Animal Models of Liver Diseases

Yoshihisa Takahashi , Toshio Fukusato , in Animal Models for the Study of Human Disease (Second Edition), 2017

3.5.2.2 High-Fat Diet

A HF diet is widely used to induce NAFLD/NASH in various experimental animals. Lieber et al. (2004) fed a HF liquid diet (71% of energy from fat, 11% from carbohydrates, and 18% from protein) to Sprague Dawley rats and examined the effects. The rats fed the HF diet ad libitum for 3 weeks developed panlobular steatosis. The diet caused abnormal mitochondria and mononuclear inflammation. Plasma insulin was elevated, which reflected insulin resistance, a pathogenic characteristic of NASH. It has subsequently been reported that the HF diet induced a metabolic profile (obesity and insulin resistance), serum data (abnormal aminotransferase activity, hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hypertriglyceridemia), and histopathology (hepatic steatosis, necroinflammation, mitochondrial lesions, hepatocyte apoptosis, and pericentral fibrosis) that corresponded to NASH in experimental animals (Ito et al., 2007; Svegliati-Baroni et al., 2006; Zou et al., 2006). However, other authors have reported that a HF diet did not induce hepatic steatosis or NASH in experimental animals (Romestaing et al., 2007). NAFLD/NASH induced by a HF diet may be relatively mild and highly variable, and may be affected by the composition and duration of the HF diet and by the species, strain, sex, and age of the animals. In a comparison of the effects of a HF diet between mouse strains, BALB/c male mice accumulated more hepatic lipid than C57BL/6J male mice, and middle-aged C57BL/6J mice increased the ratio of fat to body weight and hepatic lipid accumulation more than young mice (Nishikawa et al., 2007). To induce NASH more certainly using the HF diet, Deng et al. (2005) fed a HF diet to mice via an implanted gastrostomy tube for 9 weeks and increased the intake by up to 85% of the standard amount. As a result, overfed C57BL/6 mice progressed to obesity, with 71% larger final body weights. They had increased visceral white adipose tissue, hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance, and insulin resistance. Of these mice, 46% developed steatohepatitis with increased plasma ALT, neutrophilic infiltration, and sinusoidal and pericellular fibrosis. Although this method seems to be the most certain way to induce NASH using the HF diet, it has the disadvantage that it requires specific equipment and special techniques.

Recently, various modified methods using the HF diet have been tried. The products of lipid peroxidation from oxidized low-density lipoprotein (OxLDL) are known to initiate intracellular oxidative stress (Maziere et al., 2000). It has been reported that OxLDL administration to HF diet–fed mice not only aggravates hepatic steatosis, fibrosis, and lipid metabolism, but also results in intense inflammation, including severe hepatic injury and inflammatory cell infiltration, which are the typical histological features of NASH (Yimin et al., 2012).

Ogasawara et al. (2011) determined whether mice treated with gold thioglucose—known to induce lesions in the ventromedial hypothalamus, leading to hyperphagia and obesity—and fed a HF diet had a comprehensive histological and dysmetabolic phenotype resembling human NASH. They found that gold thioglucose + HF induced dysmetabolism, with hyperphagia; obesity with increased abdominal adiposity; insulin resistance and consequent steatohepatitis with hepatocyte ballooning; Mallory–Denk bodies; and perivenular and pericellular fibrosis, as seen in adult NASH.

Fujii et al. (2013) established a reproducible NASH-HCC model in mice by combining a HF diet and the administration of streptozotocin, a naturally occurring chemical that is toxic to the insulin-producing β-cells of the mammalian pancreas. Neonatal male mice exposed to low-dose streptozotocin developed liver steatosis with diabetes after 1 week on a HF diet. A continuous HF diet decreased hepatic fat deposits but increased lobular inflammation with foam cell–like macrophages, which resembled NASH pathology. In parallel with the decreased phagocytosis of macrophages, fibroblasts accumulated to form chicken-wire pattern fibrosis. All the mice developed multiple HCC at approximately 20 weeks of age. Although this is an unnatural model, it has the advantage that HCC associated with NASH develops rather quickly.

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Cancer Health Equity Research

Bradley Krisanits , ... David P. Turner , in Advances in Cancer Research, 2020

4.1 High-fat diet

A high-fat diet (HFD) is a diet consisting of at least 35% of total calories is consumed from fats, both unsaturated and saturated. In addition to the popular processed foods, many other foods have a high fat content including but not limited to animal fat, chocolate, butter, and oily fish. Commonly higher in fat content, most processed foods are easier to obtain as they are normally cheaper considering socioeconomical factors, such as lower family income. Many dishes among different cultures and ethnicities such as fried foods or "soul food" contain ingredients with high fat such as oils, butters, and fats to increase flavor and appeal.

Animal studies have explored the impact of high-fat diet on pubertal growth in various strains of mice. Genetic background is important as many studies have shown that different outcomes can be observed depending on the strain used. C57BL/6 mice fed a HFD during puberty led to reduced ductal length, as well as number of TEBs, a sparse ductal tree, increased mammary adiposity, and reduced mammary epithelial cell proliferation when compared to mice fed a control diet (Olson et al., 2010). A HFD in C57BL/6 mice was also shown to reduce E2 responsiveness, a key hormonal factor in the developing mammary gland. When BALB/c mice were fed a HFD during puberty, a similar morphological change was observed in the glands; however, BALB/c mice showed increased mammary epithelial cell proliferation and reduced E2 responsiveness with no change in adiposity of the gland. BALB/c mice, genetically related to A/J mice, are less susceptible to HFD-induced obesity compared to C57BL/6 as seen in the increased mammary adiposity and associated differences among the strains. Interestingly, weight loss initiated in C57BL/6 mice from switching of diets, HFD to control, restored TEB formation and ductal elongation, showing weight gain and mammary gland adiposity to be key players in pubertal mammary development (MacLennan & Ma, 2010; Olson et al., 2010). BALB/c mice fed a HFD also showed increased recruitment of immune cells, such as eosinophils and mast cells, to periepithelial mammary stroma, as well as hyperplastic lesions during pubertal development (3 weeks). Increased vascularization was observed later in pubertal development to sustain the increased proliferation (Aupperlee et al., 2015).

Rodent models have also explored the impact of HFD on breast cancer risk. BALB/c mice fed a HFD throughout puberty, showed a reduced latency of a median time of 115 days versus 204 in LFD in 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors, which were similar to human basal-like breast cancer (Aupperlee et al., 2015). The group showed that the reduced latency is most likely a result of increased growth factor expression, as well as increased inflammatory and angiogenic processes. Prior to tumor formation, mice fed the HFD showed increased proliferation, hyperplasia, and macrophage recruitment. Resultant tumors also showed increased proliferation, M2 macrophage recruitment, as well as increased vascularization. Interestingly, mice fed a HFD diet during early puberty (3 weeks), then switched to a low-fat diet (LFD) in late puberty (9 weeks), still showed similar reduced latency in tumors with human basal-like characteristics compared to mice fed only HFD for 45 weeks, emphasizing the importance of the pubertal window of insult (Zhao et al., 2013; Zhu et al., 2016). Similar studies in rats showed that treatment with the carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) during early puberty (~   6 weeks of age) and fed a HFD for 25 weeks, results in an increase in tumor incidence with associated increases in tumor proliferation and growth, as well as stromal invasion compared to rats fed a LFD (Snyderwine, Davis, Schut, & Roberts-Thomson, 1998; Snyderwine et al., 1998). Furthermore, mammary glands from rats fed the HFD during puberty showed a loss of luminal epithelial cell marker gene expression and an increase in mesenchymal cell marker gene expression (Vimentin) and breast cancer invasive genes, similar to human basal-like characteristics, suggesting that a HFD may induce genes associated with a poorer prognosis when consumed during specific times of development (Martinez-Chacin, Keniry, & Dearth, 2014).

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Specific fatty acids and structured lipids for weight control

M.S. Westerterp-Plantenga , in Improving the Fat Content of Foods, 2006

7.3.3 Metabolic satiety and Etomoxir

High-fat diets may stimulate voluntary fat intake. The high palatability of high-fat diets could make overeating more likely, and the high energy density of fat- rich diets has been shown to increase energy intake, 72 probably by 'passive overeating' (see also Chapter 6). On the other hand, obesity-prone subjects seem to have more difficulties adjusting their fat oxidation when switched to a high-fat intake, favoring storage of fat. Post-obese women failed to increase their fat oxidation appropriately after a 3-day adaptation period to a 50% fat diet, while control subjects could adapt. 73 However, both groups could adapt to a low-fat diet. These results suggest that partitioning of fat between storage and oxidation is important in the development of obesity on a high-fat diet. Interestingly, the oxidation of fuels has been suggested to result in metabolic satiety signals. Evidence for the importance of metabolic satiety signals in food intake regulation comes from studies showing that eating appears to be inversely related to the rate of fuel utilization. 74 , 75 Fuel oxidation in the liver is thought to provide feedback to the appetite regulating centres of the brain on the energy status of the body (see Section 7.2.7). High metabolism in the liver signals a state where a lot of substrate is available for oxidation and when food intake can thus be decreased. Evidence that, in particular, fat oxidation in the liver can act as a satiety signal comes from studies in which fatty acid oxidation was experimentally manipulated. Ingestion or intragastric administration of medium chain fatty acids (MCTs), which are easily taken up by the liver and are metabolized quickly has been shown to inhibit eating in animals 76 , 77 and humans. 78 , 79

On the other hand, different inhibitors of fatty acid oxidation have been shown to cause an increase in food intake in rats and mice, especially when they are adapted to a high-fat diet. 80 , 81 An important strategy to inhibit fatty acid oxidation, is to block carnitine O-palmitoyltransferase-I, the rate-limiting enzyme in the transport of long chain fatty acids into the mitochondrion, where β-oxidation takes place.

A substance able to do this in humans is Etomoxir. It has been shown clinically that a single dose of Etomoxir increased food intake in a population of young men, habitually eating a high-fat diet, 82 but this occurred in the absence of a detectable decrease in fat oxidation (as measured by indirect calorimetry in a ventilated hood system). In a later study, a respiration chamber was used to measure substrate oxidation after adaptation to a high-fat or a low-fat diet. Changes in substrate oxidation in response to repeated administration of Etomoxir in the high-fat situation were measured. This study showed that in a state of adapted oxidation, administration of Etomoxir resulted in decreased satiety, measured by visual analog scales. 37

It was shown that fat oxidation was significantly inhibited by Etomoxir and was 13.7% lower than in the placebo situation, while there was a tendency towards an increased carbohydrate oxidation. Moreover, the respiratory quotient (RQ) was significantly different from the food quotient (FQ), when using Etomoxir, revealing that Etomoxir partially reversed the adaptational change in fat oxidation. Carbohydrate balance was negative, and the fat balance was positive. Etomoxir significantly increased 24-h RQ and sleeping RQ compared with the placebo. The repeated administration of Etomoxir resulted in a gradual decrease of fat oxidation. 37

Although the 24-h hunger and satiety ratings did not differ significantly between the treatments, there was a significant correlation between the differences in satiety ratings and differences of beta-hydroxybutyrate (BHB) concentrations indicating a role of liver fatty acid oxidation in satiety. 36 These correlations show that the subjects who decreased their BHB most in response to Etomoxir also experience a greater decrease in satiety. 37 Taken together, a clear effect of Etomoxir on substrate oxidation was shown, as well as evidence for a role of liver fatty acid oxidation in induction of satiety. 36 , 37 This may have implications for the lack of satiating power of a low-fat diet, or a diet using fat replacers, such as Olestra.

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Dietary Fats and Inflammation

Glen D. Lawrence , in Handbook of Lipids in Human Function, 2016

Intestinal Microbiota and Systemic Inflammation

High-fat diets are often used to induce obesity in animal studies, with low-grade inflammation a common coincident condition. Pattern-recognition receptors in the immune system recognize lipopolysaccharide (LPS), which is produced by Gram negative bacteria in the digestive tract, as well as during certain bacterial infections. The most studied receptor in this category is toll-like receptor 4 (TLR4). Low-grade systemic inflammation is often caused by increased levels of LPS in the circulation. There are two routes by which intestinally derived LPS can enter the circulation and provoke an immune response that increases markers of inflammation. Specific microbial species produce substances that weaken the integrity of the intestinal epithelial barrier to LPS produced by certain gut microbiota. Consequently, LPS is able to cross from the intestinal lumen to the blood stream (Teixeira et al., 2012). A second mechanism elicits the lipophilic character of LPS that allows it to associate with lipids during chylomicron formation (Ghoshal et al., 2009). A meal containing fats will stimulate chylomicron formation and augment LPS absorption from the gut, which results in a systemic immune response. High-sugar or high-fructose diets may stimulate bacteria that produce LPS, so a combination of sugar and high fat will optimize LPS entry into the circulation for an augmented immune response and inflammatory state (Payne et al., 2012).

There is a prevalence of small intestinal bacterial overgrowth (SIBO) in severely obese patients (Teixeira et al., 2012) and speculation that microbial overgrowth in the small intestine is responsible for increased obesity and systemic inflammation. A high incidence of constipation in obese individuals results in decreased intestinal motility, which along with ileocecal valve dysfunction, may account for SIBO. Altered gut microbiota (dysbiosis) can result from specific dietary constituents, which in turn affect adiposity and inflammation. High-fat diets are generally believed to cause dysbiosis, consequent obesity, and systemic inflammation, simply because high-fat diets are used to induce obesity in animals that are genetically prone to obesity. A study of relatively healthy obese individuals demonstrated that high-fat, low-carbohydrate diets decrease serum triglycerides and high-sensitivity C-reactive protein while increasing serum HDL and adiponectin relative to low-fat, high-carbohydrate diets (Ruth et al., 2013). Although diet consumption was not closely monitored, such studies in humans indicate a more favorable serum lipid profile and decreased inflammation when consuming more fat and less carbohydrate in the diet.

High fructose diets also induce obesity in animal models and markedly increase circulating LPS in mice, along with consequent systemic inflammation. TLR4 knockout mice (lacking the LPS receptor) had similar amounts of circulating LPS with fructose feeding as wild-type mice, but TLR4-deficient mice did not have increased levels of the inflammatory cytokine TNF-α in the circulation and did not develop insulin resistance nor fatty liver as their wild-type counterparts did (Spruss and Bergheim, 2009). High-fructose diets produce profound metabolic effects with numerous consequences, including increased lipogenesis in liver and fatty liver disease, oxidative stress, systemic inflammation, hypertension, and increased adipose tissue mass (Dekker et al., 2010 ). In terms of dietary factors in humans that promote obesity and subsequent systemic inflammation, insulin resistance, and adverse metabolic consequences, a high-sugar or high-fructose diet seems to be a more powerful initiator of these conditions than a high-fat diet. A meta-analysis of low-carbohydrate, high fat diets compared to calorie-restricted low-fat diets for weight loss showed insignificant differences in overall effectiveness with regard to several metabolic parameters ( Hu et al., 2012), but such studies often carefully limit sugar intake for the calorie-restricted low-fat diets.

The connection between gut microbiota and obesity is supported by the fact that germ-free mice do not become obese when fed the same diets as their normal counterparts. When germ-free mice were exposed to intestinal microbes from conventionally raised mice, their body fat increased by 60% and they developed insulin resistance within 14 days (Backhed et al., 2004). In addition, alteration of gut microbiota with antibiotics in high-fat-fed mice and genetically prone obese (ob/ob) mice resulted in a reduction in fat mass and less inflammation, greater insulin sensitivity, less circulating LPS, and fewer adipose tissue macrophages, which are characteristic of both models of obesity in mice (Cani et al., 2008). Obese mice have an increase in Firmicutes and a proportional decrease in Bacteroides intestinal organisms (Ley et al., 2005). Transplanting gut microbiota from genetically obese ob/ob mice to germ-free mice results in a greater increase in body fat compared to mice that receive intestinal organisms from lean mice (Turnbaugh et al., 2006). The shift in gut microbiota results in increased energy harvested from partially digested and nondigestible dietary carbohydrates that accounts for greater energy recovered from a given diet (Musso et al., 2011). The microbes convert those carbohydrates to short-chain fatty acids (acetate, propionate, and butyrate) that are absorbed by the host and rapidly utilized for energy, sparing other energy sources such as glucose.

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Disorders of the Musculoskeletal System

Stephanie J. Valberg , in Equine Internal Medicine (Fourth Edition), 2018

Selection of Fat Source

High-fat diets increase plasma free fatty acid concentrations and thus the availability of fats for oxidation in skeletal muscle. 98 The major sources of dietary fat for horses are vegetable-based fat, including vegetable oils and rice bran, or animal-based fat (tallow, lard, fish oil). Vegetable oils are highly unsaturated, very digestible (90%–100%), and very energy dense. Suitable forms include soybean, corn, safflower, canola, flaxseed, linseed, peanut, and coconut. Controlled research studies in exercising PSSM horses have shown a decrease in muscle pain and serum CK in response to the addition of corn oil and also a product containing soy hulls, soybean oil, and rice bran (RE•LEVE®). 86,98 The amount of oil added in these trials constituted at least 13% of daily DE. Some veterinarians have advocated as much as 25% of DE be fed in the form of fat to PSSM horses. 27 As discussed, the principal consideration here should be whether this provides excessive calories and additional weight gain because feeding 13% DE as fat may well be effective in reducing muscle pain.

Limited research has been performed on the form of oil to feed PSSM horses. An odd carbon 7 chain fat (triheptanoin) fed to PSSM horses had a detrimental effect on muscle pain, exercise tolerance, and serum CK activity whereas long-chain fats fed in the form of corn oil or a rice bran/soy oil–supplemented feed had a beneficial effect on lowering serum CK activity. 98 Whether there is any direct beneficial effect on skeletal muscle of providing energy in the form of omega-3 versus omega-6 fatty acids has yet to be determined. Corn oil, sunflower oil, and safflower oil are high in omega-6 and lower in omega-3, whereas soybean and canola oils are moderately high in omega-6 and omega-3. Flax seed, linseed, and fish oils contain more omega-3 than omega-6. It is usually cost-prohibitive to provide sufficient energy to a PSSM horse each day in the form of dense omega-3 fat supplements. Soybean and canola oils provide a relatively affordable alternative with moderately high omega-6 or a mix of these oils and flax or fish oil can be provided. Due to the potential additional oxidant stress of fats, vitamin E (1000–5000 U/day) is recommended for horses receiving oil-supplemented diets.

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Caloric intake, dietary lifestyles, macronutrient composition and dementia

H.C. Fivecoat , G.M. Pasinetti , in Lifetime Nutritional Influences on Cognition, Behaviour and Psychiatric Illness, 2011

17.2 Obesity and the metabolic syndrome in Alzheimer's disease (AD)

High-fat diets and sedentary lifestyles have become major concerns throughout the world. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and hyperglycemic conditions, known collectively to be components of metabolic syndrome (Torpy et al., 2006). These health conditions are well known to develop along with, or be precursors of, atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of AD. Of note, accumulating evidence suggests a mechanistic link between cholesterol metabolism in the brain and the formation of amyloid plaques in AD development (Martins et al., 2006; Reid et al., 2007).

Epidemiological studies have demonstrated that individuals with obesity and diabetes have a four-fold increased risk for AD. Health risks associated with obesity, including evidence that obesity may causally promote the AD degenerative process, are of high concern for public health. By the beginning of the twenty-first century, the fraction of Americans considered to be obese reached 'epidemic' levels, according to a study published in the Journal of the American Medical Association (Mokdad et al., 1994). This study, carried out between 1991 and 1998, observed a steady increase in weight in all 50 states; across genders, age groups, races, and educational levels; and occurring regardless of smoking status. This study found that obesity had increased from 12.0   % in 1991 to 17.9   % in 1998. Likewise, national survey data has shown that in the periods 1976-1980 and 1988-1994, the age-adjusted prevalence of obesity increased by eight percentage points, from 14.5   % to 22.5   %, in the US adult population ages 20-74   years (Flegal at al., Flegal and Troiano, 2000).

Several major studies have been conducted in humans to explore the relationship between obesity and the brain. Recently, Pannacculli and colleagues (2006) explored the association between body fat and regional alterations in brain structure using voxel-based morphometry (VBM) imaging (based on high-definition 3D magnetic resonance imaging (MRI)). Compared to lean subjects, obese individuals were found to have significantly lower gray matter density in the post-central gyrus, frontal oper-culum, putamen, and middle frontal gyrus, indicating differences in the brain regulation of taste, reward, and behavioral control. Additionally, Whitmer and colleagues (2005) evaluated the possible association between obesity (as measured by body mass index (BMI) and skinfold thickness) in middle age and risk of dementia in later life in a large-scale, multi-ethnic population-based cohort. Findings revealed that obese individuals (BMI   >   30) in middle age had a 35   % higher risk for dementia compared to normal weight individuals (18.6   <   BMI   <   24.9), independent of other co-morbid conditions. Additionally, Balakrishnan and colleagues (2005) investigated the association between blood plasma Aβ levels (which promote AD development), BMI, and fat mass (FM) in healthy adults, and found significant correlations of BMI and FM with plasma Aβ1–42 levels, and also noted that the presence of certain proteins known to play a role in inflammation, cardiovascular disease and Type 2 diabetes strengthened these correlations.

Researchers have also investigated the role of leptin, a protein hormone secreted in fat cells associated with obesity (which regulates appetite and metabolism), in AD pathogenesis. In pathological conditions of aging such as in AD, it has been demonstrated that the transport of leptin across the blood-brain barrier (BBB) is significantly impaired, in particular by the downregulation of megalin, a protein to which leptin must bind in order to enter the brain (Dietrich et al., 2007). Leptin has also been shown to reduce β-secretase activity in neuronal cells, possibly by altering the lipid composition of membrane rafts, and thereby affecting Aβ generation. In fact, chronic administration of leptin actually reduced Aβ load in the brains of AD transgenic mice, suggesting the potential of leptin as a treatment for AD (Fewlass et al., 2004) and providing further support for the hypothesized link between obesity and AD.

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Apricot

Wanpeng Xi , Yun Lei , in Nutritional Composition and Antioxidant Properties of Fruits and Vegetables, 2020

38.2.4 Antimetabolic disorder in dyslipidemia

A high-fat diet results in great alterations in plasma lipid profiles and liver functions. Apricot kernel oil (AO) treatment showed significantly lower levels of total cholesterol (TC), total triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), alanine-aminotransferase (ALT), and aspartate aminotransferase (AST) activities, as well as high levels of high-density lipoprotein-cholesterol (HDL-C) and total protein of rats in comparison with the hypercholesterolemic group. AO under study are useful for the treatment of hypercholesterolemia (Ramadan et al., 2011).

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DRUG TREATMENT

Edward B. Bromfield , in Neurology and Clinical Neuroscience, 2007

KETOGENIC DIET

A high-fat diet that produces metabolic changes mimicking starvation can produce complete or dramatic seizure reductions in 30% to 50% of children with multiple seizure types (usually cryptogenic or symptomatic generalized epilepsy syndromes). Short-term risks include weight loss, renal stones, acidosis, hemolytic anemia, lethargy, and elevated liver function values; treatment is usually initiated in the hospital and maintained with the assistance of a dietitian. Much less information is available concerning feasibility, effectiveness, and long-term safety in adults. More palatable modifications of this high-fat, low-carbohydrate diet, such as the "low glycemic index," South Beach, and Atkins diets, are under study.

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Mitochondria as a Target for Safety and Toxicity Evaluation of Nutraceuticals

João S. Teodoro , ... Carlos M. Palmeira , in Nutraceuticals, 2016

Resveratrol in Obesity and Diabetes

In HFD-fed mice, RES supplementation increased insulin sensitivity (Baur and Sinclair, 2006; Baur et al., 2006). However, as with aging, there is a dual behavior of RES in regard to weight loss, because low doses of RES cause HFD-fed mice to gain weight (Pearson et al., 2008) and high doses cause weight loss (Lagouge et al., 2006), once more demonstrating that "one size fits all" treatment with RES is not adequate and in fact might be harmful. Accordingly, insulin sensitivity was also only improved in diabetic patients (Liu et al., 2014). Nevertheless, RES increases fatty acid oxidation and reduces blood pressure and cardiac hypertrophy (Dolinsky et al., 2013). Similarly, lower glucose levels, improved β-cell function, and increased insulin sensitivity were achieved with RES in nonhuman primates (Jimenez-Gomez et al., 2013) and in diabetic humans (Elliott et al., 2009). These effects occur synergistically with current antidiabetic treatments (Novelle et al., 2015). Further, activation of SirT1 with RES causes activation of the peroxisome proliferation-activated receptor γ (PPARγ) co-activator 1α (PGC-1α), a known master regulator of mitochondrial homeostasis and biogenesis, which is accompanied with a reduction in ROS generation (Lagouge et al., 2006).

Typically associated with obesity is low-grade inflammation, in part because of elevated production of proinflammatory cytokines by lipid-engorged adipocytes. RES supplementation was able to reduce adipocyte size in HFD-fed animals while decreasing several classes of inflammatory markers (Jimenez-Gomez et al., 2013; Novelle et al., 2015). Hepatocellular damage in a condition commonly associated with obesity (nonalcoholic fatty liver disease) was reduced by RES supplementation (Faghihzadeh et al., 2014), although some other works failed to obtain the same results (Chachay et al., 2014), a phenomenon once more associated with the metabolic status of the patients (Novelle et al., 2015), illustrating the need for careful analysis of the literature and conclusive studies on the matter.

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New Research and Developments of Water-Soluble Vitamins

Jean-Marc Zingg , in Advances in Food and Nutrition Research, 2018

10.6 Insulin Resistance, Metabolic Syndrome, and Diabetes

A high-fat diet has been causally linked with insulin resistance as a result of accumulation of intracellular free fatty acids which impair the signal transduction from the insulin receptor to Akt mainly as a consequence of activation of PTEN, p38, JNK, PKC, NF-κB, and ATF-2 (Boucher, Kleinridders, & Kahn, 2014; Kennedy & Kashyap, 2011; Liang, Han, Senokuchi, & Tall, 2007; Wang et al., 2006). CD36 deficiency increases insulin sensitivity in muscle but induces insulin resistance in the liver in mice, and insulin resistance was the result of the uptake of fatty acids into cells and tissues rather than the presence of fatty acids in plasma (Goudriaan et al., 2003). Thus, since αT and more so αTP reduce CD36 surface exposition and intracellular lipid accumulation, it may prevent the development of insulin resistance. In addition to that, αTP may alleviate insulin resistance by activating the CD36/PI3K/Akt-signaling pathway via hTAP/SEC14L2-mediated lipid exchange in an insulin/insulin receptor-independent manner (Zingg et al., 2014; Zingg et al., 2015, 2017). In fact, a high dose of vitamin E transiently reduced insulin resistance and associated parameters in overweight subjects (Manning et al., 2004).

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