The Preventive Mechanisms of Bioactive Food Compounds against Obesity-Induced Inflammation

Dietary patterns are promising strategies for preventing and treating obesity and its coexisting inflammatory processes. Bioactive food compounds have received considerable attention due to their actions against obesity-induced inflammation, with limited harmful side effects. They are perceived as food ingredients or dietary supplements other than those necessary to meet basic human nutritional needs and are responsible for positive changes in the state of health. These include polyphenols, unsaturated fatty acids, and probiotics. Although the exact mechanisms of bioactive food compounds’ action are still poorly understood, studies have indicated that they involve the modulation of the secretion of proinflammatory cytokines, adipokines, and hormones; regulate gene expression in adipose tissue; and modify the signaling pathways responsible for the inflammatory response. Targeting the consumption and/or supplementation of foods with anti-inflammatory potential may represent a new approach to obesity-induced inflammation treatment. Nevertheless, more studies are needed to evaluate strategies for bioactive food compound intake, especially times and doses. Moreover, worldwide education about the advantages of bioactive food compound consumption is warranted to limit the consequences of unhealthy dietary patterns. This work presents a review and synthesis of recent data on the preventive mechanisms of bioactive food compounds in the context of obesity-induced inflammation.


Introduction
Obesity is a disease characterized by the excessive amount or distribution of adipose tissue (AT) in the human body [1]. In the International Classification of Diseases, ICD-11, obesity is 5B8 [2]. Obesity affects over one billion people worldwide. The majority of people with obesity are adults, reaching 650 million people in the world. Around 340 million adolescents and 39 million children are obese [3]. Excessive body weight is associated with over 2.8 million deaths annually [4]. Obesity increases the risk of hospitalization and generates high healthcare costs in most countries. As an epidemic of the 21st century, it is a challenge to public health [5].
An anthropometric indicator, body mass index (BMI), is used to diagnose obesity. It is a simple, cheap, quick, and non-invasive diagnostic tool. BMI is the quotient of body weight expressed in kilograms and the square of height in meters (kg/m 2 ). A score above 30 kg/m 2 makes it possible to diagnose obesity. Waist circumference is also used for the diagnosis of the discussed disease. A waist circumference of ≥94 cm in men or ≥80 cm in women is diagnostic of abdominal obesity [6]. This disease can also be diagnosed by determining the percentage of AT using the electrical bioimpedance method. Growth charts are also used in children and adolescents [7]. TNF-α, (IL)-1β, IL-6, IL-8, and IL-12 through the NF-κB-mediated pathway. The binding of resistin to adenylate cyclase (CAP-1) increases the expression of NF-κB, cAMP, and protein kinase A (PKA). This has the effect of inducing a proinflammatory response [42].
Plasminogen activator inhibitor 1 is an inhibitor of the fibrinolytic system. Its increased concentration is a predictor of myocardial infarction. It is produced in ectopic adipose tissue by macrophages. PAI-1 concentrations in the blood depend on the AT distribution in the body. The level of PAI-1 positively correlates with the marker of oxidative stress (OS). Increasing ROS production in AT impairs PAI-1 secretion in obesity. The increased expression of PAI-1 by ROS may be prevented by a dominant negative inhibitor of NF-κB [43]. Lowering the PAI-1 concentration seems to be promising for lowering IR in patients with obesity by improving insulin sensitivity in adipose tissue.
Chronic OS also affects the formation of WAT, appetite regulation, increased preadipocyte proliferation, adipocyte differentiation, and the size of mature adipocytes [44]. H 2 O 2 levels in WAT are controlled by catalase, glutathione peroxidase (GPX), and peroxiredoxins (Prdxs). Peroxiredoxin 3 (Prdx3) intercepts H 2 O 2 in WAT and reduces OS. In obesity, the level of Prdx3 is reduced. This increases the oxidative imbalance in WAT [45].
To sum up, visceral adipose tissue accumulation leads to abdominal obesity. VAT exerts the most substantial proinflammatory effect. Its amount is strongly correlated with IR [46]. Therefore, in obesity, the AT distribution in the body is also essential in addition to its excess [46]. The increased amount of AT induces the synthesis of the abovementioned proinflammatory cytokines and adipokines, promoting increased ROS and nitrogen production by macrophages and monocytes. Changing nutrition, following a diet with antioxidant potential, and reducing body weight seem to be promising strategies for attenuating the secretion of proinflammatory factors in obesity [47]. Moreover, it seems that bioactive food compound intake can improve and accelerate the obesity treatment process and reduce inflammation.

Antioxidant Potential of Bioactive Food Compounds in Obesity Management
As mentioned above, increased AT causes increased proinflammatory cytokine expression and ROS generation. This condition is aggravated by dietary patterns rich in simple sugars and saturated fatty acids. The opposite effect is exerted by a diet high in bioactive food ingredients [48].
Bioactive food compounds include many ingredients that have diverse effects on the human body. However, these compounds show the strongest antioxidant activity. Their importance is crucial in reducing obesity-induced inflammation. Consuming products containing bioactive food components may reduce inflammation and OS in the human body [49][50][51]. An appropriate composition of anti-inflammatory agents in the diet may represent a new approach to obesity treatment [52]. These compounds are mainly found naturally in plant products. These include polyphenols, unsaturated fatty acids, lactic acid bacteria, vitamins, dietary fiber, certain trace elements, and oligopeptides [27]. These compounds suppress the NF-κB/MAP kinase pathway and maintain or slightly increase the level of M2 macrophages, which induces the production of anti-inflammatory cytokines. They also affect the regulation of proinflammatory adipokines [44], increase the level of NAD in the cell, inhibit lipid synthesis, and increase energy expenditure and thermogenesis [53]. Anti-inflammatory compounds are also available as dietary supplements [54].
Polyphenols are a diverse group of bioactive food ingredients. These are organic compounds of plant origin. Berries, colorful vegetables, green tea, cocoa, and nuts are the primary sources of these compounds. Both animal and clinical studies have demonstrated the health benefits of food-derived polyphenols in obesity. Polyphenols may improve the functioning of the cardiovascular system, have anti-inflammatory effects, and normalize the lipid profile and blood pressure value. Resveratrol (RSVL) has an antioxidant effect and supports the immune system, inhibits lipogenesis, reduces inflammation in obesity, and increases energy expenditure [55]. Catechins present in green tea attenuate the proliferation of 3T3-L1 adipocytes by reducing the levels of phosphorylated ERK1/2, cdk2, and cyclin Antioxidants 2023, 12, 1232 5 of 30 D1 proteins. They also inhibit cell growth in Go/G1 and induce apoptosis in mature adipocytes. Phenolic compounds present in blueberries reduce the expression of TNF-α and IL-10 genes in macrophages, which decreases inflammatory processes [56].
The following nutritional compounds with antioxidant capacity are dietary fats. Fatty acids are divided into saturated and unsaturated (mono-and polyunsaturated) depending on the presence and number of unsaturated bonds. Omega-3 fatty acids have the strongest anti-inflammatory effect. It has been shown that supplementation with n-3 fatty acids reduces the concentration of interleukins IL-1 and IL-6 and prostaglandin (PG) and cytokine levels. Consuming more n-3 fatty acids than in a standard diet affects the anti-inflammatory cytokine response [57].
In recent years, special attention has been paid to the human microbiome and its influence on metabolic health and the inflammatory response. Lactic acid bacteria are capable of obligately fermenting carbohydrates to form lactic acid. Lactobacillus bacterial strains have numerous beneficial health aspects. In the diet, they are found in fermented foods. The lactic acid produced by these bacteria has an antioxidant effect. This leads to the reduction of ROS. It also affects the production of antioxidants, superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) [58]. Lactobacillus bacterial strains also affect the lowering of IL-1 and IL-6 [59].
Bioactive food compounds also include vitamins A [60], C [61], and D [62,63] and dietary fiber. Dietary fiber is an element of plant products not digested by human digestive enzymes. These include, in the most significant amounts, cellulose, hemicelluloses, pectins, gums, lignins, and cutins. They significantly affect the intestinal microflora. Dietary fiber has an antioxidant effect mainly due to the high contents of phenolic compounds. Their amount depends on the species and the part of the plant. Dietary fiber reduces the production of IL-6 and IL-8 in humans as well as the production of endothelial proinflammatory cytokines by inhibiting NF-κB and proteasome activity [64]. Of the oligopeptides showing antioxidant activity, glutathione has been the most studied. This is a cellular non-enzymatic antioxidant. It is a cofactor for glutathione peroxidase, glutathione S-transferase, and glyoxalase [65]. A good dietary source of glutathione is spinach, which was first shown in 1978 [66].
Dietary foods and/or supplements contain many numerous antioxidant compounds. Each of them represents a different antioxidant effect on humans. Thus, this review describes the antioxidant potential of selected polyphenols, omega-3 fatty acids, and probiotics against obesity-induced inflammation.

Polyphenols
Polyphenols or phenolic compounds are plant metabolites arising from the polyketide acetate/malonate pathway, the shikimate/phenylpropanoid pathway, or both [67]. In nature, around 8000 molecules have been identified as polyphenols [68]. This term refers to compounds with one or more hydroxyl substituents bound to aromatic rings. Their structure is very varied, ranging from simple molecules (such as phenolic acids) to complex polymers with high molecular weight (such as tannins) ( Figure 1) [69,70]. There are many different classifications of polyphenols, although the main categorization distinguishes between groups of flavonoids and non-flavonoids, including stilbenes, lignans, phenolic acids, and others ( Figure 2) [50,71]. Polyphenols are the most abundant phytochemicals in the plant kingdom, with a prominent presence in fruits and vegetables. Their bioavailability depends on many factors, such as the kind and amount of the food, the intestinal condition, interactions with other food products and/or medicines, and the pharmacokinetic profile [53,72]. The presence of one or more aromatic rings in the molecule and a different number of hydroxyl groups determine the antioxidant activity of polyphenols. Thus, the chemical structure determines the rate of absorption and the nature of its metabolites circulating in the plasma. Consequently, the biological properties of polyphenols differ from one to another, and their absorption through the gut barrier is correlated with an increase in antioxidant capacity [73].
It has been shown that polyphenols have antioxidant, anti-inflammatory, immunomodulatory [74], anti-cancerogenic [75,76], and anti-obesity [29,77] properties. Although their exact mechanisms of action are still not fully understood, emerging data suggest their positive influence on human health. The main effect of the action of phenolic compounds is their ability to increase the expression and activity of antioxidant enzymes and inhibit the production of free radicals [31,78]. Moreover, they can modulate cell functions in obesity, especially the number and size of adipocytes (inhibition of adipogenesis), control lipid metabolism and fatty acid oxidation, and inhibit lipid accumulation [78,79]. Due to the large number of different polyphenols compounds, in this review, we describe resveratrol, curcumin (CUR), and catechins in the context of the attenuation of obesity-induced inflammation. and/or medicines, and the pharmacokinetic profile [53,72]. The presence of one or more aromatic rings in the molecule and a different number of hydroxyl groups determine the antioxidant activity of polyphenols. Thus, the chemical structure determines the rate of absorption and the nature of its metabolites circulating in the plasma. Consequently, the biological properties of polyphenols differ from one to another, and their absorption through the gut barrier is correlated with an increase in antioxidant capacity [73].
It has been shown that polyphenols have antioxidant, anti-inflammatory, immunomodulatory [74], anti-cancerogenic [75,76], and anti-obesity [29,77] properties. Although their exact mechanisms of action are still not fully understood, emerging data suggest their positive influence on human health. The main effect of the action of phenolic compounds is their ability to increase the expression and activity of antioxidant enzymes and inhibit the production of free radicals [31,78]. Moreover, they can modulate cell functions in obesity, especially the number and size of adipocytes (inhibition of adipogenesis), control lipid metabolism and fatty acid oxidation, and inhibit lipid accumulation [78,79]. Due to the large number of different polyphenols compounds, in this review, we describe resveratrol, curcumin (CUR), and catechins in the context of the attenuation of obesity-induced inflammation.

Resveratrol
Resveratrol, 3,4′,5-trihydroxystilbene, is a non-flavonoid polyphenol compound found in grapes (mainly grape skin), red wine, peanuts, and some berries (blueberries and cranberries). Plants synthesize RSVL in response to severe conditions, that is, UV irradiation, fungal infections, or injuries [80]. There are two isometric forms of RSVL: trans, primarily in grape skin and grape juice, and cis in red wine. Although both forms have high biological activity and similar antioxidant properties, the main object of interest is trans-RSVL due to the unstable form of the cis configuration [81]. Importantly, although RSVL is well absorbed by the human digestive system, its bioavailability is relatively low because of its rapid metabolism and excretion [82]. The concentration of RSVL (both resveratrol and its metabolites) 30 min after its oral administration (25 mg/70 kg men) varies between 416 and 471 μg/L and depends on the source of RSVL (vegetable

Resveratrol
Resveratrol, 3,4 ,5-trihydroxystilbene, is a non-flavonoid polyphenol compound found in grapes (mainly grape skin), red wine, peanuts, and some berries (blueberries and cranberries). Plants synthesize RSVL in response to severe conditions, that is, UV irradiation, fungal infections, or injuries [80]. There are two isometric forms of RSVL: trans, primarily in grape skin and grape juice, and cis in red wine. Although both forms have high biological activity and similar antioxidant properties, the main object of interest is trans-RSVL due to the unstable form of the cis configuration [81]. Importantly, although RSVL is well absorbed by the human digestive system, its bioavailability is relatively low because of its rapid metabolism and excretion [82]. The concentration of RSVL (both resveratrol and its metabolites) 30 min after its oral administration (25 mg/70 kg men) varies between 416 and 471 µg/L and depends on the source of RSVL (vegetable juice, grape juice, red wine) [83]. The content of RSVL in red wine (2-12.6 mg/L) is higher than in grapes (0.24-1.25 mg/cup/160 g) or grape juice (1.14-8.69 mg/L), which results from the fermentation of grape skin used to produce wine. Nevertheless, it has been suggested that eating grapes and/or drinking grape juice is sufficient for RSVL intake without consuming alcohol [82,84,85].
RSVL shows antioxidant and anti-inflammatory activity and has beneficial effects in preventing and treating metabolic disorders such as obesity [86]. Studies conducted on cell cultures (especially AT culture models-3T3-L1 adipocytes) showed that RSVL might inhibit adipogenesis by reducing the expression of PPAR-γ through ubiquitin-dependent proteasome degradation [87,88]. It also prevents lipid (triglyceride) accumulation due to an increase in the liver's expression of sirtuin 1 (SIRT 1), a molecule regulating energy metabolism and mitochondrial homeostasis in cells [89]. RSVL decreases lipogenesis in adipocytes through the downregulation of lipogenic genes, such as lipoprotein lipase (LPL), sterol regulatory element-binding protein-1c (SREBP1c), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD1) [88,90]. Activated by resveratrol, AMP-activated protein kinase (AMPK) phosphorylates and blocks acetyl-CoA carboxylase, which results in a decrease in the synthesis of malonyl-CoA, a stimulator of lipogenesis [91]. Cell culture studies also showed that RSVL increases lipolytic activity in human [92] and rat [93] adipocytes via an increase in cyclic adenosine monophosphate (cAMP) levels. It has been pointed out that this effect was potentiated when RSVL administration was combined with genistein [94]. Thus, it seems that RSVL may enhance fatty acid β-oxidation, mitochondrial biogenesis, and their activity [95].
Animal studies also indicated the potential positive effect of RSVL administration on reducing AT inflammation. These studies were based mainly on diet-induced obese animal models. The results from different studies indicate that RSVL administration not only attenuates obesity-induced chronic inflammation (i.a. by attenuating the expression of proinflammatory molecules, such as IL-6, TNF-α, or interferon (IFN-γ and IFN-β)) [99,100] and inhibits OS (i.a. by decreasing malondialdehyde (MDA) and glutathione disulfide (GSSG) levels) [101] but also enhances the antioxidant capacity (i.a. by increasing the activity of liver SOD or catalase) [99,101]. Kim et al. confirmed the anti-inflammatory effect of RSVL in vitro in an experimental AT mouse model. In this study, RSVL attenuated high-fat-dietinduced (HFD) inflammation in mouse WAT by inhibiting the levels of proinflammatory cytokines (such as TNF-α and IL-6) and their upstream signaling molecules (such as NF-κB; Table 1) [100]. The analyzed compound may also reduce macrophage infiltration into AT in Zucker rats [92], as well as lead to a decrease in the proinflammatory M1 phenotype (CD11cþ) together with an increase in M2 polarity (CD206þ) in the WAT of sleep apnea mice [102]. In research conducted on primates, high-fat, high-sugar (HFHS) diet-fed adult rhesus monkeys showed that RSVL supplementation decreases adipocyte size and the mRNA levels of IL-6, TNF-α, and IL-1β; increases SIRT1 expression; inhibits NF-κB activation; and improves insulin sensitivity in the VAT of animals (Table 1) [103].
Clinical studies indicated that RSVL intake might positively affect obesity-induced inflammation. A systematic review and meta-analysis of randomized controlled trials (RCT = 24) conducted by Tabrizi  among patients with metabolic syndrome, with no changes in Il-6 and SOD concentrations [104]. Similar results were provided by another meta-analysis of seventeen studies (n = 736), which showed significant reductions in the levels of TNF-α (weighted mean difference (WMD), −0.44; 95% CI, −0.71 to −0.164; p = 0.002; Q statistic = 21.60; I2 = 49.1%; p = 0.02) and hs-CRP (WMD, −0.27; 95% CI, −0.5 to −0.02; p = 0.033; Q statistic = 26.95; I2 = 51.8%; p = 0.013) after RSVL supplementation [105]. More observational studies evaluated the anti-obesity effect of RSVL not only due to its anti-inflammatory properties but also due to other pathways. In a randomized, double-blind crossover study, the authors observed that 150 mg of RSVL per day induced metabolic changes (i.a. increased energy expenditure and decreased AT lipolysis and plasma fatty acids) in obese humans, mimicking the effects of calorie restriction (Table 1) [106]. Other authors reported that 30 days of RSVL treatment (150 mg/day) significantly decreased adipocyte size and improved AT function in obese men [107].
To sum up, the potential anti-obesity mechanisms of resveratrol include the inhibition of preadipocyte differentiation, a reduction in adipocyte proliferation, and the induction of adipocyte apoptosis. Moreover, RSVL decreases lipogenesis, enhances lipolysis and fatty acid β-oxidation, and limits AT inflammation ( Figure 3) [81,85,108]. Table 1. Polyphenols and their effects on inflammation in obesity (results from selected in vitro, animal, and human studies).

Curcumin
Curcumin (CUR) is a bioactive non-flavonoid compound extracted from turmeric (Curcuma longa). The latter is a spice widely consumed in India and other Asian countries. The nutritional value of 100 g of turmeric represents around 354 kcal, 8 g of protein, 19 g of fats (with no cholesterol), 65 g of carbohydrates (including 21 g of fiber and 3 g of sugar), and minerals such as sodium (38 mg) and potassium (about 2.5 g) [123]. The beneficial health effects of turmeric are associated with curcuminoids, a group of chemically related low-molecular-weight polyphenols containing around 77% CUR, 17% demethoxycurcumin, and 3% bidemethoxycurcumin [124]. Moreover, it was indicated that turmeric contains more than 100 bioactive compounds [125]. Curcumin, the most studied turmeric component, is characterized by good tolerance (even at dosages of up to 12 g/day with no side effects) by humans [126]. It is estimated that the average intake of turmeric is 2 g/day (among adult Indians), which corresponds to 200 mg of CUR [127]. Curcumin is weakly absorbed in the intestines, although other natural phytochemicals, such as piperine, increase its bioavailability [128]. Antioxidants 2023, 12, x FOR PEER REVIEW 9 of 32  Curcumin has well-documented anti-inflammatory, antioxidant, anti-obesity, antiangiogenic, and anti-carcinogenic activities [129,130]. CUR plays an important role in regulating enzymes, cytokines, kinases, receptors, growth factors, transcription factors, and metastatic and apoptotic molecules in different phases of the development of many diseases, such as obesity [131].
Ejaz et al. examined CUR's in vitro and in vivo effects on 3T3-L1 adipocytes and HF mice on a diet supplemented with a 500 mg CUR/kg diet for 12 weeks. In vitro, CUR (5-20 µmol/L) suppressed 3T3-L1 differentiation by suppressing the phosphorylation of mitogen-activated protein kinases (mitogen-activated protein kinases (MAPKs), ERK, c-Jun N-terminal kinases, and p38 MAPKs), caused apoptosis, and inhibited adipokine-induced angiogenesis. For HF mice, supplementation with CUR did not affect food intake, reduced body weight gain and adiposity, and decreased the expression of vascular endothelial growth factor (VEGF) and its receptor. Moreover, CUR decreased the serum cholesterol level and inhibited the expression of PPAR-γ and CCAAT/enhancer-binding protein, which are critical transcription factors involved in adipogenesis and lipogenesis [132]. In another study conducted with the use of 3T3-L1-derived adipocytes (with or without TNFα stimulation), CUR and RSVL treatment reduced NF-κB activation, as well as caused a reduction in IL-1β, IL-6, TNF-α, and cyclooxygenase 2 (COX-2) gene expression (inhibitory concentration-IC50 = 2 muM). Moreover, the study showed a reduction in secreted IL-6 and PGE2 (IC50 = 20 muM), key mediators of the inflammatory response (Table 1) [112].
Weisberg et al. found that CUR ameliorated diabetes by improving glucose and insulin tolerance and hemoglobin A1c (HbA1c) values in HF-diet-induced obese (n = 5) and leptindeficient ob/ob male C57BL/6J mice (n = 5). CUR treatment (3% by weight of admixture of CUR) significantly reduced macrophage infiltration in WAT, increased adiponectin production, and reduced NF-κB activity, as well as the concentration of markers of hepatic inflammation (i.a. MCP-1; Table 1). The authors also indicated that mice from CUR groups (vs. controls) consumed significantly more daily food, representing a lower body weight and body adipose tissue [113]. Other authors indicated that CUR significantly decreased body weight/fat gain, glucose disposal, and IR development in HFD mice. In addition, CUR blocks the effects of HFD on macrophage infiltration and the inflammatory and oxidative pathways in AT and attenuates lipogenic gene expression in the liver (Table 1) [114].
CUR attenuates obesity-associated inflammation by inhibiting the activation of NF-κB, a key proinflammatory transcription factor. Its downregulation reduces the expression of molecules such as TNF-α, MCP-1, and IL-1, thus limiting the infiltration of macrophages into adipose tissue ( Figure 3) [134,137]. These findings provide evidence for the antiinflammatory effects of CUR supplementation and support further studies to confirm the dose, duration, and formulation to optimize its anti-inflammatory effects in obese humans with chronic inflammation.
The anti-inflammatory potential of green tea catechins (GTCs) in obesity management has been shown in cell culture, animal, and human studies. In obese states, GTCs inhibit preadipocyte differentiation and decrease adipocyte proliferation. Moreover, they induce adipocyte apoptosis, suppress lipogenesis, and promote fatty acid oxidation [141]. It is worth adding that the potential mechanism by which EGCG acts as an antioxidant is the scavenging of reactive oxygen species, leading to the attenuation of NF-κB activity. It also controls other redox-sensitive transcription factors, such as Nrf2 and AP-1 [142]. As a result, GTCs decrease the concentrations of inflammatory biomarkers and OS in obese subjects ( Figure 3) [81].
Several clinical studies have shown that green tea consumption affects obesity-induced inflammation in humans. Nonetheless, their results are inconclusive. Bogdański et al. observed that GTC consumption not only improves the metabolic profile (IR, lipid parameters, blood pressure) but also attenuates inflammatory states (by decreasing hs-CRP and TNF-α levels and increasing TAS) in patients with obesity-related hypertension (Table 1) [121]. Additionally, Bagheri et al. showed the positive influence of GTC (500 mg/d) supplementation together with endurance training on hs-CRP [146], as well as hs-CRP and IL-6 [147] values in overweight subjects. On the other hand, not all authors confirmed these results, indicating no effect of GTC intake on inflammatory markers [122,148]. Moreover, meta-analyses also provide ambiguous information. Rasaei et al. [149] analyzed sixteen RCTs, including 760 participants, and the results indicated that GTC supplementation had significant effects on TAC (WMD, 0.20 mmol/L; 95% CI 0.09 to 0.30, I2 = 98.6%, p < 0.001), which were associated with BMI and gender. No relationship between GTC supplementation and MDA has been observed, although a meta-regression analysis showed an inverse association between the dosage and MDA changes (r = −2117.18, p = 0.017). Other results obtained by Serban et al. [150] showed that GTC intake does not have a significant effect on plasma hs-CRP concentrations. Many more results were provided by Asbaghi et al. [151]. After analyzing eight articles with 614 T2DM patients, the authors found that GTC consumption significantly decreased CRP levels (WMD, −5.51 mg/dL, 95% CI −9.18 to −1.83, p = 0.003), with no effect on the plasma concentrations of TAC and MDA (0.02 mg/dL, CI, −0.06 to 0.10, and −0.14 mg/dL, CI, −0.40 to 0.12, respectively).
As mentioned above, there are a few different mechanisms thanks to which GTCs exhibit anti-inflammatory properties. The anti-adipogenic effect of GTCs, especially EGCG, occurs via the activation of AMPK, the main switch in energy metabolism regulation, as well as the attenuation of forkhead box protein O1 (FoxO1) and SREBP1c [152,153]. EGCG seems to increase the expression and phosphorylation of AMPK in adipocytes and the phosphorylation of acetyl CoA carboxylase (ACC), which results in a reduction in fatty acid esterification and, in turn, enhances their oxidation [154]. The anti-inflammatory effects of GTCs also involve their ability to modify the secretion of different adipokines. EGCG suppresses the secretion of resistin, a proinflammatory molecule, via ERK-dependent mechanisms. On the other hand, GTCs inhibit the expression of Krüppel-like factor 7 (KLF7) protein. KLF7 is a factor involved in reducing the expression and production of adiponectin and other adipogenesis-related genes, such as leptin, CCAAT/enhancer-binding protein α (C/EBPα), and PPAR-γ. Thus, its inhibition leads to the modification of the synthesis of the mentioned molecules [85,155]. It seems that further studies are needed, especially with the human population, to evaluate the exact mechanism of action of GTCs against obesity-induced inflammation.

Omega-3 Fatty Acids
Dietary fatty acids play an important role in humans as a main source of energy, elements of cell membranes, precursors of hormones, and immune complexes. Moreover, they protect organs from damage and participate in the absorption of fat-soluble vitamins [156]. Based on their structure, fatty acids can be divided into three categories, that is, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs). PUFAs are classified into two subgroups (according to the position of the first double bond): omega-3 (n-3) and omega-6 (n-6) fatty acids. Omega-3 fatty acids have a carbon-carbon double bond situated three carbons from the methyl end of the chain. Health-promoting properties characterize PUFAs, and they have become valuable food constituents. Special attention is paid to the role of n-3 in attenuating inflammatory processes [157].
Omega-3 fatty acids are represented by α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). The main dietary sources of n-3 are marine fish (mackerel, sardines, mullet, salmon, tuna, trout, bluefish), nuts, and plant oils (rapeseed, linseed oil). While fishes are rich in long-chained EPA (C20:5) and DHA (C22:6), the plant sources of n-3 primarily deliver short-chained ALA (C18:3) [29]. The health benefits of ALA result from its ability to reduce the proinflammatory response, which has been proven in many studies [158][159][160]. These effects may be explained by the fact that, in mammals, ALA is converted to EPA and DHA during metabolic transformation. Thus, EPA and DHA seem to have stronger health protective effects due to their ability to incorporate into membrane lipids and to create precursors of anti-inflammatory lipid indicators, that is, novel specialized pro-resolving mediators (SPMs): resolvins, protectins, and maresins [29].
A large amount of evidence from both in vitro and in vivo studies indicates that n-3 significantly affects the different mechanisms responsible for the inflammatory response. In an in vitro co-culture model of murine 3T3-L1 adipocytes and RAW 264.7 macrophages, it was shown that DHA decreased the secretion of MCP1 and IL-6 from adipocytes and attenuated the mRNA expression of M1 polarization markers (iNOS, TNF-α, and NF-κB) while increasing the mRNA expression of IL-10, a solid anti-inflammatory cytokine ( Table 2) [161].
Animal studies showed that EPA supplementation attenuates the inflammatory process by inhibiting cytokine expression (IL-6, TNF-a, MCP-1) in the stromal vascular fraction (SVF) as well as in AT from HFHS-fed mice. Moreover, supplementation with EPA suppresses CLS formation in mouse WAT and alters macrophage phenotypes to M2 (CD206) from M1 (CD11c) in the SVF by decreasing JNK and NF-κB activity [162]. In another study, it was shown that mice supplemented with long-chain n-3 PUFAs incorporated with phospholipids (n-3PL) or triacylglycerols (n-3TG) caused a reduction in proinflammatory processes and decreased the size of adipocytes (Table 2) [163]. It seems that n-3 supplementation prevents inflammation due to mechanisms involving enhanced PPAR-α signaling and diminished NF-κB activation [164].
Clinical studies have indicated that n-3 fatty acids attenuate obesity-associated chronic inflammation in adipose tissue. Itariu et al. showed that treatment with n-3 tended to decrease the expression of proinflammatory markers (such as IL-6) and increase the expression of anti-inflammatory molecules (such as adiponectin) in the subcutaneous adipose tissue (SAT) of severely obese nondiabetic patients (Table 2) [165]. In addition, other human studies showed an inverse association between EPA and DHA status and blood markers of inflammation, such as C-reactive protein [166][167][168] and cytokines [167,168], in obese subjects. On the other hand, some clinical studies could not confirm these results, indicating no effect of n-3 on inflammation [169,170].
Omega-3 fatty acids impart anti-inflammatory activity to adipose tissue through a few pathways (Figure 3). One of them involves attenuating the proinflammatory transcription factor NF-κB by inhibiting the phosphorylation of its inhibitory subunit, that is, IκB [174]. Another involves the activation of the PPAR-γ receptor and a plasma membrane G proteincoupled receptor (GPR120), as well as the inhibition of arachidonic acid-mediated increases in proinflammatory eicosanoids by n-3. These eicosanoids act as ligands for GPR120. Thus, DHA activation of GPR120 reduces NF-κB activity in macrophages [175]. As mentioned above, n-3 fatty acids are recognized as precursors for the synthesis of SPMs (resolvins, protectins, and maresins), which are key examples of inflammation resolution agonists. In the case of n-3 deficiency, the promotion of various diseases with proinflammatory responses is initiated [176]. To sum up, the anti-inflammatory effects of n-3 include the inhibition of the secretion of proinflammatory mediators and a reduction in macrophage migration into AT. Moreover, it has been proven that n-3 intake prevents adipocyte proliferation, inhibits lipogenesis, and increases fatty acid oxidation, which may be considered their indirect anti-inflammatory effects [177]. Table 2. Omega-3 fatty acids and their effect on inflammation in obesity (results from selected in vitro, animal, and human studies).

Probiotics
In the multifactorial pathogenesis of obesity, much attention is paid to the gut microbiota (GM) and its influence on host metabolism [179]. The GM is defined as a complex and dynamic ecosystem of microorganisms inhabiting the gastrointestinal tract, composed of bacteria, fungi, archaea, viruses, and their genomes. The human GM consists of five main bacterial genera, including Firmicutes and Bacteroidetes, which account for about 90% of the total number of bacteria, and Proteobacteria, Actinobacteria, and Verrucomicrobia. Among Firmicutes, the human microbiota is mainly composed of butyrate-producing Eubacterium, Faecalibacterium, and Roseburia, as well as Lactobacillus, Ruminococcus, and Clostridium. Among the Bacteroidetes, there are Bacteroides, Prevotella, and Xylanibacter. In healthy adults, the most prevalent are Eubacterium, Clostridium, Ruminococcus, Lactobacillus, and Bacteroides [180]. However, the GM's composition, diversity, and abundance may vary from person to person depending on many factors, including prenatal factors, age, ethnicity, the environment, medications and supplements taken, and overall lifestyle [180]. Apart from the inter-individual variation, three main GM enterotypes are distinguished depending on the dominant type of microorganisms in the environment: Bacteroides, Prevotella, and Ruminoccocus [181]. The GM is involved in various biological processes, including physiology and/or pathophysiology. It is a key regulator of the host's energy homeostasis, the growth of pathogens, gut epithelial integrity, and immune function [180,182,183].
Previous studies have shown that GM dysbiosis, characterized by an increased Firmicutes-to-Bacteroideses ratio, reduced diversity, and changes in the activity of the GM, is closely linked to a variety of health problems, such as obesity and metabolic syndrome, cardiovascular diseases, and gastrointestinal disorders, as well as a chronic inflammatory disease [184,185]. Therefore, maintaining or restoring the balance of the GM through probiotics seems to be a promising and safe tool in obesity and obesity-related inflammation management.
The World Health Organization defines probiotics as live microorganisms that, when administered in adequate amounts, confer a health benefit to the host [186]. Available scientific studies have proven that interventions based on probiotic supplementation lead to beneficial changes in body weight and body composition, especially reductions in body fat, BMI, and waist circumference [187,188]. Moreover, by remodeling the GM, they are able to improve the cardio-metabolic profile [189]. Probiotics have been proposed as a new promising strategy in obesity treatment, not only because they are substances affecting body weight reduction or the restoration of glucose and lipid homeostasis but also because they positively affect markers of inflammation.
Akkermansia muciniphila is one of the most promising postbiotics in obesity and metabolic disorder treatment [214]. Moreover, its anti-inflammatory properties have also been described. In the study by Wu et al. [215], the colonization of A. muciniphila in a mouse model of immune-mediated liver injury reduced circulating LPS and significantly decreased the levels of proinflammatory cytokines.
In a study by Ashrafian et al. [216], the administration of A. muciniphila and its extracellular vesicles (EVs) positively influenced the intestinal barrier integrity, inflammatory state, fatty acid oxidation, energy homeostasis, and biochemical parameters (glucose and lipid levels) in mice with HFD-induced obesity [216], where the effect of A. muciniphiladerived EVs was greater compared with the bacterium itself. Similarly, in another study, A. muciniphila alleviated weight gain and reduced chronic low-grade inflammation in mice fed a normal chow diet [217]. After five weeks of supplementation, a decrease in the plasma levels of lipopolysaccharide (LPS)-binding protein (LBP) and leptin and the inactivation of LPS/LBP downstream signaling (mediated via decreased JNK phosphorylation and increased expression of IKBA) were described.
In the only clinical study conducted in this field, it was confirmed that A. muciniphila supplementation, apart from a significant effect on weight reduction and improvements in metabolic indicators, has an inflammation-modulating effect [218]. A 3-month supply of pasteurized A. muciniphila decreased LPS levels, enzyme DPP-IV activity, sCD40L levels, and the expression of the chemokine GRO. The positive metabolic effect can be explained by the effect of A. muciniphila on PPAR-α activation by mono-palmitoyl-glycerol [218].
Interventions using multi-strain probiotics, both in animal model studies and in clinical trials, also revealed the promising role of probiotics in enhancing obesity-induced inflammation and OS.
In an animal model study by Wang et al. [219], VSL#3 supplementation prevented weight gain and improved metabolic outcomes in mice with HFD-induced obesity. Additionally, VSL#3 effectively reduced adipose inflammation by restoring visceral adipose iNKT and stimulating iNKT cells to shift from a pre-inflammatory to an anti-inflammatory (IL-4+ iNKT cells) phenotype [219]. A similar immunomodulatory effect of probiotics on iNKT cells was described earlier by Ma et al. [208] in a mouse model of HFD-induced steatosis and insulin resistance. In a randomized, double-blind, placebo-controlled clinical study, the multi-strain probiotic Ecologic ® Barrier influenced TNF-α and IL-6 in a dosedependent manner in postmenopausal women with obesity [220]. Similarly, a three-strain probiotic, including L.salivarius, L. rhamnosus, and BB.animalis, reduced TNF-α and beneficially modulated the proinflammatory adipokines leptin and adiponectin in children with excessive body mass [221]. The selected studies focused on evaluating the effects of probiotic therapy on obesity-induced inflammation are presented in Table 3. Table 3. Supplementation with probiotics and their effects on inflammation in obesity.
Based on the above, probiotic administration seems to be a promising tool for treating obesity and improving obesity-induced chronic low-grade inflammation. As bioactive compounds with the ability to reverse the state of intestinal dysbiosis, probiotics have a positive effect on many different metabolic pathways, including glucose and lipid metabolism, energy homeostasis, antioxidant defense, and the modulation of the immune response via TLR4/NF-κB signaling pathway inhibition (Figure 3) [193]. Their administration reversed gut barrier dysfunction and, in consequence, led to an improvement in metabolic endotoxemia. Previous studies proved that probiotic intake decreased circulating LPS and LBP levels and attenuated local inflammation cascades by influencing nuclear factor-KB (NF-KB) and JNK and downregulating the expression of inflammatory cytokines such as TNF-α and IL-6, chemokines, adipokines, or intestinal inflammatory markers, e.g., zonulin or occludin [217].

Conclusions
Dietary patterns involving natural, bioactive food compound consumption seem to have a promising protective effect against obesity-induced inflammation, with limited harmful side effects. Numerous basic (in vivo and in vitro) as well as clinical studies have shown the relationship between the positive health outcomes of bioactive food compound intake and the attenuation of proinflammatory processes in the adipose tissue. They involve the modulation of the secretion of cytokines, adipokines, and hormones by adipocytes and their ability to regulate gene expression in adipose tissue. Although the exact mechanisms of bioactive food compounds' action still need to be established, targeting the consumption and/or supplementation of food products with anti-inflammatory potential, such as polyphenols, omega-3 fatty acids, and probiotics, may represent a new approach for the prevention and treatment of obesity-induced inflammation, as well as its complications. Nonetheless, more clinical studies are warranted to establish the strategies for bioactive food compound intake. No less important is worldwide education about the advantages of bioactive food compound consumption, especially in the context of the prevention of Western-diet-induced obesity.