.; Zhou, F.; Owen, Y. D.; Qin, H.; Zhao, J.; WenYu; Huang, Y.; Chen, J.; Fu, H.; Yang, N.; Chen, D.; Li, J.; Tan, R.; Shen, P. Activation of PPARgamma by a Natural Flavonoid Modulator, Apigenin Ameliorates Obesity-Related Inflammation Via Regulation of

286

Macrophage Polarization. EBioMedicine. 2016, 9, 61-76.

287

19. Yoshida, H.; Watanabe, H.; Ishida, A.; Watanabe, W.; Narumi, K.; Atsumi, T.; 14

ACS Paragon Plus Environment

Page 14 of 24

Page 15 of 24

Journal of Agricultural and Food Chemistry

288 289

Sugita, C.; Kurokawa, M. Naringenin suppresses macrophage infiltration into adipose tissue in an early phase of high-fat diet-induced obesity.

290

Biochem. Biophys. Res. Commun. 2014, 454 (1), 95-101.

291

20. Shin, H. S.; Kang, S. I.; Ko, H. C.; Park, D. B.; Kim, S. J. Tangeretin Improves

292

Glucose Uptake in a Coculture of Hypertrophic Adipocytes and

293 294

Macrophages by Attenuating Inflammatory Changes. Dev. Reprod. 2017, 21 (1), 93-100.

295 296

21. Mackert, J. D.; McIntosh, M. K. Combination of the anthocyanidins malvidin and peonidin attenuates lipopolysaccharide-mediated inflammatory gene

297 298

expression in primary human adipocytes. Nutr. Res. 2016, 36 (12), 1353-1360.

299 300 301

22. Nepali, S.; Son, J. S.; Poudel, B.; Lee, J. H.; Lee, Y. M.; Kim, D. K. Luteolin is a bioflavonoid that attenuates adipocyte-derived inflammatory responses via suppression of nuclear factor-kappaB/mitogen-activated protein

302

kinases pathway. Pharmacogn. Mag. 2015, 11 (43), 627-635.

303 304

23. van den Elsen, L. W.; Poyntz, H. C.; Weyrich, L. S.; Young, W.; Forbes-Blom, E. E. Embracing the gut microbiota: the new frontier for inflammatory and

305 306 307 308 309 310 311 312

infectious diseases. Clin. Transl. Immunology 2017, 6 (1), e125. doi: 10.1038/cti.2016.91 24. Boulange, C. L.; Neves, A. L.; Chilloux, J.; Nicholson, J. K.; Dumas, M. E. Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med. 2016, 8 (1), 42. doi: 10.1186/s13073-016-0303-2 25. Remely, M.; Ferk, F.; Sterneder, S.; Setayesh, T.; Roth, S.; Kepcija, T.; Noorizadeh, R.; Rebhan, I.; Greunz, M.; Beckmann, J.; Wagner, K. H.; Knasmuller, S.; Haslberger, A. G. EGCG Prevents High Fat

313

Diet-Induced Changes in Gut Microbiota, Decreases of DNA Strand

314

Breaks, and Changes in Expression and DNA Methylation of Dnmt1 and

315 316

MLH1 in C57BL/6J Male Mice. Oxid. Med. Cell Longev. 2017, 2017, 3079148. doi: 10.1155/2017/3079148

317 318 319 320

26. Qiao, Y.; Sun, J.; Xia, S.; Tang, X.; Shi, Y.; Le, G. Effects of resveratrol on gut microbiota and fat storage in a mouse model with high-fat-induced obesity. Food Funct. 2014, 5 (6), 1241-1249. 27. Tung, Y. C.; Lin, Y. H.; Chen, H. J.; Chou, S. C.; Cheng, A. C.; Kalyanam, N.; 15

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

321 322

Ho, C. T.; Pan, M. H. Piceatannol Exerts Anti-Obesity Effects in C57BL/6 Mice through Modulating Adipogenic Proteins and Gut

323

Microbiota. Molecules. 2016, 21 (11). doi: 10.3390/molecules21111419

324

28. Aleksandrova, K.; Romero-Mosquera, B.; Hernandez, V. Diet, Gut Microbiome

325

and Epigenetics: Emerging Links with Inflammatory Bowel Diseases

326 327

and Prospects for Management and Prevention. Nutrients. 2017, 9 (9). doi: 10.3390/nu9090962

328 329 330 331 332

29. Chen, Y. K.; Cheung, C.; Reuhl, K. R.; Liu, A. B.; Lee, M. J.; Lu, Y. P.; Yang, C. S. Effects of green tea polyphenol (-)-epigallocatechin-3-gallate on newly developed high-fat/Western-style diet-induced obesity and metabolic syndrome in mice. J Agric. Food Chem. 2011, 59 (21), 11862-11871.

333 334

16

ACS Paragon Plus Environment

Page 16 of 24

Page 17 of 24

Journal of Agricultural and Food Chemistry

Table 1. Potential effects of food bioactives on energy metabolism Mechanism studied and outcome

Model

Mode of action and molecular/signaling target

Food bioactives Sources

Compounds

Upregulate brown adipose tissue thermogenesis and mitochondrial biogenesis

a. HFD-induced obesity in C57BL/6J mice

Green tea

EGCG

(10)

Induce the beige adipocytes development in both IAT and EAT Enhance WAT browning in HFD-induced obese mice

a. MDI-induced differentiation in 3T3-L1 preadipocytes b. hAMSCs c. HFD-induced obesity in C57BL/6J mice a. HFW-induced obesity and metabolic syndrome in C57BL/6J mice a. HFD-induced obesity in New Zealand black mice

↑Body temperature and mtDNA replication ↓Lipids and leptin (Plasma, Liver and Fecal) ↑AMPK activity, UCP1, UCP2, PRDM16, CPT-1β, PGC-1α, NRF1, ACC2 and Tfam (BAT) ↓Adipogenesis ↓PPARγ, CEBPα, FABP4, adiponectin, resistin and lipin1 (3T3-L1, hAMSCs, EAT and IAT) ↑p-AMPK, p-ACC, UCP1, PGC-1α, TMEM26, TBX1 and CD137 (3T3-L1, hAMSCs, EAT and IAT) ↓Blood glucose, liver damage and lipid absorption ↓TC, IL-6, G-CSF, MCP-1 and CRP (Plasma)

Peaches Tomatoes Corn, Lemon Chamomile Green tea

Farnesol

(15)

EGCG

(29)

Green tea

EGCG

(14)

Grape

Resveratol

(11)

Passion fruit Whole raw Honey Propolis, Cocoa

Chrysin

(16)

Spinach Kale Perilla Parsley Onions Thyme

Luteolin

(12)

Activates energy metabolism

Alleviate fatty liver incidence, insulin resistance

Promote fat oxidation and energy expenditure Reduce diet digestibility and lipogenesis Inhibit fatty acid uptake and de novo lipogenesis Induce brown fat phenotype Block lipid catabolism and lipogenesis

a. HSD/HFD-induced obesity in Sprague-Dawley rats a. MDI-induced differentiation in 3T3-L1 preadipocytes

Improve hepatic steatosis and insulin resistance Normalize hepatic metabolite expressions

a. HFD-induced obesity in C57BL/6J mice

↓Respiratory quotient during night ↓Leptin, SCD1, ME and GK (WAT and liver) ↓Lipogenic enzyme activities ↓HR-LPL, HSL, G6PDH, FASN and ACC (WAT) ↓Adipogenesis and TG accumulation ↓CEBP/α (3T3-L1) ↑Browning, lipolysis and fat oxidation ↑PGC-1α, PPARα/γ/δ, UCP1, PRDM16, CEBP/β, HSL, PLIN, CPT1, ACO, p-ACC and p-AMPK (3T3-L1) ↑CIDEA, CITED1, FGF21, PGC-1α, PRDM16, TBX1, TMEM26, and UCP1 (3T3-L1) ↓Lipogenesis, lipid droplets and lipid absorption ↓G6PD, FAS, ME, PAP, HMGCR, ACAT, ACC, SREBP2, PPARγ, glycogen, glucokinase, PEPCK, and G6Pase (Liver) ↓FA and TG synthesis-associated genes (Liver) ↑Glucose tolerance ↑SREBP1, PPARγ, ACC (EAT)

17

ACS Paragon Plus Environment

Ref.

Berries

Journal of Agricultural and Food Chemistry

↑Lipids (Fecal) ↑FA oxidation-associated genes (Liver) ↑Lipolysis/ FA oxidation-associated genes (EAT) ↑TCA cycle -associated genes (WAT)

Page 18 of 24

Peppermint

Abbreviations: ACC, acetyl-CoA carboxylase; ACO, acyl-CoA oxidase; ACAT, acyl-CoA:cholesterol acyltransferase; AMPK, Adenosine monophosphate-activated protein kinase; CPT1, carnitine palmitoyltransferase 1; CEBPα, CCAAT/enhancer-binding protein alpha; CIDEA, cell death-inducing DFFA-like effector a; CITED1, CREB-binding protein/p300-interacting transactivator with Asp/Glu-rich C-terminal domain; EAT, epididymis adipose tissue; FABP4, FABP4 fatty acid binding protein 4; FASN, Fatty acid synthase; FA, fatty acid; FGF21, fibroblast growth factor 21; Fizz1, found in inflammatory zone 1; G6Pase, glucose-6-phosphatase; G6PDH, Glucose-6-phosphate dehydrogenase; G6PD, Glucose-6-Phosphate Dehydrogenase deficiency; GK, Glycerolkinase; G-CSF, granulocyte colony-stimulating factor; HR-LPL, heparin-releasable lipoprotein lipase; HFD, high fat diet; HFW, Western-style diet; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; HSL, hormone sensitive lipase; hAMSCs, human adipose tissue-derived mesenchymal stem cells; IAT, inguinal adipose tissue; IL-6, interleukin-6; ME, malic enzyme; MCP-1, monocyte chemoattractant protein-1; NRF1, Nuclear respiratory factor 1; PAP, phosphatidate phosphohydrolase; PEPCK, Phosphoenolpyruvate carboxykinase; PGC-1α, peroxisome proliferator- activated receptor gamma coactivator-1α; PLIN, PPARγ, peroxisome proliferator–activated receptor γ; PRDM 16, PR domain containing 16; SCD1, Stearoyl-CoA desaturase-1; SREBP2, sterol-regulatory element binding protein 2; TBX1, T-box transcription factor; TC, total plasma cholesterol; Tfam, Mitochondrial transcription factor A; TG, triglyceride; TMEM26, transmembrane protein 26; UCP, uncoupling proteins; WAT, white adipose tissue.

18

ACS Paragon Plus Environment

Page 19 of 24

Journal of Agricultural and Food Chemistry

Table 2. Potential effects of food bioactives on M1/M2 macrophage polarization Mechanism studied and outcome

Model

Mode of action and molecular/signaling target

Sources

Compounds

a. HFD-induced obesity in C57BL/6J mice b. MDI-differentiated 3T3-L1+ RAW264.7 co-cultured in a contact system a. HFD-induced obesity in C57BL/6J mice b. LPS-induced inflammation in BMDMs c. MDI + indomethacin-induced differentiation in 3T3-L1 preadipocytes

↓Blood glucose and lipids ↓Mac-2, MCP-1 and JNK/p-IκBα (EAT) ↓MCP-1 (3T3-L1 and RAW264.7)

Citrus peel Grapes

Naringenin

(19)

↓Mast and macrophage cell recruitments ↓M1/M2 subtype ratio and BMDMs polarization ↓Insulin, leptin, adiponectin, TNF-α, IL-6 and MCP-1 (Serum and EAT) ↓mMcp-4, Cd11c and Nos2 (EAT) ↓Nos2, IL-6, IL-1β, MCP-1 (BMDMs) ↑Glucose uptake ↑GLUT4 translocation and p-Akt (EAT and 3T3-L1) ↑UCP1 (BAT) ↑Mgl2, Chil3l and IL-10 gene, AMPKα1 activity, SIRT1, p-LKB1 and AMP/ATP ratio (EAT and BMDMs) ↑Glucose uptake ↓IL-6, IL-1β, TNF-a, iNOS, COX-2 (3T3-L1 and RAW264.7) ↓M1 macrophages phenotype, lipid droplets (Liver, Skeletal Muscle and WAT) ↓Monocytes differentiation (THP-1 cells) ↓Macrophages antigen-presenting and phagocytic abilities and ROS production (ANA-1 and RAW264.7 cells) ↓MHCII+, CD80, CCR7, IL-1β, TNF-α and NO (ANA-1 cells) ↓ALT, AST, IL-1β and TNF-α (Serum) ↑IL-10 and adiponectin (Serum)

Apple Onions Broccoli Tea Strawberries

Quercetin

(17)

Citrus peels

Tangeretin

(20)

Passion fruit Whole raw honey Propolis Cocoa

Chrysin

(13)

Changes in M1–M2 macrophage polarization Suppress macrophage infiltration

Reduce obesity-associated ATM infiltration and systematic inflammation Improve obesity-induced insulin resistance

Attenuate obesity-induced insulin resistance and inflammation Reduce obesity-induced inflammation, hepatic and muscular steatosis, Prevent adipose tissue monocytes and macrophages infiltration

a. MDI-differentiated 3T3-L1+ RAW264.7 co-cultured in a contact system a. HFD-induced obesity in C57BL/6J mice b. Mouse primary macrophages derived from ND or HFD mice c. TPA/LPS-induced M1 macrophage in THP-1 cells d. TPA/IL-4-induced M2 macrophage in ANA-1 and RAW264.7 cells

19

ACS Paragon Plus Environment

Food bioactives

Ref.

Journal of Agricultural and Food Chemistry

Impair inflammation and insulin resistance

a. LPS-induced inflammation in primary human SV cells

Inhibit obesity-induced inflammation and hepatic steatosis Restore the M1/M2 macrophages status

a. HFD-induced obesity in C57BL/6J mice b. C57BL/6J ob/ob mice c. Peritoneal macrophages derived from C57BL/6J mice d. ATM derived from EAT e. LPS-induced M1 and IL-4-induced M2 macrophages in ANA-1 and RAW264.7 cells f. pIRES-hPPARγ/PPRE-Luc expressed HEK293 cells a. TLI-induced inflammation in 3T3-L1 adipocytes

Oppose inflammation Improve insulin sensitivity

↑M2 macrophages phenotype ↑MGL1/2, Arg1 activity, PPARγ transcriptional activity, IL-10, CD206, Ym1, Arg1, Fizz1 and CD36 (ANA-1 cells and Mouse primary macrophages) ↓Inflammation ↓MCP-1, IL-1β, IL-6, IL-8, TNFα, COX-2, TLR-2, IP-10 and PTP-1B (SV cells) ↑Lipolysis and glucose uptake ↑HSL (SV cells) ↓Inflammatory cells infiltration and M1/M2 subtype ratio ↓lipid accumulation and cell structures derangement (Liver and Skeletal muscle) ↓IL-12, TNF-α, IL-6, IL-1β and MCP-1 (Serum) ↓NOS2, TNF-α, IL-1β and CXCL-10 (RAW264.7 cells) ↓p65 and p-IκBα (Mouse primary macrophages) ↓p65 and PPARγ interaction (ANA-1 cells) ↑IL-10 (Serum) ↑Ym1, CD163, CD206, Arg1 and IL-10 (RAW264.7 cells) ↑PPARγ transcriptional activity (293T cells) ↑CD36 (ANA-1 cells) ↓Inflammation and NO production ↓iNOS, COX-2, IL-6, resistin and MCP-1 (3T3-L1) ↓p-IκBα, NF-κBp65 translocation and MAPKs (3T3-L1) ↑IRS1/2, GLUT4 and p-PI3K (3T3-L1)

Page 20 of 24

California table grapes

Malvidin Peonidin

(21)

Spices Parsley Onions Celery

Apigenin

(18)

Spinach Kale Thyme Peppermint

Luteolin

(22)

Abbreviations: ALT, Alanine aminotransferase; Arg1, arginase 1; AST, Aspartate aminotransferase; BMDMs, Bone Marrow Derived Macrophages; CCR7, C-C chemokine receptor type 7; Chil3l, chitinase-like 3; COX-2, cyclooxygenase-2; CXCL-10, C-X-C motif chemokine 10; GLUT4, Glucose transporter type 4; iNOS, inducible nitric oxide synthase; IRS1/2, insulin receptor substrate 1/2; IP-10, Interferon gamma-induced protein 10; IL-1β, Interleukin 1 beta; IL-10, Interleukin 10; IL-12, Interleukin 12; IL-4, Interleukin 4; IL-8, Interleukin 8; JNK, c-Jun N-terminal kinase; LPS, Lipopolysaccharide; Mgl2, macrophage galactose N-acetyl-galactosamine specific lectin 2; MGL1/2, macrophage galactose-type lectin-1/2; MHCII+, major histocompatibility complex II+; MAPKs, mitogen-activated protein kinases; mMcp-4, mouse mast cell protease 4; Nos2, Nitric oxide synthase 2; 20

ACS Paragon Plus Environment

Page 21 of 24

Journal of Agricultural and Food Chemistry

p-IκBα, phospho-inhibitor of kappa Bα; p-LKB1, phospho-liver kinase B1; p-PI3K, phospho-Phosphoinositide 3-kinase; PTP-1B, protein-tyrosine phosphatase 1B; ROS, Reactive oxygen species; SIRT1, silent information regulator 1; TLI, tumor necrosis factor-α, lipopolysaccharide, and interferon-γ; TLR-2, Toll-like receptor 2; TNF-α, Tumor necrosis factor alpha; TPA, 12-O-Tetradecanoylphorbol-13-acetate.

21

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

Page 22 of 24

Table 3. Potential effects of food bioactives on gut microbiota Mechanism studied and outcome

Model

Mode of action and molecular/signaling target

Alterations in gut microbiota

Sources

Lighten DNA damage in liver

a. HFD-induced obesity in C57BL/6J mice

Improve the gut microbiota dysbiosis Reduce de novo lipogenesis

a. HFD-induced obesity in Kunming mice

Decrease lipogenesis in adipose tissue and liver Alter gut microbiota composition

Food bioactives

a. HFD-induced obesity in C57BL/6J mice

↓Firmicutes/Bacteroidetes ratio (Fecal) ↓MLH1 gene (Liver) ↑MLH1 promoter CpG2 methylation and DNMT1 promoter CpG1 methylation (Liver) ↑DNMT1 promoter CpG2 methylation and IL-6 gene (Colon) ↓Blood glucose, insulin and lipids ↓Enterococcus faecalis growth (Fecal) ↓LPL, Cyp7a1, and SCD1 gene (Ileum and Liver) ↓PPARγ, ACC1 and FASN (EAT) ↑Bacteroidetes/Firmicutes ratio, Lactobacillus and Bifidobacterium growth (Fecal) ↑Fiaf (Ileum tissue) ↓Blood glucose and lipids ↓C/EBPα, PPARα and FASN (EAT and Liver) ↓Bacteroidetes (Fecal) ↑p-AMPK and p-ACC (EAT and Liver) ↑Firmicutes and Lactobacillus (Fecal)

Ref.

Compounds

Green tea

EGCG

(25)

Grape skin Grape seeds

Resveratrol

(26)

Piceatannol

(27)

Berries Peanuts

Red wine Blueberries Grapes Passion fruit

Abbreviations: Cyp7a1, cytochrome P450 family 7 subfamily A member 1; DNMT1, DNA (cytosine-5)-methyltransferase 1; LPL, Lipoprotein lipase; MLH1, mutL homolog 1.

22

ACS Paragon Plus Environment

Page 23 of 24

Journal of Agricultural and Food Chemistry

Figure 1. Mechanisms linking food bioactives with obesity-associated IBD. Mechanisms by which food-based bioactives could contribute to prevention of obesity-associated intestinal inflammation are proposed. Diet induced obesity and the gut microbiota dysbiosis can directly and indirectly participate in low grade inflammation and fat deposition via alteration of immune homeostasis in the intestine, disruption of intestinal mucosa and induction of intestinal permeability, which in turn enhances fat-derived inflammatory adipokines. Daily consumption of vegetables and fruits improves the obese adipose tissue-associated metabolic syndromes and intestinal inflammation by the HFD/HFW diet, including activating energy metabolism, switching from M1 (pink) to M2 (blue) macrophages, increasing gut microbiota diversity, and reversing epigenetic changes.

23

ACS Paragon Plus Environment

Journal of Agricultural and Food Chemistry

Table of Contents (TOC) Graphic

24

ACS Paragon Plus Environment

Page 24 of 24