In addition to using the whole herb or its extracts, numerous scientific in vitro and clinical trials have confirmed the anti-obesity activities of phytochemicals [33,35,36,37]. The pharmacological mechanisms of the anti-obesity effects of active compounds from pomegranate, citrus fruits, rosemary, black seeds, cumin, ginger, olive leave/oil, turmeric, cinnamon, fenugreek, and garlic have been evaluated through tests on cells, animals, and humans [33,34,35,36,37]. Dietary compounds, medicinal plants, and phytochemicals generated from them were reported to fight obesity by affecting different processes in the body. These include the blocking of pancreatic lipase and glucosidase, the suppression of hunger, the stimulation of thermogenesis and lipid metabolism, and the inhibition of fat breakdown and adipogenesis (Figure 2). Phytochemicals have been found to target fat cells in several ways, including inhibiting fat cell formation, promoting fat breakdown, and reducing energy intake while increasing energy expenditure (Figure 3). These findings come mainly from laboratory and animal studies. However, more high-quality research is needed to confirm the effectiveness of these phytochemicals in humans. Some examples of polyphenols include quercetin, myricetin, diadzein, genistein, cyanidin, luteolin, apigenin, kaempferol, proanthocyanidin, xanthohumol, and epigallocatechin gallate (EGCG). Numerous scientific studies demonstrated that these compounds exhibit weight-reducing and anti-obesity effects [33,35,36,37,38,39] (Figure 2).

Due to their rich content in plant secondary metabolites, including polyphenols and terpenoids, WEPs are prime candidates for use in nutraceuticals or functional foods. The Mediterranean area is renowned for its abundant variety of WEPs that are edible and form a vital component of this diet. Local communities have long acknowledged the nutritional, protective, and medicinal benefits of these plants, even before their advantages were scientifically validated. In the eastern Mediterranean, WEPs continue to be valued as healthy food sources and are often collected by women as a means of subsistence and income generation in rural areas with limited economic opportunities [40,41,42]. The scientific community has recently shown an increased interest in traditional Arab-Islamic herbal medicine, particularly in its potential for treating metabolic and chronic diseases [38,39]. This practice, known as Greco-Arab medicine, remains dominant in the Mediterranean region as well as in many Arab and Islamic countries. According to surveys, the Middle East is home to over 2600 species of plants, of which more than 700 are utilized in treating various ailments. Currently, Arab traditional medicine uses fewer than 200–250 plant species to treat various diseases. Many of these species are WEPs that have been assessed in cell culture, in vivo, and in clinical trials and were found to contain pharmacology active compounds [43]. WEPs have similar effects as medicinal plants. They can modulate appetite, lipase activity, thermogenesis and fat synthesis and degradation, satiation, adipogenesis, and adipocyte apoptosis. Additionally, targeting adipocyte growth and differentiation with diverse medicinal plants/diet is a significant strategy for devising new anti-obesity drugs that can intervene in preadipocytes, maturing preadipocytes, and mature adipocytes.

Many plant extracts from the Mediterranean region and their natural compounds have been tested for their anti-obesity effects in the past ten years [33,34,41]. Specifically, 31 plant species showed the ability to block the pancreatic lipase enzyme. The flavonoid rutin (found in citrus and in a wide range of herbs) and the phenolic acids p-coumaric (found in a wide variety of herbs) and ferulic acids (an antioxidant found in a wide range of plants), which are three bioactive compounds, were found to be successful in blocking this enzyme. It was also shown that trans-anethole and resveratrol, two natural compounds, work by stimulating the brown fat tissue [41].

In addition, wild cranberries can influence fat cell formation, and blueberries have shown a remarkable ability to lower blood lipids. In addition, 28 plants from the Mediterranean region and 21 active substances from them have shown promising effects on sugar metabolism. Many studies have examined how plant extracts and pure substances can block digestive enzymes related to obesity and T2D (α-amylase, α-glucosidase, and pancreatic lipase). For example, the effects of 18 WEPs that people eat in southern Italy’s Calabria region on pancreatic lipase, an enzyme that breaks down fats, were tested in a recent study [44,45]. Nine of the plant extracts could inhibit the enzyme at a concentration of less than 10 mg/mL. The leaves of purslane (Portulaca oleracea) and bladder campion (Silene vulgaris), extracted with water and ethanol, had the strongest inhibition, with 5.48 mg/mL and 6.02 mg/mL needed to block half of the enzyme activity, respectively. Among the plants from the mint family (Lamiaceae), spearmint (Mentha spicata) and rosemary (Rosmarinus officinalis) showed inhibition, with 7.85 mg/mL and 7.00 mg/mL required, respectively. The most effective plants from the sunflower family (Asteraceae) and the cabbage family (Brassicaceae) were common sowthistle (Sonchus oleraceus) (9.75 mg/mL) and perennial wall-rocket (Diplotaxis tenuifolia) (7.76 mg/mL), respectively.

Many phytochemicals can help reduce weight by decreasing the absorption of lipids and inhibiting pancreatic lipase. For example, green tea contains catechins and saponins, such as EGCG, which have this effect. Pomegranate (Punica granatum) contains punicalagin, ellagic acid, and anthocyanins; rosemary has rosmarinic acid and carnosic acid; black seed contain thymoquinone; and soybean contains proteins and isoflavones that can also help with weight reduction [33,35]. However, most of the studies on how plant extracts affect the body were conducted in vitro or on animals. In addition, many new substances and natural products from plants were found to block pancreatic lipase, an enzyme that breaks down fat, better than orlistat, a common drug for weight loss. Some of these extracts have strong effects on fat digestion because of their compounds like polyphenols, saponins, and terpenes. Many natural products that stop pancreatic lipase are being tested on animals or cells, but none of them have been tested on humans yet. Sometimes, it is hard to apply the findings from these tests to clinical use, because they may not work as well in practice. Therefore, the main problem with these studies is that even though many plant chemicals are stronger than orlistat, we do not know how safe they are compared to orlistat.

When energy intake consistently exceeds energy expenditure, the excess energy is mostly stored as triglycerides in fat tissue. An increase in adipose tissue mass can result from an increase in cell size, cell number, or both. The cellular pathways that control the growth of pre-adipose cells, adipose differentiation, and lipogenesis in adipocytes were thoroughly investigated [1,3,4] (Figure 4). Recently, the differentiation of pre-adipocytes has garnered research attention and has been investigated through in vitro adipogenesis models, including the 3T3-L1 cell line [46,47,48,49]. Many published reports focused on the effects of medicinal plants and their active compounds on adipocyte life cycle. Curcumin (from turmeric), oleuropein (from olive oil), thymoquinone (from black seeds), rosmarinic acid (from rosemary), resveratrol (from grapes), punicalagin (from pomegranate), coumestrol (from soybeans), quercetin (found in many fruits, flowers, and vegetables), Luteolin (found in many fruits, vegetables, and medicinal herbs), and fisetin (found in many fruits and vegetables such as strawberry, apple, and onion) were reported to affect the adipogenesis (Figure 3).

Our bodies maintain an equilibrium of body mass, specifically body lipids, through the coordinated functioning of the autonomic, nervous, endocrine, and metabolic systems. This equilibrium is based on an ‘ideal’ level determined by the central nervous system weight loss. This system can cause 80% of the weight to be regained. Brown adipose tissue plays a key role in energy expenditure by generating heat through thermogenesis. This process is regulated by a metabolic pathway involving the hormone leptin and the protein PGC-1𝛼. This pathway is responsible for burning fat and generating heat, but it can also make it difficult to sustain weight loss due to opposition from the body’s equilibrium. Thermogenesis is a process that mainly takes place in brown adipose tissue but also in beige cells located in white adipose tissue. This process, which is beneficial for preventing obesity, has been shown to be accelerated by capsaicin, caffeine, ephedrine, resveratrol, EGCG, gingerol, and oleuropein. It has been proposed that these compounds could be used to treat obesity and being overweight. For example, caffeine produces thermogenic effects by preventing the degradation of cAMP caused by phosphodiesterase. Caffeine has been shown to decrease food intake and lipid storage. Human studies have also demonstrated that capsaicin, (an active component of chili peppers) and EGCG can increase thermogenesis. Capsaicin treatment stimulates the secretion of catecholamines from the adrenal medulla in a dose-dependent manner, resulting in a thermogenic effect. EGCG increases thermogenesis by inhibiting catechol methyl-transferase, an enzyme responsible for the degradation of norepinephrine [33,41].

The main ingredients of the Mediterranean diet (MedDiet) are among the most researched dietary components for treating and preventing various metabolic disorders and CVD. They are recognized for decreasing the risk of CVD, hypertension, T2D, being overweight/obesity, breast and colon cancers, asthma, and mental decline [33,34,50]. The MedDiet, which is rich in antioxidants and has anti-inflammatory, hypotensive, and hypolipidemic properties, is a great alternative to a diet high in red meat for reducing the risk of CVD. Its positive effects are similar to those of standard drugs such as beta-blockers, aspirin, and angiotensin-converting enzyme inhibitors [50,51,52,53,54,55,56]. However, it is not yet clear whether these benefits come from individual components of the diet or their combined and synergistic effects [50,51,52,53].

There is a lot of evidence that shows a lower risk of mortality from CVD, T2D, specific types of cancer, and cognitive problems when following a MedDiet [53,54]. A comprehensive review of 27 meta-analyses based on 70 cohort studies found 34 different ways to measure the MedDiet [57]. There are various ways to evaluate the MedDiet [58,59], and all of them involve the common food groups that define this dietary pattern. These include a high intake of fruits, vegetables, nuts, legumes, fish, whole grain cereals, and extra virgin olive oil; a moderate consumption of alcohol, preferably red wine; and a low consumption of dairy products, red meat, and processed meat.

Recent meta-analyses of observational studies have consistently shown that following a MedDiet is associated with positive health outcomes [60,61,62]. Critical reviews of both observational studies and RCTs have also confirmed the health benefits of this diet [63,64,65,66]. A recent Cochrane review concluded that the evidence supporting the effectiveness of the MedDiet in preventing CVD is only of low to moderate certainty. A recent Cochrane review concluded that the evidence supporting the effectiveness of the MedDiet in preventing CVD is only of low to moderate certainty [63]. Nutrition research RCTs are often limited by factors such as small sample sizes, high dropout rates, and short follow-up periods, whereas larger samples, lower dropout rates, and longer follow-up periods are needed to observe patient-relevant outcomes [64]. Some discrepancies may arise from the use of varying definitions of the dietary pattern being studied. Inconsistencies may also result from differences in the diets being compared.

The health benefits of the MedDiet may be attributed to its impact on the composition and metabolism of the gut microbiota. A systematic review was recently conducted to investigate the effects of this diet on the gut microbiota, as observed in both observational studies and randomized controlled trials. While some research has indicated that a MedDiet may have a positive effect on certain microbiota, a systematic review found that this diet did not consistently alter the composition or metabolism of the microbiota. This inconsistency may be attributed to variations in methodology among studies, particularly in the composition of the MedDiet [65].

A recent long-term RCT (CORDIOPREV study) from Córdoba, Spain, with a 7-year follow-up, compared the effects of the Mediterranean and low-fat diets on the secondary prevention of CVD based on cardiovascular outcomes in patients with coronary heart disease [66]. The study involved 1002 patients, with 500 assigned to a low-fat diet group and 502 to a MedDiet group. The primary outcome was a composite of major cardiovascular events, including myocardial infarction, revascularization, ischaemic stroke, peripheral artery disease, and cardiovascular death. The primary endpoint occurred in 198 participants: 87 in the MedDiet group and 111 in the low-fat group. Multivariable-adjusted hazard ratios of the different models ranged from 0.719 to 0.753 in favor of the MedDiet. These effects were more evident in men, with primary endpoints occurring in 16.2% of the men in the MedDiet group versus 22.8% of the men in the low-fat diet group. These data suggest that, in terms of preventing major cardiovascular events in secondary prevention, the MedDiet was more effective than a low-fat diet [66].

6. Anti-Obesity Effects of MedDiet Polyphenols and Their Possible Mechanisms of Action