**2. Food sources and therapeutic potential**

Several herbs and foods have been used medicinally for centuries, although mechanism of action was not known and in some cases remains unclear. Many of the compounds found in common herbs and foods have been discovered to be ligands of the nuclear receptors such as PPARγ. A variety of studies presented summarize the compound identified to harbor therapeutic potential as a PPARγ ligand resulting in partial activation of the transcription factor and expression of a variety of metabolic and growth genes. Many of these compounds are found in overlapping herbs or spices. For example, cinnamon contains numerous compounds that are demonstrated ligands including: 2-hydroxychalcone, cinnamaldehyde, catechin, eugenol, ethylcinnamate, epicatechin, and cinnaminc acid. As expected, cinnamon has been used medicinally to treat digestive disorders and metabolic problems for decades.

Given the large number of compounds that function as PPARγ ligands, detailed discussion of each is warranted, but an overall summary is also important. **Table 1** identifies several of the compounds of interest, their food sources and conveniently lists references that pertain to the studies. Apigenin acts as a partial agonist for PPARγ, inducing an effect of agonism in the absence of a full agonist, and antagonism in the presence of a full agonist. This is due to the low binding affinity that apigenin has for PPARγ itself [6, 39]. However, even with this low binding affinity, it has shown to still produce beneficial effects through this pathway. Due to its interactions with PPARγ, apigenin has anti-inflammatory effects, and has been used for treatment of colitis, or inflammation of the intestines. However, beyond its interactions with PPARγ, apigenin has also been shown to decrease food-intake, and help with weight loss [39]. Apigenin has a lot of potential clinical use and application, and can be found in marjoram, sage, thyme, holy basil, parsley, and alfalfa [6, 39].

2-Hydroxychalcone is another example of a partial agonist for PPARγ. Similar to apigenin, this partial agonism of PPARγ leads to anti-inflammatory effects induced by 2-Hydroxychalcone. Although the pathways for these effects are not yet understood in the case of 2-Hydroxychalcone, it is an example of a PPARγ ligand that has shown anti-inflammatory effects [4, 6, 39]. As for food sources of 2-Hydroxychalcone, it is primarily found in cinnamon [6, 39].


#### **Table 1.**

*Select compounds that function as PPARγ agonists and the food sources.*

#### *Food-Based PPARγ Ligands DOI: http://dx.doi.org/10.5772/intechopen.104633*

Luteolin acts as a partial agonist for PPARγ, thus affecting PPARγ-dependent gene expression and causing agonism, or an increase in gene expression in the absence of a full agonist, and causing antagonism, or a decrease in gene expression in the presence of a full agonist. However, luteolin uniquely acts as a full agonist for the gene expression of insulin dependent glucose transporters (GLUT-4) in the 3 T3-L1 mouse cell model [4]. Currently it is unclear if this effect is also seen in humans, however it is a potential target for future research. Luteolin also has an effect on inflammation through its effect on proinflammatory cytokines such as interleukin-8 (IL-8) [4]. Although the clinical implications are still unclear for luteolin, recent studies have started to uncover some of the potential beneficial effects it may have. In an in vitro study in human intestinal cells, luteolin has shown to prevent the damage caused by chemotherapeutic treatment. As for the sources of luteolin, luteolin has been shown to be present in marjoram, sage, rosemary, tarragon, thyme, parsley, and alfalfa [6, 39].

Similar to luteolin, rosmarinic acid also acts as a partial agonist for PPARγ, allowing for weak agonism in the absence of a full agonist, and antagonism in the presence of a full agonist [6]. Rosmarinic acid has shown to have anti-inflammatory activity in cell culture assays, however its clinical applications should still be further explored and elaborated on. Rosmarinic acid does however have a poor bioavailability, so its application in humans may be limited regardless of its ability to bind to PPARγ [39]. It still has shown activity as a PPARγ ligand though, so it may be worth further investigation. As far as where rosmarinic acid can be found, it is seen in marjoram, oregano, rosemary, sage, thyme, and lavender [6, 39].

Cinnamic acid and cinnamaldehyde work very similarly. Cinnamaldehyde acts as a partial agonist for PPARγ, allowing for weak agonism in the absence of a full agonist, and antagonism in the presence of a full agonist. Cinnamic acid functions in a similar way, but with a much higher binding affinity for PPARγ [6, 44]. They have both shown a plethora of beneficial effects related to its effect on PPARγ. These include, but are not limited to reducing amyloid-β plaques in Alzheimer's disease, anti-inflammatory effects, as well as improving glucose and lipid levels as well as insulin sensitivity in Diabetes [39, 44, 45]. Although not all of these effects have been shown in humans yet, some have, and there is great potential for clinical application of cinnamaldehyde. As far as the sources of cinnamaldehyde and cinnamic acid, they can both be found in cinnamon as well as clove [6, 39].

Similar to luteolin, resveratrol also acts as a partial agonist for PPARγ-dependent gene expression, which leads to slight agonism in the absence of a full agonist, and antagonism in the presence of a full agonist. Resveratrol affects both glucose and lipid metabolism, and can also have an effect on inflammation in animal models. Resveratrol has also been shown to improve insulin sensitivity in human patients, which is a contributing factor for Type 2 Diabetes, and can help in control of that disease state beyond metabolism of foods consumed. These mechanisms indicate Resveratrol as potentially beneficial in patients with Type 2 Diabetes, as it can help with glucose metabolism, insulin action, and the storage of fat, potentially lowering their risk of cardiovascular events associated with fats [4]. As for the sources of resveratrol, resveratrol has been shown to be present in foods such as bilberries (European blueberries), grapes, wines, and peanuts [5, 6].

Quercetin acts as a partial agonist for PPARγ-dependent gene expression, causing agonism, or an increase in gene expression in the absence of a full agonist, and causing antagonism, or a decrease in gene expression in the presence of a full agonist [4, 6]. Quercetin has also been shown in a mouse fibroblast cell model (3 T3-L1), that it promotes glucose uptake through insulin-dependent glucose transporters (GLUT-4),

however does not affect the production of lipid stores through adipogenesis [4]. Additionally quercetin has shown anti-inflammatory effects in vivo, and is very similar in this regard to resveratrol [4, 39, 46, 47]. Quercetin is also fairly abundant in food sources, and can be found in dill, bay leaves, oregano, pomegranate fruit, apples, tarragon, parsley, chive, and lovage [6, 39].

Catechin too binds to PPARγ, however unlike the previous compounds mentioned, catechin acts as a full agonist for PPARγ-dependent gene expression, and as such does not provide antagonism [4]. This being said, the effects of catechin are expected to differ from the other compounds mentioned previously. One of these differences seen is that the negative enantiomer of catechin promotes the differentiation of mesenchymal stem cells into adipocytes, or fat cells [40]. Alternatively, the positive enantiomer of catechin has anti-inflammatory properties, similar to those previously mentioned [41]. Altogether, both enantiomers of catechin appear to have beneficial effects in terms of health, and both appear to affect the PPARγ pathways. Additionally, the sources of catechin are plentiful, as it can be found in apples, marjoram, sage, rosemary, cinnamon, pomegranate fruit, cacao, green tea, grapes, apricots, and cherries [4, 6, 40, 41].

Although the activities of eugenol through PPARγ are not yet well-defined, it is known to bind to PPARγ with a greater affinity than that of catechin, which acts as a full agonist [4, 6]. Eugenol is also a compound that has been demonstrated to increase insulin sensitivity, and has seen use in essential oils for that purpose [39]. Eugenol has also shown anti-inflammatory effects, like all of the other compounds discussed in this chapter [39]. As for where eugenol is found though, it is seen mostly in clove and cinnamon [6, 39].

Ethyl cinnamate is very similar to cinnamic acid and cinnamaldehyde. It too works similarly in terms of agonism, but has a binding affinity more similar to that of cinnamic acid as opposed to cinnamaldehyde [6]. Additionally, as a PPARγ agonist, it shows the same anti-inflammatory effects that all of the other compounds previously mentioned exhibit [39]. In terms of food sources for ethyl cinnamate though, it is seen in mainly cinnamon and clove [6, 39].

Epicatechin is very similar to the compound discussed earlier, catechin. They both have great binding affinities for PPARγ, and have very similar effects [6]. Like catechin, epicatechin has anti-inflammatory properties. However unlike catechin, epicatechin has also been shown to inhibit PPARγ signaling as well as adipogenesis, or the development of fat stores. Altogether, epicatechin has many positive effects, whether related to its actions on PPARγ, or it's other bioactivities, and has great promise for medicinal application [42, 43]. In terms of sources of epicatechin, it can be found most prominently in cacao, but also in tea, cinnamon, thyme, apples, grapes, and many other fruits and vegetables [6, 42, 43].
