Curcuma longa rhizomes (Turmeric) have a long history of use as a health-promoting agent [21,22,24,46,47,48,49]. The roots of turmeric have been known for their health values for hundreds of years in Ayurveda, Chinese, and Greco-Arab and Islamic medicine [50,51]. Over 800 scientific reports and more than 100 clinical trials have investigated the cellular, molecular, and pharmacological effects of curcumin. Many of these reports emphasize the potential benefits of curcumin in the treatment of chronic diseases such as cardiovascular disease, T2D, overweight/obesity, cancer, autoimmune diseases, neurological and mental disorders [39,40,41,42,46]. Most published reports have linked the benefits of turmeric to its antioxidant and anti-inflammatory properties [52].

Curcumin, the major polyphenol from turmeric, has been reported to promote weight loss and reduce the incidence of obesity-related diseases [41,42,43]. Curcumin intake reduces levels of TNF-α and IL-6 and increases the level of adiponectin in the plasma of obese and overweight individuals. In addition, curcumin regulates a number of biochemical and molecular targets, including transcription factors (NF-kB, NLP3), signaling pathways, and other complex regulatory systems, resulting in attenuation of the chronic low-grade inflammatory response in adipose tissue.

Several clinical studies have shown that the interaction of curcumin with transcription factors, cellular receptors, growth factors, enzymes, cytokines, and chemokines reduces inflammation in obese individuals by restoring the balance between pro-inflammatory and anti-inflammatory mediators [53,54]. Several published studies clearly indicate that curcumin significantly decreases pro-inflammatory cytokine levels and increases plasma adiponectin levels in obese and overweight individuals. Furthermore, curcumin can affect multiple molecular targets, including transcription factors (NF-kB, NLP3), signaling pathways, and other complex regulatory systems in adipose tissue, resulting in the attenuation of chronic low-grade inflammatory response. In addition, there are some reports suggesting that curcumin enhances the effect of diet and lifestyle intervention in overweight/obese people with metabolic syndrome [55,56]. However, the poor bioavailability of curcumin poses a problem for its use. To increase the bioavailability of curcumin, various delivery systems, such as micelles, liposomes, phospholipid complexes, nanostructured lipid carriers, and biopolymer nanoparticles have been developed [38,41,42,43,57,58,59]. The future of curcumin as an approved option for the prevention or treatment of obesity and its associated low-grade inflammation and other complications depends on the results of high-quality and large cohort studies in the future. However, based on current knowledge, curcumin has a good safety profile and is well tolerated. This low toxicity may be due to the low bioavailability, therefore, an increase of biodisponibility must be carried out cautiously.

Camellia sinensis (Tea leaves) are the source of white, green, and black tea. Several observational clinical trials have shown that the consumption of tea or green tea has a beneficial effect against obesity. The effects observed in these studies are low, so statistical confirmation is especially difficult in rather healthy people. For example, a cross-sectional study of 1210 adults showed that regular tea drinkers for more than 10 years showed a 19.6% reduction in body fat percentage and a 2.1% reduction in waist-to-hip ratios when compared with irregular tea drinkers [60]. Recent results from a clinical trial of 6472 adults showed that tea consumers had a lower average waist circumference and body mass index (BMI) than non-consumers [61]. However, a more recent study of 3539 participants showed that green tea was not associated with visceral obesity or metabolic syndrome [62]. Therefore, further studies are needed to clarify the anti-obesity properties of green tea.

Epigallocatechin-3-gallate (EGCG), derived from green tea, and theaflavins, derived from black tea, are the best-studied active compounds from tea. EGCG, the main polyphenolic compound in green tea, has a number of health-promoting effects. These include anti-inflammatory, antioxidant, anti-obesity, anti-cancer, and anti-diabetic properties. The anti-inflammatory effects of EGCG, such as attenuating the secretion of resistin from adipocytes, are exerted through the ERK-dependent pathway. EGCG-enhanced production of adiponectin is mediated, at least in part, by inhibition of the protein Krueppel-like factor 7 (KLF7), which downregulates the expression of genes controlling adipogenesis [46,63,64,65,66,67,68,69,70,71]. EGCG also reduced inflammation and oxidative stress associated with aging in high-fat diet-induced rats. EGCG significantly reduced systemic levels of IL-6, tumor necrosis factor-α (TNF)-α, ROS, and superoxide dismutase (SOD). EGCG also increased the expression of sirtuin-1 (SIRT1), catalase, fatty acid-binding protein-1, glutathione S-transferase (GST)-A2, and acyl-CoA synthetase-1, but significantly decreased the expression of nuclear factor (NF)-κB, ACC -1, and FASN in the liver [72].

A fat-soluble alkaloid, extracted from Capsicum (hot pepper) fruits is the major bioactive compound in red chili peppers. It is a pungent molecule that affects thermoregulation, triggers autonomic reflexes, and is well absorbed [73]. Capsaicin is in the pipeline for phase III clinical trials as a treatment option for rheumatoid arthritis, postoperative pain, and chronic neuropathic and musculoskeletal pain [73]. In recent decades, the pharmacological benefits of capsaicin and its underlying mechanisms have been extensively studied. The main beneficial medicinal properties of capsaicin include analgesic, antioxidant, anti-inflammatory, anti-cancer, anti-obesity, cardio-protective, and metabolic modulatory effects [74,75,76,77]. Capsaicin binds to Transient Receptor Potential Channel Vanilloid type-1 (TRPV1) [10,11], a transmembrane ion channel [78]. TRPV1 is expressed in many cell types and tissues, including nerve fibers, trigeminal ganglia, testis, adipocytes, smooth muscle cells, endothelial cells, pancreatic β-cells, liver, heart, skeletal muscle, and kidneys [79]. Selective silencing of TRPV1 by specific RNA interference reduced the effect of capsaicin on calcium influx and inhibition of adipogenesis in 3T3-L1 adipocytes [80].

Several metabolic studies have shown that capsaicin is a potent anti-inflammatory substance [81,82,83] that could attenuate metabolic inflammatory conditions such as obesity, T2DM, osteoarthritis, and non-alcoholic fatty liver disease. Capsaicin has been shown to attenuate (via blocking NF-κB, which is likely mediated by PPARγ activation) the expression and secretion of MCP-1 and IL -6 from adipose tissue of mice and to increase the production of adiponectin. It has also been shown that capsaicin administration in vivo improves obesity-induced insulin resistance [46,74,75,76,77]. Moreover, in healthy rats, capsaicin decreased oxidative stress measured by malondialdehyde and diene conjugation in tissues [84]. Capsaicin prevented lipid peroxidation and carbonyl formation in proteins in human erythrocytes subjected to oxidative stress [85].

An herbaceous perennial plant of the family Zingiberaceae, it is one of the most famous medicinal herbs in traditional Greco-Arab and Islamic medicine, Ayurveda, and Chinese medicine for centuries. It is reported to have several health-promoting properties. These include antiulcer, anti-inflammatory, antioxidant, antiplatelet, anti-diabetes, anti-obesity, anti-hyperlipidemia, as well as cardiovascular and anti-cancer activities. The anti-obesity activities of ginger are most likely due to the highly significant inhibitory action of ginger on the absorption of dietary fats by reducing pancreatic lipase activity. Ginger contains active compounds such as gingerol, paradol, and 6-shogaol responsible for the anti-inflammatory effects of ginger. 6-shogaol elevates adiponectin production and inhibits the TNF-α-induced downregulation of adiponectin production in adipocytes, most likely by upregulating PPARγ activity. As for 6-shogaol, 6-gingerol inhibits TNF-α-mediated inhibition of adiponectin in adipocytes; however, the pathways of their inhibitory effects are different; 6-gingerol inhibits JNK signaling pathways in TNF-α-induced adipocytes without affecting PPARγ transactivation, whereas the anti-inflammatory effects of 6-shogaol is PPARγ-dependent [4,16,27,86].

Systematic review and meta-analysis of 16 randomized controlled trials RCTs comprising 1010 participants provide convincing evidence for a significant effect of ginger in lowering circulating C-reactive protein (CRP), high sensitivity C-reactive protein (hs-CRP), and TNF-α levels. Large-scale RCTs are still needed to draw concrete conclusions about the effect of ginger on other inflammatory mediators [87].

Nigella sativa (Black seeds), also called black cumin or black seed, is famous for its culinary uses and was historically valuable in traditional Greco-Arab and Islamic medicine and other traditional medicines. Prophet Muhammad (PBUH) (570–632 AD) said, “Black seed can cure any disease except death.” Avicenna (980–1037 AD) mentioned black seed in his canon of medicine as “the seed that stimulates the energy of the body and promotes recovery from fatigue and dejection” [4,16,88,89,90]. Numerous scientific papers have been published addressing the safety and efficacy of black seed and thymoquinone (the main active ingredient). A “Medline” and “Google Scholar” search with “black seed”/“Nigella sativa” or “thymoquinone” yields more than 1100 publications.

Nigella sativa exhibits pleiotropic pharmacological activity and a wide range of health-promoting effects (Figure 2). Both the seeds and their major bioactive constituent thymoquinone have been found to exert significant antioxidant, anti-inflammatory, immune enhancing, cell survival improving, and energy metabolism promoting effects underlying various health benefits. These include protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological diseases, T2DM, obesity, hypotension, allergies, antimicrobial effects, and cancer [24,25]. Despite significant advances in pharmacological benefits, these black seeds and their active compounds are still far from the clinical application [91].

Black seed and thymoquinone attenuate the obesity-related low-grade inflammation through activation of natural killer cells proliferation and differentiation, monocyte activities, T-cell based immunity, as well as stimulation macrophage activity. For example, black seed significantly attenuates nitric oxide production and serum levels of pro-inflammatory cytokines and mediators, including IL-4, IL-5, IL-6, IgE, IgG1, and OVA-specific IgG1 ovalbumin-treated rats. Rats treated with black seed experienced a reduced T-cell response and attenuated T-cell proliferation in the spleen without histopathological changes in lung tissue. Control, untreated rats exhibited a thickening of the alveolar wall and increased numbers of goblet cells. These data suggest that black seed inhibits Th-2-induced T-cell proliferation and differentiation, thereby halting the inflammatory response [92,93,94]. Pretreatment with thymoquinone attenuated Th-2-cell mediated lung inflammation, lung eosinophilia, and goblet cell hyperplasia. Furthermore, thymoquinone downregulated COX-2 expression, PGD2 production, and a slight inhibition in COX-1 expression and PGE2 production in rats. COX-2 mediates the inducible inflammatory response by converting arachidonic acid to prostaglandins (a pro-inflammatory cytokine), whereas COX-1 mediates constitutive or “housekeeping” inflammation. Long-term elevated COX-2 activity is recognized as an underlying cause of many chronic inflammatory disorders, thus, inhibition of COX-2 is favorable in cases of chronic inflammatory conditions. Black seeds and thymoquinone exert their anti-inflammatory effects primarily via downregulation of COX-2 and PGD2 production [88,89,90].

Nigella sativa oil reduced the levels of IL-6 and IL-1β in human pre-adipocytes [92]. Treatment with Nigella sativa oil (400 mg/kg) in rats with carrageenan-induced paw edema, improved the pro-inflammatory cytokines IL-6, IL-12, and TNF-α in paw exudates and sera [93,94]. Furthermore, topical application of balm stick containing 10% Nigella sativa oil in rats with paw edema markedly alleviated acute and sub-acute inflammation with a significant edema reduction, with a 43% lower leucocytes count and 50% lower TNF-α level compared to control on the inflammation area [95].

Overall, the evidence supports the anti-inflammatory potentials of black seeds and thymoquinone, however, most of the studies so far have been conducted in animal models. Future clinical trials should focus on determining the anti-inflammatory potential in ameliorating human diseases

Punica granatum (pomegranate) has long been used in major traditional medicine systems to promote health and treat many diseases. In recent decades, a large number of scientific papers have been published on the health-promoting effects of pomegranate. These include antioxidant, anti-inflammatory, cardiovascular, anti-obesity, anti-diabetic, and anti-cancer effects (Figure 3).

Pomegranate fruits and other aerial parts of the plant contain several bioactive molecules. These include phenolic acids, hydrolyzable tannins, condensed tannins, and flavonoids, as well as other types of bioactive constituents responsible for the observed antimicrobial, anti-cancer, antioxidant, and anti-inflammatory activities. Pomegranate-derived punicalagin isomer, ellagic acid, and anthocyanins are known for their antioxidant properties and reduction of lipid oxidation. Pomegranate extracts and juice are also effective in stimulating vascular endothelial NO synthase and plasma NO levels, suggesting clinical application in metabolic syndrome [4,16,24,25,96].

As mentioned earlier, obesity is associated with elevated levels of adipocyte-derived pro-inflammatory cytokines such as TNF-a and IL-6, which affect metabolism in several ways. Pomegranate affects adipocyte-specific gene expression, triacylglycerol release, lipoprotein lipase downregulation, and insulin sensitivity [96,97,98,99]. Pomegranate active compounds have been shown to reduce the secretion of IL-6, thereby reducing the complications associated with obesity. Thus, in vitro experiments reported that pomegranate seed oil (PSO) decreased the activities of cyclooxygenase and lipoxygenase. The activity of cyclooxygenase, a key enzyme in the conversion of arachidonic acid to prostaglandins (important mediators of inflammation), was reduced to 60% by PSO. Lipoxygenase, which catalyzes the conversion of arachidonic acid to leukotrienes, also important mediators of inflammation, was inhibited by PSO by 75% compared to controls [96]. The effects of pomegranate extract consumption on plasma inflammation, oxidative stress biomarkers, and serum metabolic profiles were investigated in a randomized, double-blind, placebo-controlled clinical trial in overweight and obese subjects. In this study, 48 overweight and obese participants were randomized to receive either 1 g of pomegranate extract or placebo, daily for 30 days. Ingestion of pomegranate extract resulted in significant reductions in mean serum levels of glucose, insulin, total cholesterol, LDL-C, plasma malondialdehyde (biomarker of oxidative stress), and IL-6. These results suggest that the consumption of pomegranate extract may reduce the complications associated with obesity [95,96,97,98,99].

A systematic review of 20 clinical trials suggests that pomegranate and its active ingredients lower BMI, hypertension, blood glucose levels, triglycerides, total cholesterol, and LDL. It may also increase HDL levels and improve insulin resistance. Although relevant effects have been observed, further well-designed clinical studies are needed to determine the proper formulations and dosages that can be used to prevent or treat metabolic syndrome components [100].

Regarding the anti-inflammatory effects of pomegranate, a recent review article considered 16 randomized controlled trials (RCTs) involving 572 subjects [101]. Pomegranate intake significantly lowered levels of hs-CRP, IL-6, and TNF-α compared with placebo. No significant reduction was observed in CRP, E-selectin, ICAM, VCAM, or MDA compared to placebo [101].

Grapes, peanuts, and many berries contain resveratrol, a nonflavonoid that belongs to the stilbene group. Resveratrol is a promising phytochemical that can be easily incorporated into the diet to combat adipose tissue inflammation and other obesity-related metabolic diseases. There are several lines of evidence that resveratrol has antiadipogenic effects (Figure 4). In vitro studies show that resveratrol stimulates apoptosis in mature adipocytes and targets triacylglycerol metabolism at WAT. These effects appear to be mediated by the attenuation of fatty acid uptake and lipogenesis in adipose tissue. In addition, the increase in BAT thermogenesis and associated energy depletion may help explain the body fat-lowering effects of resveratrol. However, a meta-analysis of 19 clinical trials found that only three studies showed any type of beneficial effect. The meta-analysis found no significant effect on weight or BMI. A small effect was found on waist circumference [102].

Resveratrol is a potent anti-inflammatory phytochemical that attenuates the activity of NF-κB and ERK. In mouse adipose tissue, resveratrol attenuated the production of TNF-α, interferon α, and (IFNα and IFNβ), and IL -6 and their upstream signaling molecules, including TLR 2/4 triggered by a high-fat diet, Toll IL-1 receptor (TIR) domain-containing adaptor protein (TIRAP), TIR domain-containing adapter-inducing interferon (TRIF), TNF receptor-associated factor 6 (TRAF6), interferon regulatory factor 5 (IRF5), p-IRF3, and NF-κB. In addition, improvement of insulin sensitivity and attenuation of inflammation by resveratrol are mediated via inhibition of adipokine production (e.g., resistin and retinol-binding protein 4), attenuation of oxidative stress, and stimulation of Akt-mediated insulin signaling [26,27,46,103,104].

A systematic review of 17 RCTs involving 736 subjects found significant reductions in TNF-α and hs-CRP levels after resveratrol supplementation. Resveratrol supplementation had no significant effect on the levels of IL-6. Statistically, significant heterogeneity was observed in relation to the type of sample IL-6 and study duration for the inflammatory markers IL-6, TNF-α, and hs-CRP [105].