**5. Mechanisms of the antioxidant and metabolic syndrome-suppressing effects of dietary factors**

While some food components promote a pro-oxidative and pro-inflammatory state as discussed in the previous section, other dietary factors inhibit oxidative stress and inflammation. They do this through various mechanisms, but the most widely considered mechanisms are those associated with lipid oxidation, including scavenging of free radicals such as peroxyl radicals and alkoxyl radicals, chelation of metal ions that participate in formation of such radicals, and singlet oxygen quenching.

#### **5.1 Free radical scavenging and singlet oxygen quenching**

Carotenoids, phenolic substances, tocopherols and ascorbic acid are well known for their antioxidant activities targeting the neutralization of reactive radicals and/ or singlet oxygen quenching. Thus, carotenoids reduce oxidative stress and lipid oxidation, resulting in adipocyte beiging and obesity prevention [142]. There is decreased adipose beta carotene in obese subjects, and this was suggested to at least partly be due to their depletion under the high ROS environment [142]. Likewise, tocopherols and tocotrienols have been shown to be protective against all components of the metabolic syndrome [143]. Thus, the high tocotrienol content of palm oil may reduce its potential harm from the high palmitate content [144]. Unfortunately, radical scavenging antioxidants also exhibit pro-oxidant activity, depending on their concentrations and the level of prooxidative factors [145]. Hence, there is need to consider a broad range of dietary factors that prevent oxidative by alternative mechanisms, such as those outlined hereafter. A single molecule can act by multiple mechanisms, and the more mechanisms involved, the greater might be the benefit.

#### **5.2 Insulin-mimicking**

Insulin signaling activates akt, which reduces oxidative stress by promoting mitophagy and by activating nrf2 to induce antioxidant enzymes [81, 146]. Moreover, nrf2, via heme oxygenase 1 (HO-1), inhibits NFkB and associated upregulation of NADPH oxidase and iNOS [147]. Quercetin and ferulic acid are examples of molecules that have demonstrated oxidative stress and metabolic syndrome amelioration at least partly through PI3K-akt signaling in various cell types [148–150]. Resveratrol and ferulic acid inhibit LPS- and oxidative stress-induced intestinal barrier injury through this signaling pathway [151, 152].

#### **5.3 AMPK and SIRT1 activation**

AMPK and/or sirt1 reduce mitochondrial oxidative stress in adipocytes, pancreatic beta cells, hepatocytes, endothelial cells, and thus are useful in preventing all aspects of the metabolic syndrome. In addition to insulin mimicking, quercetin and ferulic acid, also activate these proteins [153–155].

#### **5.4 Adiponectin and adiponectin receptor enhancement**

Compounds that activate AMPK, sirt1 and/or PI3K-akt in adipose tissues limit adipocyte hypertrophy and inflammation, and enhance adiponectin production. Adiponectin has systemic effects in reducing insulin resistance and oxidative stress, because it activates both PI3K-akt and AMPK in insulin target tissues, and also promotes anti-inflammatory polarization of macrophages [156]. Dietary compounds

#### *Lipid Peroxidation as a Link between Unhealthy Diets and the Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.98183*

than ameliorate metabolic syndrome through enhanced adiponectin secretion and/ or upregulating adiponectin receptor include n3-fatty acids, sesamin, the citrus derived polymethoxyflavonoids nobiletin and tangeretin, quercetin and resveratrol [157–160].

### **5.5 Ceramide reduction**

Adiponectin signaling increases ceramidase activity, thus reducing ceramide levels [161]. Hence, the adiponectin and adiponectin receptor enhancers should contribute to reducing ceramide-induced oxidative stress. Not much research has been done along this line, but it has been reported that DHA inhibits ceramide biosynthesis [162]. In mice, dietary inulin reduces ceramide synthesis by suppressing neutral sphingomyelinase expression and activity [163].

### **5.6 Vasodilation**

Vasodilation reduces blood pressure, and thus reduces pressure-dependent oxidative stress as well as LDL oxidation and Lox-1 dependent oxidative stress [164]. Thus, for people with prehypertension or hypertension, vasodilation may be a major strategy for reducing oxidative stress and lipid oxidation. Cinnamaldehyde has vasodilatory and antihypertensive activity through effects on smooth muscle contractility [165]. Dietary nitrate achieves vasodilation through NO release, and this is associated not only with pressure regulation, but also other components of the metabolic syndrome including blood glucose and lipid improvement [166]. Adiponectin induces AMPK dependent eNOS activation in endothelial cells, hence adiponectin enhancers such as imperatorin also promote NO synthesis and vasodilatation [167].

#### **5.7 Reactive carbonyl, ALEs and AGEs scavenging**

Scavengers of reactive carbonyls such as HNE, acrolein and MDA have been demonstrated to ameliorate oxidative stress, lipid peroxidation and the metabolic syndrome. Examples of compounds with such effects include carnosine, carnosinol, epigallocatechin-3-gallate and the mulberry anthocyanins cyanidin 3-glucoside (C3G) and cyanidin 3-rutinoside (C3R) [46, 168–170]. Aminoguanidine attenuates hypertension by scavenging AGES [171].

#### **5.8 Gut microbiota modulation**

Probiotic microorganisms suppress the growth of pathogenic microorganisms. They also produce metabolites such as short chain fatty acids with beneficial effects on the metabolic syndrome. For example, butyrate promotes PI3K-akt signaling to prevent oxidative stress and maintain intestinal barrier integrity [172, 173]. Quercetin, resveratrol and n-3 fatty acids have been demonstrated to positively influence gut microbiota and decrease intestinal barrier permeability in animal studies [153, 174].

## **6. Conclusions**

Lipid peroxidation is a major contributor to the pathogenesis of the metabolic syndrome, especially through highly reactive and bioactive aldehydes such as acrolein, 4-hydroxy-2-nonenal, malondialdehyde and glyoxal. Mechanisms of formation of these products are now well-understood. For example, this article has highlighted that formation of MDA from linoleic acid may be easier than previously thought. The mentioned aldehydes propagate oxidative stress and inflammation by inducing insulin resistance, inhibiting sirt1 and AMPK, reducing adiponectin secretion, as well as forming AGEs and ALEs that activate the RAGE receptor. Inhibiting LPO and the LPO product-associated oxidative stress and inflammation is necessary for preventing and/or ameliorating progression of the metabolic syndrome. This may not be effectively accomplished by dietary agents that merely scavenge free radicals and/or quench singlet oxygen, but also by those that inhibit the signaling pathways that generate non-lipid ROS, or scavenge the reactive carbonyls, ALEs and AGEs. In addition, saturated fat, sugar, meat, and salt, that fuel the signaling pathways that initiate LPO should be reduced. The metabolic influence of some dietary components such as salt and n-6 PUFAs is particularly influenced by genetics, and this should be duly considered when making dietary recommendations.
