Diet Induced Obesity

The DIO female rat model of human obesity has the disadvantage that middle-aged female rats need to be maintained on the simplified cafeteria diet for at least 12 weeks before their obesity stabilizes.

From: International Review of Neurobiology , 2011

Spontaneous, Surgically and Chemically Induced Models of Disease

Dwight R. Owens , in The Laboratory Rat (Second Edition), 2006

DIETARY-INDUCED OBESITY PRONE RAT.

This dietary-induced obesity (DIO) prone rat model of obesity is a outbred, albino, and polygenic model that has been selectively bred to develop obesity associated with impaired glucose tolerance, dysplipidemia, and insulin resistance when fed a high-fat, high-sucrose, and high-caloric diet (Levin et al., 1997). The rat is a useful model for the study of obesity because the obesity is expressed only when the rats are fed a diet moderately high in energy and fat content, allowing control of the obesity rate and leptin production. Obesity in the DIO rat shares many characteristics of human obesity conditions, including polygenic inheritance, insulin resistance, reduced growth hormone secretion, and a propensity to oxidize carbohydrate preferentially over fat (Levin and Dunn-Meynell, 2000). Similar to many obese humans, DIO rats reduce their resting metabolic rate when calorically restricted and return to their previously high body weight when restriction is discontinued (Levin and Dunn-Meynell, 2000).

The DIO rat was developed by the selective breeding of a group of outbred CD (Sprague-Dawley rats). CD rats develop a bimodal obese and lean populations when fed a high energy diet. After feeding the rats a high-fat, high-energy diet (Research Diets D 122266B; Research Diets, New Brunswick, NJ) based on condensed milk, bimodal groups of animals were selected for further breeding to develop the DIO and diet-resistant lines. The DIO line was selected for high weight gain; the diet-resistant line, for low weight gain (Levin et al., 1997).

In weight-matched studies using regular laboratory diet (4% fat), DIO rats had 44% greater carcass fat than did diet-resistant rats having similar energy intake and feed efficiency. The basic insulin level of the DIO rats was 70% higher and blood glucose 14% greater than levels for the diet-resistant rats. It was further noted that DIO rats ate 25% more food compared with the intake of diet-resistant animals and gained 115% more body weight (Levin et al., 2000; Levin and Dunn-Meynell, 2002).

The DIO rat is a useful model for studies of non-leptindeficient obesity and for investigations of glucose tolerance and insulin resistance, "metabolic syndrome X". The DIO rat develops significant obesity with normal levels of leptin, whereas most other models of obesity are leptin deficient. In addition, the DIO rat can be used to study the development of hypertension in the obese state; development of vascular and renal changes are common. In this regard, the DIO rat closely resembles obesity of humans (Dobrian et al., 2000).

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Evolving Concepts of Leptin

H. Münzberg , T.W. Gettys , in Encyclopedia of Biological Chemistry (Second Edition), 2013

Leptin Resistance and Obesity

Diet-induced obesity in mice and humans is commonly associated with insensitivity to leptin, with high-circulating leptin levels and reduced anorexigenic leptin effects, and has been termed 'leptin resistance'. The development of leptin resistance may involve several levels and stages, including leptin transport mechanisms, cellular signaling mechanisms, as well as reorganization of axonal processes.

Leptin is too large a protein to cross the blood–brain barrier by perfusion, and a saturable, regulated transporter is needed for leptin access into the brain. Obese individuals show a reduced transport capacity of serum leptin into the cerebrospinal fluid, suggesting that the brain is exposed to lower leptin levels than available in the serum of obese individuals. This is further supported by the fact that leptin resistance in rodents can be improved (even though not entirely recovered) by central leptin application, thus bypassing the blood–brain barrier and the need for a transporter system and indicating that defective leptin transport depicts one component in the development of leptin resistance.

Leptin resistance is also manifested at the cellular level and a severe reduction in leptin-induced signal transducer and activator of transcription-3 (STAT3) phosphorylation. A deamplification of LepRb signaling can occur on several levels, for example, a decrease in LepRb availability or negative-feedback mechanisms via inhibitory molecules like suppressor of cytokine signaling-3 (SOCS-3) as well as protein tyrosin phophatase PTB1B. SOCS-3 expression is induced by leptin signaling, and thus high circulating leptin levels may chronically increase SOCS-3 levels resulting in a decreased LepRb signal. PTP1B is also upregulated in response to leptin, resulting in decreased LepRb signaling; even though the specific molecular mechanisms are less well understood. Furthermore, even though leptin is able to induce the expression of SOCS-3 and PTB1B, they both are also regulated by other cytokines that are likely induced in obese subjects. Whole body deletion of either SOCS-3 or PTP1B, as well as neuron-specific deletion of SOCS-3 in POMC neurons, attenuates body weight gain on a high-fat diet and increased leptin sensitivity. Thus, inhibitory molecules such as SOCS-3 and PTB1B in specific neuronal populations like POMC neurons present a further level in the development of leptin resistance ( Figure 5 ).

Figure 5. Schematic model of leptin signaling through LepRb, resulting in the activation of several signaling pathways as well as interaction with PTP1B and SOCS-3, which causes the deamplification of leptin signaling.

The concept that leptin induces its own resistance by inducing SOCS-3 and PTP1B has been discussed as a mechanism for increased weight gain on a high-fat diet. Indeed, chronic and central infusions of leptin cause leptin resistance over time. By contrast, low leptin levels have been commonly associated with increased leptin sensitivity, for example, fasted mice or leptin-deficient ob/ob mice are known to respond more sensitively to leptin treatment. The evolutionary importance of a system with major anorexigenic leptin effects when body weight is already low does not seem to be favorable. However, to evaluate the capability to survive energy-demanding periods, such as reproduction, a sensitive system to communicate body fat stores would be particularly important during famine and thus when fat stores are low.

Leptin resistance does not affect all physiological end points of leptin action. Whereas leptin resistance clearly blunts anorexigenic leptin effects, the sympathetic tone to the kidney remains leptin sensitive in some obese mice, resulting in increased blood pressure in obese individuals with high circulating leptin levels. A selective leptin resistance has also been found in diet-induced obese mice and seasonal mammals with upregulated SOCS-3 and decreased leptin-dependent STAT3 phosphorylation specifically in the ARC, but not other hypothalamic sites. Neuronal processes of ARC LepRb neurons can access the circulation directly and respond more sensitively and faster to changes in circulating leptin as well as other obesity-induced cytokines compared to other hypothalamic sites. Therefore, ARC neurons would be more susceptible to increase SOCS-3 levels in response to high circulating leptin levels than other hypothalamic sites and could explain the appearance of ARC-specific leptin resistance. By contrast, pregnancy has been associated with leptin resistance confined to the ventromedial hypothalamus (VMH). Several LepRb neurons in the VMH also express estrogen receptors, so that interactions of the estrogen-signaling pathway with LepRb signaling might provoke VMH-specific leptin resistance during pregnancy, indicating that leptin resistance can be differentially modulated depending on the physiological context.

Leptin resistance could also occur at the level of translation of SNS input in peripheral tissues. In adipose tissue, activation of β-adrenoceptors initiates the transcriptional program of adaptive thermogenesis in a cAMP-dependent manner. Analysis of the promoter structure of many genes transactivated during this response shows that the nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), is an essential component of the transcriptional complex. Although the endogenous ligand for this receptor has yet to be identified, in vitro studies have shown that long-chain-polyunsaturated fatty acids and their metabolites can act as partial agonists. The relevance of PPARγ to adaptive thermogenesis is apparent from work with obesity-prone strains of mice, where it is known that high-fat diets compromise the ability of sympathetic stimulation to initiate thermogenic responses in adipose tissue. Remarkably, simultaneous provision of synthetic PPARγ agonists with sympathomimetics rescues the compromised adaptive thermogenic response of obesity-prone mice and produces a significant loss of WAT. Coadministration of PPARγ agonists with sympathomimetics is not required in obesity-resistant mice, as high-fat diets do not compromise their adaptive thermogenic responses. Although the underlying mechanism is not yet known, high-fat diets accentuate leptin resistance by altering the requirement for endogenous PPARγ agonists to support transcriptional activation of genes involved in adaptive thermogenesis. The consensus at present is that changes in dietary fat content and composition alter synthesis of the endogenous ligands for PPARs in a manner that produces coordinated, integrated transcriptional responses in and among metabolically active target organs. Collectively, the PPARs are viewed as a lipid-based nutrient-sensing system. In the case of adipose tissue, the productive integration of signaling inputs from leptin-induced SNS outflow and lipid-sensitive PPAR activation is required for a full and effective adaptive thermogenic response. A better understanding of the signaling systems, which interact to regulate and limit leptin signaling, is an important missing component in our overall understanding of the mechanisms of energy homeostasis.

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Recent Advances in Nutrigenetics and Nutrigenomics

Maria G. Stathopoulou , ... George Dedoussis , in Progress in Molecular Biology and Translational Science, 2012

4 Animal Models and In Vitro Studies

In a diet-induced obesity mice model, a high-calcium diet for 21 weeks altered the expression of 129 genes in the adipose tissue, particularly those participating in the biological pathways of insulin and adipocytokine signaling and fatty acid metabolism. 37 A high-calcium diet for 14 days also altered the expression of 10 genes in the colon of rats, especially the mucosal pentraxin (Mptx) gene, which is colon specific and is associated with colon cell turnover and disease. 38 A comparative microarray approach in three different mouse models of colon cancer fed a Western diet showed that increasing dietary calcium and vitamin D can be effective in inhibiting tumor formation. 39 Also, low calcium was associated with alteration in gene expression in mice and human adenocarcinoma-derived Caco-2 cells on markers of inflammation, detoxification, and the vitamin D system (protection against tumorigenesis). 40

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Animal Models of Dietary-Induced Obesity

Louise Thibault , in Animal Models for the Study of Human Disease, 2013

Conclusions

Animal models of dietary-induced obesity are important and can provide valuable insights into the pathophysiology of the obese syndrome in humans. The use of fat-rich diets that mimic human diet has thrown light on physiological mechanisms such as the high efficiency of dietary fat in being stored in the body, the low satiating effects of fats leading to overconsumption of fat-rich diets, and alterations in the hormones involved in energy balance. Animal studies should be designed so that fat-rich diets meet the animals' minimal protein and micronutrient requirements, to eliminate the possibility of overconsumption of the diet to fulfill these nutrient needs; obesogenic effects of fatty acids with different degrees of saturation should also be accounted for. Hyperleptinemia and hyperinsulinemia are found with feeding fat-rich diets, but leptin and insulin resistance accompanies this, whereas a lowered suppression of ghrelin secretion is found after a fat-rich meal. Among the behavioral mechanisms of dietary-induced obesity, a sensory-specific facilitation of intake is found with fat-rich diets. Diurnal rhythmicity of feeding and meal pattern analysis of fat-rich-fed animals has linked diurnal feeding and large meals to the obese state. Failure to learn associatively happens with a high-fat maintenance diet, which could explain overeating and obesity. An area of future research is to investigate obesity as a result of memory- and motivation-related feeding behavior. Reversal of obesity requires the use of restricted, low-fat diets, as these diets fed ad libitum fail to induced body weight loss.

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Volume 2

Steven M. Anderson , ... Margaret C. Neville , in Knobil and Neill's Physiology of Reproduction (Fourth Edition), 2015

Animal Models of High Fat Feeding and Maternal Diet-Induced Obesity

Rodent models of diet-induced obesity have historically been the most common models used to study the effects of obesity on pregnancy and lactation. Typically, obesity is induced by feeding a HF diet using either a cafeteria-style diet where rodent chow is supplemented with high calorie human snacks 439,443,479–481 or a semipurified diet using lard or vegetable oil as the primary fat source. 445,482,483 There are benefits and downfalls of both HF-feeding paradigms. Cafeteria-style diets are more representative of the human condition; however, the specific source of calories is not as well controlled as with semipurified HF diets. Additionally, when a rodent is left to choose its own food there is the potential for deficiencies in essential nutrients, which can have adverse effects on lactation independent of HF feeding. 484,485 Finally, it is important to consider the composition of the fatty acids used to induce obesity, as different types of fat substantially affect milk composition. 22,480,486

Further, the conclusions that can be drawn from studies with diet-induced obesity models are confounded by the problem that HF diets themselves may have effects on lactation separate from effects of obesity. Typically, short-term exposures to HF diets are employed in lean animals to dissect these two effectors. 445,487–489 This approach is particularly useful in examining how HF feeding affects the various stages of mammary gland development. Separating the effects of chronic HF feeding from obesity is more challenging. To achieve this objective, some researchers have switched HF-fed, obese animals to a low fat diet during pregnancy, lactation, or both. 490 Such an approach, however, reflects an acute dietary change, rather than dissecting chronic HF feeding from the effects of obesity.

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Metabolic Profiling and Biomarkers of Type 2 Diabetes and the Effective Evaluation of the Tianqi Jiangtang Capsule

Xijun Wang , ... Aihua Zhang , in Chinmedomics, 2015

18.1 Introduction

The prevalence of diet-induced obesity is increasing globally, and posing significant health problems for millions of people in the world. Diet-induced obesity is a major contributor to the global pandemic of Type 2 diabetes (T2D), which is a manifestation of Xiaoke Syndrome in TCM (Rubin, 2013; DeFuria et al., 2013). Typically, a civilization disease, particularly T2D, represents one of the most significant global health problems because it is associated with a large economic burden on the health systems of many countries (Seaquist, 2014). However, little is known about this inherited metabolic relation. In order to give a new insight into the diabetic process itself, as well as conduct clinical instruction, it is necessary to clarify the global metabolic alteration that characterizes its progression. The burden of T2D is growing worldwide, and with it an urgent requirement for better tools to detect, diagnose, and monitor the disease. The new platform of metabolomics, focuses on a holistic investigation of living systems to external stimuli, based on the global metabolite profiles in biological samples, provides variation of whole metabolic networks for characterizing pathological states, as well as giving mechanistic insights into the biochemical effects of TCM (Jiang et al., 2011; Tian et al., 2014; Gao et al., 2014).

The Tianqi Jiangtang Capsule (TJC) has been efficiently and widely used to treat T2D or Xiaoke Syndrome in TCM. It is composed of 10 herbs, including: Astragalus membranaceus (Fisch.) Bunge., Dried root of Trichosanthes kirilowii Maxim., Panax ginseng C. A. Mey., Dendrobium nobile Lindl, Fructus Ligustri Lucidi, Coptis chinensis Franch., Cortex Lycii, Cornus officinalis Sieb. et Zucc., Eclipta prostrate, and Rhus chinensis Mill (Zhang et al., 2010). The detailed therapeutic mechanism, based on the metabolomics of TJC against T2D, remains unknown. By utilizing this comprehensive biochemical profiling approach, we seek to identify metabolites with different concentrations in T2D, and thereby allowing new insights into the pathophysiological progression of this important metabolic disease. Various analytical techniques, with multivariate data analysis, such as partial least squares-discriminant analysis (PLS-DA) have been applied in metabolomics-based metabolism studies. UPLC coupled with MS has become one of the widely applied techniques in metabolomics owing to its high sensitivity and reproducibility. Herein, urinary metabolomics based on UPLC-MS was applied to investigate the metabolic profiles, and the potential biomarkers in a rat model of T2D, which may facilitate understanding the pathological changes of T2D when treated by TJC.

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RNA and metabolic disorders

Gaurav Verma , Susana González-Rico , in Rna-Based Regulation in Human Health and Disease, 2020

The inheritance of metabolic disorders

The prevalence of metabolic disorders is highly dependent on demography, but recent estimates put the number of American adults with metabolic syndrome on an upward trend at almost 35% [2,17,18]. Although genetics contribute to some predisposition to the development of metabolic syndrome [19–21], environmental factors such as a sedentary lifestyle, poor intrauterine conditions, malnutrition and physical inactivity contribute largely to metabolic disorders and may turn out to be the key targets to control the epidemy [22,23]. As such, while the environment and genetic predisposition play a role in disease manifestation, mutations within the non-coding elements of genes can be associated with causing pathologies. One example of such pathology is diabetes. The bone morphogenic protein receptor 2 (BMPR2) is a member of the transforming growth factor beta (TGFβ) receptor family that has been found to play a significant role in pulmonary arterial hypertension, obesity, and insulin resistance [24]. Indeed, studies have found that over 80% of heritable pulmonary arterial hypertension and 20% of idiopathic pulmonary arterial hypertension patients have mutations within their BMPR2 gene [25,26].

The frequency of occurrence of metabolic disorders, and its pattern of heritability cannot be explained by Mendelian transmission of mutational events, and are reminiscent of epigenetic heredity. Genetic variants account poorly for the observed heritability of disease risk less than 2% for obesity and 5%–10% for Type 2 Diabetes [24] and the missing heritability is being revealed in epigenetic studies that address the impacts of prenatal and postnatal environment on the epigenome and metabolic disease risks. For instance, nutritional deficiency or excess (either prenatally or postnatally) leads to epigenetic reprogramming that is significantly correlated with increased obesity incidence [27]. Thus, understanding metabolic disorders from an epigenetic perspective may offer new strategies to prevent or treat these diseases.

The paternal inheritance of diet-induced obesity, diabetes and metabolic disorders, was first suggested by epidemiological analysis of human cohorts and later confirmed by experimental analysis. Grandjean in 2016 [28] reported that by injecting testis or sperm RNA from mice raised on a western-like diet into naive one-cell embryos, they could induce symptoms similar to those of diet-induced pathologies. Metabolic disorders were also induced and inherited after micro-injection of a unique microRNA, i.e., mir-19b, that was found to be up-regulated in the sperm of males that were fed a Western-like Diet. Female rats born to fathers on a high-fat diet had impaired insulin secretion and glucose tolerance [24].

The frequency of occurrence of metabolic disorders and its pattern of heritability cannot be explained by simple Mendelian transmission of mutational events.

Epigenetics mechanisms seem to play a very important role in the development of obesity patterns.

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Obesity

Dominic S. Ng , in Vitamins & Hormones, 2013

2.3 LDL receptor deficiency augments the protective phenotypes of LCAT deficiency in mice

LDLR knockout mice develop accentuated high fat diet-induced obesity and IR when compared to the C57Bl/6 wild-type mice, but the underlying mechanism remains poorly understood (Schreyer, Vick, et al., 2002). Mechanistically, Li et al. recently demonstrated that LDLR knockout mice developed elevated hepatic ER stress even under chow-fed condition and an accentuated induction of ER stress in response to a HFHS diet (or high fat diet) when compared to the C57Bl/6 wild-type mice. In this LDL receptor null metabolic background, Li et al. reported that rendering the LDLR knockout mice also LCAT deficient led to a normalization of baseline hepatic ER stress under chow-fed condition. Further, the LDLR knockout mice made LCAT deficient also showed marked resistance to the HFHS diet induction of ER stress in conjunction with a dramatic protection from HFHS diet-induced obesity and glucose intolerance (Li et al., 2011). The underlying mechanism of the protection from ER stress in LCAT deficiency is not yet known. It is conceivable that LCAT deficiency may, through yet-to-be defined pathways, directly modulate hepatic ER stress. In the case of protection from HFHS diet-induced ER stress, it is also possible that this is a consequence of the LDLR/LCAT double knockout mice being protected from diet-induced obesity.

Regarding the question whether LCAT deficiency directly modulates hepatic ER stress, my laboratory has recently provided preliminary evidence in support of this notion. First, we showed that the LDLR knockout mice developed elevated hepatic total and FC when compared to the wild-type control, which correlate with the elevated basal expression of the ER stress markers. In the concurrent absence of LCAT, namely, the LDLR/LCAT double knockout, the ER stress marker expression becomes normalized to the wild-type mice level, in association with a reversal of the whole hepatic tissue total and FC levels to those of the wild-type mice. We also measured FC in the ER fraction from chow-fed wild type, LDLR knockout, and LDLR/LCAT double knockout mice and observed changes in ER cholesterol being parallel to the tissue cholesterol changes. Upon feeding these three genotypic groups of mice with a 2% high cholesterol diet (HCD), we observed significant elevation of hepatic cholesterol and a parallel increase in hepatic ER stress in the LDLR knockout mice in response to the HCD. Unexpectedly, the LDLR/LCAT double knockout mice ER cholesterol and ER stress became lower than those of the wild-type mice in spite of a significant rise in the tissue cholesterol level. Combining the findings from these six groups of animals, we observed a strong correlation between hepatic ER stress and ER cholesterol, a finding further substantiating the direct role of LCAT in the modulation of hepatic ER stress, in part through regulation of ER cholesterol (Hager, Li, et al., 2012).

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Animal Models of Transgenerational Epigenetic Effects

Cheryl S. Rosenfeld , in Transgenerational Epigenetics, 2014

Diet-Induced Obesity Studies

Studies have examined whether or not diet-induced obesity in male and female parents leads to transgenerational effects. In the case of the male, the changes in dietary state would only affect the genes he passes onto his offspring. In contrast, the F0 mother's diet might affect the epigenetic state of her germline and also have direct effects on her developing offspring (F1) and the F1 germ cells that give rise to the F2 generation. Therefore, any observed effect in these F2 offspring may not be transgenerational in origin. Nonetheless, with this caveat in mind, we will consider studies that, for the most part, only included the F2 and not the F3 and F4 generations, and are, therefore, not fully conclusive.

Administration of a high-fat diet (HFD) to C57Bl6J male mice prior to breeding led to increased adiposity in the F1 offspring and F2 grand-offspring. 143 Sperm of male descendants also demonstrated altered gene expression, microRNA (miRNA) changes, and overall decreased methylation of germ cell DNA. An earlier study by this same group showed that diet-induced obesity in the F0 father led to decreased fecundity for male and female offspring through the F2 generation. 144

Diet has also been suggested to lead to transgenerational effects in insects. A diet high in sugar fed to Drosophilia females provides at least two generations of offspring larvae with altered body composition, enhanced obese-like phenotype, and upregulation of a select set of metabolic genes. 145 In contrast, Drosophilia larvae maintained on a high protein/low sugar larval diet give rise to offspring that undergo metamorphosis at a faster rate, exhibit enhanced reproduction, and altered metabolism than those derived from parents of a low protein-relative-to-sugar diet. 146

Administration of a high-fat/high-energy maternal diet has also been linked to transgenerational effects in mice and rats. 147–150 A maternal diet enriched in fats leads to increased body length and insulin resistance extending through F2 mice descendants derived from either the F1 maternal or paternal lineage. 147 Subsequent studies demonstrated that F3 female, but not male, mice exhibited an increase in body size, and that this effect was only transmittable through the paternal germline. 148 Correspondingly, these female descendants also exhibited changes in paternally but not maternally imprinted genes. Another study showed that F0 dams maintained on a diet elevated in energy by 25% relative to controls resulted in a progressive increase in Dnmt3a2 expression and reduced methylation of its own promoter site in their F1 to F3 descendants. Increased expression of this key DNA methyltransferase (DNMT) has been proposed to lead to promiscuous and abnormal de novo epigenetic marks across the generations. 150 These combined studies with mice and rats provide some limited, though not completely convincing, evidence that a maternal diet high in fat or energy can lead to transgenerational effects through the F3 generation. However, the studies should still be extended through an F4 generation to verify persistence of the epigenetic and phenotypic changes.

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Genetic Basis Linking Variants for Diabetes and Obesity with Breast Cancer

Shaik Mohammad Naushad , ... Vijay Kumar Kutala , in Molecular Nutrition and Diabetes, 2016

7 Nutrigenomics Perspective to Reduce Obesity-Mediated Breast Cancer Risk

Apple polyphenols were found to be beneficial against diet-induced obesity in animal models as they reduce Lep, Plin, and sterol regulatory element binding transcription factor 1 (Srebf1) mRNA levels and increase aquaporin 7 (Aqp7), adipocyte enhancer binding protein 1 (Aebp1), and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1a) mRNA levels in epididymal adipocytes. 46 Barth et al. demonstrated the beneficial effects of apple juice consumption in obese men especially in subjects with CC genotype of interleukin-6 −174 G>C with significant reduction in body fat. 47 Supplementation of methyl donors (choline, betaine, folic acid, and vitamin B12) during lactation to high-fat-sucrose-fed dams was shown to confer protection in offspring against liver fat accumulation when consuming an obesogenic diet. 48

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