**4. Nutrigenomic diets block both hepatic and adipose tissue damage in obese individuals**

A lack of effect of some anti-obese medications [78] in the treatment of obese patients has paved the way for nutrigenomic dieting, hopefully preventing the development of senescence of various tissues being implicated in chronic disease states [1]. In obese patients, the success to be gained in early interventional treatments of NAFLD may depend upon individuals [7, 8] having a BMI value of between 25 and 30 kg/m2 , with a genuine reversal of adipose tissue transformation being coupled to solid improvements in glucose turnover immunoregulatory capacity, as well as NAFLD. In patients showing BMI values greater than 30 kg/m2 , unhealthy diets inducing abnormal Sirt1/p53 interactions are often associated with changes in the levels of various microRNAs, inducing a chronic failure in the DNA repair system, which accelerates hepatic senescence with ensuing adipose tissue inflammatory responses, as well as a dysfunctional lipid metabolism and aberrant energy expenditure.

an important factor in the cholesterol-rich lipoprotein intercommunication network [45–47], thus impacting on LPS neutralization in metabolic diseases, with focus on diabetes [48–50].

LPS-induced production of interferon-gamma (IFγ) has been shown in both NK-cells and T- lymphocytes impacting genes encoding inflammatory cytokines, glucose metabolism, and macrophage-related modulation of genes in adipocytes [51, 52]. IFγ has also been shown to affect genes, like Sirt1 and p53 apoptosis coupled genes, whose role are being "dissociated" in dysfunctional stages of metabolism [45–53]. The impact of IFγ on chromatin modeling stimulates macrophages, controlling gene transcription, thus regulating inflammatory cytokine production in activated macrophages [46, 47]. In this context, MiR-34a and other MiRs are involved in the modulation of the IFγ-mediated innate immune responses [48, 49]. However, one has discovered an inverse correlation between adiponectin and inflammatory cytokines,

The LPS-stimulated biological effect on p53-induced apoptosis in the liver [53, 54] surpasses the effect of Sirt1 as to the deacetylation of p53, reducing the hepatic lipid turnover. Hence, the p53-mediated downregulation of PXR activity [55, 56] is not dependent of the Sirt1/PXR-mediated reactions [57–60]. Therefore, the untoward p53/PXR interactions, which lead to NAFLD, are coupled to an altered expression of miRNA species related to the turnover of xenobiotics [61–63]. In this context, xenobiotic metabolism has been shown to be disturbed in obese individuals, which is associated with enhanced lipid synthesis [63], disturbed immune reactions [62], and marked apoptosis [64, 65]. The high levels of phthalates contained within alimentary like milk, butter, and meats are linked to the Sirt1/ p53 interactions [66–68], which couples the phthalates to NAFLD and adiposity in com-

Furthermore, the focus on α-synuclein and its impact on the immune system in the periphery [69, 70] and CNS [71, 72] have emerged as knowledge about its regulatory impact on p53 transcriptional regulation of apoptosis has increased. Sirt1-mediated effects on hepatic α-synuclein and amyloid-β turnover are closely linked to LPS [72], metabolic diseases, as well as obesity, with observed impact on p53 transcriptional regulation by both α-synuclein and

**4. Nutrigenomic diets block both hepatic and adipose tissue damage in** 

A lack of effect of some anti-obese medications [78] in the treatment of obese patients has paved the way for nutrigenomic dieting, hopefully preventing the development of senescence of various tissues being implicated in chronic disease states [1]. In obese patients, the success to be gained in early interventional treatments of NAFLD may depend upon individ-

tissue transformation being coupled to solid improvements in glucose turnover immunoregulatory capacity, as well as NAFLD. In patients showing BMI values greater than 30 kg/m2

unhealthy diets inducing abnormal Sirt1/p53 interactions are often associated with changes in the levels of various microRNAs, inducing a chronic failure in the DNA repair system,

, with a genuine reversal of adipose

,

with adiponectin levels being associated with NK-cell activation [50–52].

munities worldwide [68].

10 Adiposity - Omics and Molecular Understanding

**obese individuals**

amyloid-β metabolism in the liver and brain [73–77].

uals [7, 8] having a BMI value of between 25 and 30 kg/m2

Diets containing sufficient and appropriate protein "species," carbohydrates, and low in fat upregulate both Sirt1 expression and activity in cells, leading to a positive effect on nuclear and mitochondria events, thus sustaining both lipid turnover and energy expenditure. And, not to surprise anyone, food-restricted diets in young and genetically obese and diabetic mice, induce a reversal of hepatic lipid metabolism, involving Sirt1/p53 interactions, which yields improved adipogenesis in man. Nutritional regulation may maintain p53 deacetylation by Sirt1, and thus sustain the "healthy" glucose homeostasis, which is paralleled with a swift energy disposal within adipose tissues. Additionally, ingested foods [32], able to block programmed cell death pathways, may be associated with expression of the Sirt1-gene, thus activating adipose tissues to synthesize and release factors (e.g., adiponectin) [32], which will suppress the impact of inflammatory cytokines, in order to sustain "normal" liver function, thus blocking the induction of NAFLD in humans. Nutrigenomic diets, as for instance high fiber diets [79], will kick-start an "engineered" metabolism, allowing for a joint physiological nuclear and mitochondrial interaction, which will stimulate the PPARγ-Sirt1 and Sirt1-PXR interactions coupled to both therapeutic nutrient and xenobiotic metabolism, that are associated with positive effects on p53 half-life and cell apoptosis [80].

Dieting and the immune system serve as synonymous with dietary fat and its composition being associated with NK cell activity and immune responses in the adipose tissue [81–83]. The suppression of Sirt1 expression by dietary fat is now associated with an abnormal p53 mediated posttranscriptional regulation of NK cells [69, 83]. Furthermore, dietary fat may facilitate the absorption of LPS in rodents, but also man, by modulating the suppression of Sirt1 effects, while also promoting p53-mediated cell death. Hence, food restriction slows down LPS absorption, followed by an obliteration of LPS inhibition of cholesterol turnover in macrophages by the promotion of a reverse cholesterol transport.

A plethora of theories describing the process(es) of aging have been launched, however, the "immune theory" involves fat tissue transformation alongside an activation of its inherent immune responses, encompassing macrophages and other immune cells. However, this adaptation model system is furthermore thought to include adipose tissues as the organs showing the highest susceptibility to apoptosis, with pathways of transformation largely linked to various mutations in a plethora of genes in different cells and tissues [6]. Hence, diets and our immune system are efficiently "cooperating" with our endogenous intestinal microbial flora (i.e., Gram-negative bacteria) and environmental factors, impinging on dietary fatty acid compositions, which play a pivotal role in the immune homeostasis and reactivity of the liver. The Sirt1's involvement in the mitochondria theory of aging brings about a close link to mitochondrial dysfunction (i.e., Sirt1 downregulation), as well as an abnormal immune response [68, 84–86]. An essential requirement of some amino acids (e.g., leucine) [93] may sustain a nuclear and mitochondria p53-associated transport, along with an enhancement in the half-life of p53, as well as a blockage of immune dysfunction and development of NAFLD.

Nutrigenomic diets, like the low calorie diets, activating Sirt1, may lower plasma cholesterol concentrations [30], thus preventing hepatic p53-mediated apoptosis by xenobiotics and LPS. A series of drugs, which inhibit Sirt1 [92] have been developed, which prevent leucine-mediated activation of Sirt1 and xenobiotics (e.g., phthalates), modifying Sirt1 chromatin association, with an ensuing induction of p53-mediated apoptotic responses [91–93] in both the liver and adipose tissue.
