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High Calorie Diet and the Human Brain: Metabolic Consequences of Long-Term Consumption

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Abstract

The purpose of this monograph is to present readers with a comprehensive and cutting edge description of neurochemical effects of diet (beneficial and harmful effects) in normal human brain and to discuss how present day diet promotes pathogenesis of stroke, AD, PD, and depression in a manner that is useful not only to students and teachers but also to researchers, dietitians, nutritionists and physicians. A diet in sufficient amount and appropriate macronutrients is essential for optimal health of human body tissues. In brain, over-nutrition, particularly with high-calorie diet, not only alters cellular homeostasis, but also results in changes in the intensity of signal transduction processes in reward centers of the brain resulting in food addiction. Over-nutrition produces detrimental effects on human health in general and brain health in particular because it chronically increases the systemic and brain inflammation and oxidative stress along with induction of insulin resistance and leptin resistance in the brain as well as visceral organs. Onset of chronic inflammation and oxidative stress not only leads to obesity and heart disease, but also promotes type II diabetes and metabolic syndrome, which are risk factors for both acute neural trauma (stroke) and chronic age-related neurodegenerative and neuropsychological disorders, such as Alzheimer disease (AD), Parkinson disease (PD) and depression.

Chapters (10)

Long term consumption of high calorie diet, which is enriched in high amounts of saturated fats, cholesterol, n-6 fatty acids, salt and low fibers produces obesity, insulin resistance, type-2 diabetes, and metabolic syndrome. This pathological condition is an important risk factor for heart disease, stroke, Alzheimer disease, and cancer. At the molecular level, the long term consumption of high calorie diet not only promotes oxidative stress through induction of mitochondrial dysfunction, but also through decreased activities of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Long term consumption of high calorie diet also produces neuroinflammation through the generation of proinflammatory eicosanoids and increased expression of proinflammatory cytokines. In addition, long term consumption of high calorie diet is associated with endocrine disturbances and abnormalities in cardiac function supporting the view that long term consumption of high calorie diet impairs systemic metabolic homeostasis, which is a metabolic stressor associated with oxidative and endoplasmic reticulum stress. In contrast, calorie restriction with adequate micronutrient supplementation promotes metabolic fitness, longevity, and disease protection in rodents. Mediators of caloric restriction, including growth hormone, insulin, insulin-like growth factor-1, the circulating longevity hormone (Klotho) that binds to the IGF-1 receptor, as well as the Sirtuin family of longevity genes, have been shown to modulate both organismal lifespan and healthspan across species.
Long term consumption of high fat diet induces alterations in hypothalamus and hippocampal signaling leading to neuroinflammation and oxidative stress. High fat diet-mediated alterations in hypothalamus and hippocampal signaling involve ER stress and mitochondrial dysfunctions, and insulin resistance. Several mechanisms may contribute to high fat diet-mediated inflammation in hypothalamus and peripheral tissues. These mechanisms include the activation of TLR4 receptors, induction of ER stress, and activation of IKKβ. The relative contribution of these mechanisms in the induction of hypothalamic and peripheral inflammation remains unknown. However, early onset of inflammation in the hypothalamus relative to that in peripheral tissues suggests that different processes may cause inflammation in the peripheral tissues and hypothalamus. At the molecular level, inflammation is not only supported by elevation in levels of ARA and its lipid mediators (PGs, LTs, and TXs) and increase in platelet activating factor, but also with increase in expression of proinflammatory genes including genes for cytokines (TNF-α, IL-1β, and IL-6) along with activation of proinflammatory enzymes (secretory phospholipase A2, cyclooxygenase-2, and nitric oxide synthase). High fat diet is a major cause of obesity which is closely linked to a variety of health issues, including coronary heart disease, stroke, high blood pressure, fatty liver disease, diabetes, certain cancers, and neurological disorders. The consumption of high fat diet not only produces free radicals, but also contributes to the development of systemic inflammation and insulin resistance through the involvement of lipid-sense nuclear factors such as peroxisome proliferator-activated receptors (PPARs) and liver X receptors, which play critical roles in cellular fatty acid and carbohydrate metabolism as well as cell proliferation. High fat-mediated changes in hippocampus have negative impact on cognitive function not only due to vascular defects and impaired insulin metabolism, but also due to the defect in glucose transport mechanisms in brain.
The consumption of high carbohydrate diet produces many changes in the brain including alterations in electrophysiological properties of neurons, reduction in the density of synaptic inputs, induction of gliosis and impairment in insulin signaling in hypothalamic neurons controlling energy balance. In the liver, fructose is metabolized by fructokinase, which is not regulated by the negative feedback mechanism. Utilization of ATP in fructokinase reaction results in intracellular phosphate depletion and the rapid generation of uric acid due to activation of AMP deaminase. The consumption of fructose in high calorie diet correlates closely with the rise in insulin resistance, obesity, diabetes as well as neurological disorders. Fructose is a highly lipogenic sugar. It stimulates triglyceride synthesis, and increases fat deposition in the liver. The consumption of fructose also produces oxidative stress and mitochondrial dysfunction, resulting into stimulation of peroxisome proliferator-activated receptor gamma coactivator 1-α and β (PGC1-α and PGC-1β) that drive both insulin resistance and lipogenesis. Fructose-mediated uric acid generation not only contributes to hypertension, but is also linked with endothelial dysfunction, and insulin and leptin resistance.
Short term consumption of high protein diet has been reported to cause weight loss and prevention of weight (re)gain. High protein diet not only induces satiety, increases secretion of gastrointestinal hormones, and increases diet-mediated thermogenesis, but also induces adaptations of the metabolic pathways involved in protein and energy metabolism. Depending on amino acid composition, rate of absorption, and protein/food texture, consumption of proteins produce unique effects in visceral tissues and brain. These characteristics may modulate and determine the metabolic effects of proteins in the visceral tissues and brain. However, long term consumption of high-protein diets may produce detrimental effects on human health. High levels of isoleucine, leucine, valine, tyrosine, and phenylalanine produce insulin resistance and markedly increase the risk of diabetes, cardiovascular disease, and chronic kidney disease.
The consumption of artificial sweeteners is very popular because they are low in calories. Although, Food and Drug Administration has approved aspartame, acesulfame-k, neotame, cyclamate and alitame for use as per acceptable daily intake value, but it is becoming increasingly evident that breakdown products of these sweeteners may produce harmful metabolic effects in the visceral tissues and brain. Thus, aspartame is hydrolyzed into phenylalanine, aspartic acid, and methanol. Phenylalanine regulates neurotransmitters, whereas aspartic acid plays an important role in inducing excitotoxicity in the brain. Lastly methanol is oxidized into formaldehyde and diketopiperazine, a carcinogen, which mediates a number of other highly toxic effects. In experimental rats saccharin is known to cause bladder cancer. Steviol, a natural extract from the Stevia plant is a mutagen, but the safety of steviol glycoside as well as steviol oxidatives has been proven. Sucralose (Splenda™) is chlorinated sucrose, which is 600 times sweeter than sucrose. Sucralose has been reported to cause dizziness, head and muscle aches, stomach cramps, diarrhea, chronic inflammation and bladder issues in rodents and humans. So far studies performed on the safety of artificial sweeteners have been a major concerned due to their neurological effects and cancer-related issues.
Sodium in diet is a major contributor to high BP, but effect of salt on BP depends on genetic makeup. This is because salt sensitivity is largely determined by several genes, one of which is the ACE gene. The renin–angiotensin aldosterone systems (RAAS) play a major role in the pathogenesis of high BP, which is a risk factor for coronary events, stroke, kidney failure, kidney stones and heart failure. By contrast, inadequate salt intake may lead to fatigue, postural hypotension, and insulin resistance. It is advised that most patients should use salt in moderation; i.e., to avoid high-sodium foods and not to add large amounts of salt to food during cooking or at the table. The kallikrein-kinin system (KKS) also contributes to the modulation of BP. It is hypothesized that the disruption of the RAAS/KKS balance may provoke increase in BP. In addition, endothelial dysfunction is another hallmark of high BP. It reflects the premature aging of the intima exposed to the chronic increase in arterial BP. It is caused by complex changes in the balance between endothelium-dependent vasodilator and vasoconstrictor signals. Levels of released NO and the generation of vasoconstrictor eicosanoids contribute to endothelial dysfunction. RAAS-mediated changes in brain may contribute to the pathogenesis of neurological disorders. Thus, high BP may increase the risk of microvascular brain damage and impairment in mobility, cognition, and mood. Loss of cognitive function is one the most devastating manifestations of changes in BP and vascular disease. High BP is known to cause cerebral small and large vessel disease resulting in brain damage and dementia.
Dietary fiber is the non-digestible form of carbohydrates and lignin. Consumption of high fiber diet produces beneficial effects on human health through many potential mechanisms. Thus, dietary fiber not only increases fecal bulking and viscosity, but also decreases contact time between potential carcinogens and mucosal cells. In addition, dietary fiber not only increases the binding between bile acids and carcinogens, but also promotes healthy lipid profiles, glucose tolerance, and ensures normal gastrointestinal function. In addition, dietary fiber is a substrate for fermentation by microbiota found in the rectum. Microbiota produce SCFAs (acetate, propionate, and butyrate), which are readily absorbed. Butyrate is the major energy source for colonocytes. Propionate is largely taken up by the liver. Acetate enters the peripheral circulation to be metabolized by peripheral tissues. In colonic mucosa, butyrate promotes prevention of colon cancer by inducing cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes. Collective evidence suggests that increase in SCFA production, specifically butyrate in distal colon may result in a protective effect. Collective evidence suggests that dietary fiber improves laxation, increases excretion of bile acid, estrogen, and fecal procarcinogens and carcinogens, lowers serum cholesterol, slows glucose absorption and improves insulin sensitivity. The consumption of fiber also lowers blood pressure, promotes weight loss, inhibits lipid peroxidation; and produces anti-inflammatory effects.
Long term consumption of high calorie diet, which is enriched in saturated fats, cholesterol, and n-6 fatty acids, has been reported to not only cause the synthesis of proinflammatory lipid mediators (eicosanoids and platelet activating factor), proinflammatory cytokines (TNF-α, IL-1β, and IL-6), but also reported to upregulate the expression of gp91(phox) subunit of NADPH oxidase, and downregulates superoxide dismutase (SOD) and other detoxifying enzymes. High calorie diet consumption-mediated biochemical changes produce oxidative stress, and low grade inflammation. These processes promote weight gain, obesity and insulin resistance leading to type 2 diabetes and metabolic syndrome, a pathological condition, which is an important risk factor for cardiovascular disease, osteoporosis, arthritis, and various types of cancers.
Long-term consumption of high calorie diet, which is enriched in saturated fats, cholesterol, and n-6 fatty acids produces obesity, insulin resistance, oxidative stress, low grade inflammation, and cognitive dysfunction due to abnormalities in mitochondrial function and marked alterations in signal transduction processes. High calorie diet also alters hippocampal morphology/plasticity leading to the impairment of cognitive function in rodents. This brain region is involved in learning and memory formation. Accumulating evidence suggests that long term consumption of high calorie diet not only causes oxidative stress through multiple biochemical mechanisms, but also promotes low grade chronic inflammation through increased expression of proinflammatory cytokines. Onset of chronic inflammation and oxidative stress promotes type 2 diabetes, and metabolic syndrome, which are risk factors for stroke, Alzheimer disease, and depression. In addition, long term consumption of high calorie diet also suppresses adaptive cellular response signaling by inhibiting expression of neurotrophic factors, protein chaperons, DNA-repair proteins, autophagy, and mitochondrial biogenesis.
Diet patterns modulate the onset and pathogenesis of metabolic and age-related chronic neurological disorders. Thus, long term consumption of high calorie diet with high saturated fat, cholesterol, high levels of n-6 fatty acids, high levels of refined carbohydrates, and high salt produces chronic oxidative stress and inflammation which are characterized by over production of ROS, AGE, eicosanoids, and proinflammatory cytokines along with declines in antioxidant capacity in visceral tissues and the brain. These processes not only contribute to cognitive decline, but also neurodegeneration. In contrast, Mediterranean diet with low saturated fats and low refined sugars, but rich in olive oil, n-3 fatty acids, antioxidants vitamins C, E, and polyphenolic compounds produces neuroprotective effects supporting the view that specific dietary constituents of Mediterranean diet are able to influence the onset and development of above mentioned metabolic and neurological disorders. Similarly, the consumption of ketogenic diet retards obesity, metabolic syndrome, and diabetes as well as epilepsy amyotrophic lateral sclerosis, Alzheimer, Parkinson’s disease, and some mitochondriopathies. These diseases have different pathogenesis and features, but oxidative stress and neuroinflammation are closely associated with the pathogenesis of above mentioned diseases.
... The impaired function of EPCs may be restored by improving their mobilization e.g., by statins, vascular endothelial growth factor (VEGF), estrogen, or by drugs that improve function leading to the self-repair of damaged capillaries in the diabetic retina (Caballero et al., 2007) Increased production of Advanced Glycation Endproducts (AGE) AGE compounds are formed by a highly reactive, non-enzymatic reaction between reducing sugars and proteins/lipids/nucleic acids. AGE compounds diffuse out of the cell and cause modification of ECM molecules leading to cellular dysfunction (Charonis et al., 1990;Farooqui, 2015). AGE compounds also modify intracellular proteins, change their structure, cross-linking, enzymatic activity, receptor recognition and impair their clearance. ...
... However, isolated studies have demonstrated the age dependent accumulation of AGE in vascular beds and lens in an animal model (Georgescu and Popov, 2000). AGE induce apoptosis in retinal pericytes by activation of transcription factors like FOXO1, mediated by p38 and JNK MAP Kinases (Curtis et al., 2009;Alikhani et al., 2010;Stirban et al., 2014;Farooqui, 2015). Moreover, inhibition of formation of AGE has also been found to reduce the progression of DR (Kern and Engerman, 2001;Stitt et al., 2002;Bhatwadekar et al., 2008;Thallas-Bonke et al., 2008). ...
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... This generates a new homeostatic alternation and thereby brings epigenetic changes in the neuroendocrine genes with the production of proinflammatory cytokines. On the other hand, NF-kB induced iNOS, COX-2 and inflammatory cytokine production that paves the way to the anti-inflammatory activity [49,63,64]. Studies show that the concentration of cytokines such as IL-1α, IL-1β, IL-6 and type B receptor IL-8 (IL-8RB) is elevated close to the sites where amyloid plaques are located. ...
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... The brain's reward and motivational system, in part, seems to drive for the optimization of sufficient calories for the survival of humans (Farooqui, 2015). The ingredients of calorie-dense such as sugar, fat contents play an effective role both in the stimulation of reward and motivation systems, and endogenous opioid and mesolimbic dopaminergic pathways in the brain (Berridge et al., 2010). ...
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This review aims to draw attention to current studies on syndromes related to food eating behavior, including food addiction, and to highlight the neurobiological and neuropharmacological aspects of food addiction toward the development of new therapies. Food addiction and eating disorders are influenced by several neurobiological factors. Changes in feeding behavior, food addiction, and its pharmacological therapy are related to complex neurobiological processes in the brain. Thus, it is not surprising that there is inconsistency among various individual studies. In this review, we assessed literature including both experimental and clinical studies regarding food addiction as a feeding disorder. We selected articles from animal studies, randomized clinical trials, meta-analyses, narrative, and systemic reviews given that, crucial quantitative data with a measure of neurobiological, neuropharmacological aspects and current therapies of food addiction as an outcome. Thus, the main goal to outline here is to investigate and discuss the association between the brain reward system and feeding behavior in the frame of food addiction in the light of current literature.
... The older age, unhealthy lifestyle, toxic environment exposure, high fat diet and family history are several risk factors for AD. [28] Hyperphosphorylated tau hypothesis: ...
... Nutrition habits do not only produce healthy effects but also modulate the onset and pathogenesis of metabolic diseases (obesity, type II diabetes and metabolic syndrome), age-related acute and chronic neurological disorders (Stroke, Alzheimer's disease and depression). 3 Diet high in fructose produces hepatic steatosis (the accumulation of triglycerides in the liver) and lipogenesis, which results in the impairment of lipid metabolism (hyperlipidemia). These effects contribute to weight gain, obesity and the enhancement of the expression of pro-inflammatory cytokines. ...
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... High calorie diets, rich in carbohydrates, saturated fats and cholesterol have been shown to be associated with metabolic dysregulation, increased oxidative stress and increased inflammation which are all risk factors for obesity, cardiovascular disease, metabolic disorders, arthritis and various cancers. 31 There are limited studies however on the effects of nutrition on multimorbidity. A cross-sectional study found that that individuals with high consumption of a "meat and potatoes" diet had greater likelihood of cardiometabolic morbidity, with obesity as a likely intermediate step. ...
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Objectives Cerebral ischemia is the most common cause of disability, the second most common cause of dementia, and the fourth most common cause of death in the developed world [Sveinsson OA, Kjartansson O, Valdimarsson EM. Heilablóðþurrð/heiladrep: Faraldsfræði, orsakir og einkenni [Cerebral ischemia/infarction - epidemiology, causes and symptoms]. Laeknabladid. 2014 May;100(5):271–9. Icelandic. doi:10.17992/lbl.2014.05.543]. Obesity has been associated with worse outcomes after ischemia in rats, triggering proinflammatory cytokine production related to the brain microvasculature. The way obesity triggers these effects remains mostly unknown. Therefore, the aim of this study was to elucidate the cellular mechanisms of damage triggered by obesity in the context of cerebral ischemia. Methods We used a rat model of obesity induced by a 20% high fructose diet (HFD) and evaluated peripheral alterations in plasma (lipid and cytokine profiles). Then, we performed cerebral ischemia surgery using two-vessel occlusion (2VO) and analyzed neurological/motor performance and glial activation. Next, we treated endothelial cell line cultures with glutamate in vitro to simulate an excitotoxic environment, and we added 20% plasma from obese rats. Subsequently, we isolated EVs released from endothelial cells and treated primary cultures of astrocytes with them. Results Rats fed a HFD had an increased BMI with dyslipidemia and high levels of proinflammatory cytokines. Glia from the obese rats exhibited altered morphology, suggesting hyperreactivity related to neurological and motor deficits. Plasma from obese rats induced activation of endothelial cells, increasing proinflammatory signals and releasing more EVs. Similarly, these EVs caused an increase in NF-κB and astrocyte cytotoxicity. Together, the results suggest that obesity activates proinflammatory signals in endothelial cells, resulting in the release of EVs that simultaneously contribute to astrocyte activation.
Chapter
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Mediterranean diet consists of fresh fruits, vegetables, legumes, whole grains, fish, olive oil, garlic, and red wine. Levels of saturated fats are very low in Mediterranean diet. Among Mediterranean diet components, fresh fruits and vegetables provide various vitamins, carotenoids, flavonoids, fiber, and metal ions (potassium, magnesium, and calcium). Fish provides eicosapentaenoic and docosahexaenoic acids; olive oil is enriched in polyphenols (tyrosol, hydroxytyrosol, and oleuropein); red wine contains resveratrol; and garlic is enriched in sulfur compounds (alliin, allicin, S-allyl cysteine, and diallyl trisulfide). High levels of free radicals and neuroinflammation play an important role in cardiovascular diseases, type 2 diabetes, and neurological disorders. Mediterranean diet-derived metabolites are known to block free radical damage and retard neuroinflammation in above pathological conditions. Collectively, these studies indicate that the consumption of Mediterranean diet from the childhood to the old age not only leads to decrease in cardiovascular diseases, type 2 diabetes, and many types of cancers but also slows the onset of neurological disorders.
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It is well known that curcumin produces antioxidant, anti-inflammatory, anticancer, antiviral, and antiarthritic properties. The poor bioavailability of curcumin is the major hurdle for its more widespread use in animals and humans. However, complexation and encapsulation of curcumin into liposomes, cyclodextrin, curcumin conjugate with PLGA, complexation with phospholipids, and synthesis of curcumin analogs have made it easy to bypass this problem. New ways of delivering curcumin have resulted in increased absorption and delivery of curcumin to various body tissues including brain. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (NF-κB and HIF-1), growth factors (vascular endothelial cell growth factor), inflammatory cytokines (TNF-α, IL1, and IL-6), and enzymes (protein kinases (MAPK, Akt, COX-2, and 5-LOX).
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Alzheimer disease (AD) is recognized as one of the most common causes of dementia that leads to impairment of memory, thinking and behavior in humans. The major pathological features of AD are the increased production and deposition of amyloid-β (Aβ) and intracellular accumulation of neurofibrillary tangle composed of hyperphosphorylated tau protein, besides mitochondrial dysfunction, oxidative stress, neuroinflammation, and loss of synapse and neuronal. The animal modeling of AD has been performed in invertebrates and vertebrates. The modeling has been pursued on the basis of the amyloid hypothesis and has taken advantage of mutations in the APP, MAPT, PS1, PS2 tau protein and apoE genes, which are involved in familial forms of AD. Genetic modification technology is well developed in mice. Many transgenic mouse models have been developed. These models mimic a range of AD–related neurochemistry and pathology. Although none of the models fully replicates the human disease, the models have contributed significant insights into the pathophysiology of β-amyloid toxicity, particularly with respect to the effects of different β-amyloid species and the possible pathogenic role of β-amyloid oligomers. They have also been widely used in the preclinical testing of potential therapeutic modalities and have played a pivotal role in the development of immunotherapies for AD. There is a need for developing better animal models in bigger animals, such as rats for developing better biomarkers and drug testing information.
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Alzheimer disease (AD) is a multifactorial disorder involving oxidative stress, neuroinflammation, impairments in energy metabolism, and excitotoxicity. AD affects several brain regions such as entorhinal cortex, hippocampus, basal forebrain and amygdale, which exhibit synaptic loss resulting in extensive brain atrophy. In vulnerable brain regions, AD is characterized by the accumulation of extracellular neuritic plaques and intracellular neurofibrillary tangles. The neurofibrillary tangles consist largely of hyperphosphorylated twisted filaments of the microtubule-associated protein Tau. Extracellular neuritic plaques are deposits of Aβ that are derived via sequential proteolytic cleavages of the APP. Clinically, AD patients present with symptoms of memory loss, altered personality and behavior, and impaired executive function. Neurochemically, AD is accompanied by profound biochemical alterations in multiple pathways including increased turnover of membrane phospholipid, sphingolipid, and cholesterol metabolism and increase in phospholipid-, sphingolipid-, and cholesterol-derived lipid mediators. The severity of AD pathology is associates with number of reactive astrocytes and activated microglia in the brain. Both neurons and glial cells contribute to the induction, maintenance, and progression of neuroinflammation and oxidative stress in AD by releasing proinflammatory cytokines and generating reactive oxygen and nitrogen species, which contribute to neurodegeneration in AD. Accumulating evidence suggests that AD also involves increases in metal ions (iron, copper, and zinc), nitric oxide generation, reduction in expression of trophic factors, dysfunction of the ubiquitin–proteasome system, depletion of endogenous antioxidants, and expression of proapoptotic proteins leading to synaptic and neuronal loss.
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Magnesium is the fourth most abundant mineral and the second most abundant intracellular divalent cation and has been recognized as a cofactor for >300 metabolic reactions in the body. Some of the processes in which magnesium is a cofactor include, but are not limited to, protein synthesis, cellular energy production and storage, reproduction, DNA and RNA synthesis, and stabilizing mitochondrial membranes. Magnesium also plays a critical role in nerve transmission, cardiac excitability, neuromuscular conduction, muscular contraction, vasomotor tone, blood pressure, and glucose and insulin metabolism. Because of magnesium's many functions within the body, it plays a major role in disease prevention and overall health. Low levels of magnesium have been associated with a number of chronic diseases including migraine headaches, Alzheimer's disease, cerebrovascular accident (stroke), hypertension, cardiovascular disease, and type 2 diabetes mellitus. Good food sources of magnesium include unrefined (whole) grains, spinach, nuts, legumes, and white potatoes (tubers). This review presents recent research in the areas of magnesium and chronic disease, with the goal of emphasizing magnesium's role in disease prevention and overall health.
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Vegetables are universally promoted as healthy. Dietary Guidelines for Americans 2010 recommend that you make half of your plate fruits and vegetables. Vegetables are diverse plants that vary greatly in energy content and nutrients. Vegetables supply carbohydrates, dietary fiber, and resistant starch in the diet, all of which have been linked to positive health outcomes. Fiber lowers the incidence of cardiovascular disease and obesity. In this paper, the important role of white vegetables in the human diet is described, with a focus on the dietary fiber and resistant starch content of white vegetables. Misguided efforts to reduce consumption of white vegetables will lower intakes of dietary fiber and resistant starch, nutrients already in short supply in our diets.
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Insulin resistance (IR) links Alzheimer's disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance.
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Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer prevention. Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset. They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host's immune response; anti-proliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase signaling pathways.
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The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl-terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxyl-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.Keywords: RAS, Ang II, receptor, internalization, recycling, yeast two-hybrid system
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It is increasingly recognized that certain fundamental changes in diet and lifestyle that occurred after the Neolithic Revolution, and especially after the Industrial Revolution and the Modern Age, are too recent, on an evolutionary time scale, for the human genome to have completely adapted. This mismatch between our ancient physiology and the western diet and lifestyle underlies many so-called diseases of civilization, including coronary heart disease, obesity, hypertension, type 2 diabetes, epithelial cell cancers, autoimmune disease, and osteopo-rosis, which are rare or virtually absent in hunter–gatherers and other non-westernized popula-tions. It is therefore proposed that the adoption of diet and lifestyle that mimic the beneficial characteristics of the preagricultural environment is an effective strategy to reduce the risk of chronic degenerative diseases.
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Excess intake of dietary salt is estimated to be one of the leading risks to health worldwide. Major national and international health organizations, along with many governments around the world, have called for reductions in the consumption of dietary salt. This paper discusses behavioural and population interventions as mechanisms to reduce dietary salt. In developed countries, salt added during food processing is the dominant source of salt and largely outside of the direct control of individuals. Population-based interventions have the potential to improve health and to be cost saving for these countries. In developing economies, where salt added in cooking and at the table is the dominant source, interventions based on education and behaviour change have been estimated to be highly cost effective. Regardless, countries with either developed or developing economies can benefit from the integration of both population and behavioural change interventions.
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Osteoporosis is the index disease for calcium deficiency, just as rickets/osteomalacia is the index disease for vitamin D deficiency, but there is considerable overlap between them. The common explanation for this overlap is that hypovitaminosis D causes malabsorption of calcium which then causes secondary hyperparathyroidism and is effectively the same thing as calcium deficiency. This paradigm is incorrect. Hypovitaminosis D causes secondary hyperparathyroidism at serum calcidiol levels lower than 60 nmol/L long before it causes malabsorption of calcium because serum calcitriol (which controls calcium absorption) is maintained until serum calcidiol falls below 20 nmol/L. This secondary hyperparathyroidism, probably due to loss of a "calcaemic" action of vitamin D on bone first described in 1957, destroys bone and explains why vitamin D insufficiency is a risk factor for osteoporosis. Vitamin D thus plays a central role in the maintenance of the serum (ionised) calcium, which is more important to the organism than the preservation of the skeleton. Bone is sacrificed when absorbed dietary calcium does not match excretion through the skin, kidneys and bowel which is why calcium deficiency causes osteoporosis in experimental animals and, by implication, in humans.
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It is general knowledge that glucose homeostasis possesses very limited buffering capacities, while energy homeostasis in its fat-controlling part enjoys practically unlimited energy stores. Logically, a control system with a limited buffer should thoroughly defend the “consumption” part. Indeed, existing experimental data (briefly reviewed here) show important properties of the CHO intake control that is different from or not shown for the fat intake control.
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Dietary proteins influence body weight by affecting four targets for body weight regulation: satiety, thermogenesis, energy efficiency, and body composition. Protein ingestion results in higher ratings of satiety than equicaloric amounts of carbohydrates or fat. Their effect on satiety is mainly due to oxidation of amino acids fed in excess; this effect is higher with ingestion of specific "incomplete" proteins (vegetal) than with animal proteins. Diet-induced thermogenesis is higher for proteins than for other macronutrients. The increase in energy expenditure is caused by protein and urea synthesis and by gluconeogenesis. This effect is higher with animal proteins containing larger amounts of essential amino acids than with vegetable proteins. Specifically, diet-induced thermogenesis increases after protein ingestion by 20 - 30 %, but by only 5 - 10 % after carbohydrates and 0 - 5 % after ingestion of fat. Consumption of higher amounts of protein during dietary treatment of obesity resulted in greater weight loss than with lower amounts of protein in dietary studies lasting up to one year. During weight loss and decreased caloric intake, a relatively increased protein content of the diet maintained fat-free mass (i. e. muscle mass) and increased calcium balance, resulting in preservation of bone mineral content. This is of particular importance during weight loss after bariatric surgery because these patients are at risk for protein malnutrition. Adequate dietary protein intake in diabetes type 2 is of specific importance since proteins are relatively neutral with regard to glucose and lipid metabolism, and they preserve muscle and bone mass, which may be decreased in subjects with poorly controlled diabetes. Ingestion of dietary proteins in diabetes type 1 exerts a delayed postprandial increase in blood glucose levels due to protein-induced stimulation of pancreatic glucagon secretion. Higher than minimal amounts of protein in the diet needed for nitrogen balance may play an important role for the increasing number of elderly obese subjects in our industrialized societies, since proteins exert beneficial effects in the conditions of overweight, metabolic syndrome, cardiovascular risk factors, bone health, and sarcopenia. Adverse effects of increased dietary proteins have been observed in subjects with renal impairment- this problem is frequently observed in the elderly, hypertensive, and diabetic population. Nevertheless, dietary proteins deserve more attention than they have received in the past.
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The ability to balance energy intake and expenditure is critical to survival, and sophisticated physiological mechanisms have developed in order to do this, including the control of appetite. Satiation and satiety are part of the body's appetite control system and are involved in limiting energy intake. Satiation is the process that causes one to stop eating; satiety is the feeling of fullness that persists after eating, suppressing further consumption, and both are important in determining total energy intake.Satiation and satiety are controlled by a cascade of factors that begin when a food or drink is consumed and continues as it enters the gastrointestinal tract and is digested and absorbed. Signals about the ingestion of energy feed into specific areas of the brain that are involved in the regulation of energy intake, in response to the sensory and cognitive perceptions of the food or drink consumed, and distension of the stomach. These signals are integrated by the brain, and satiation is stimulated. When nutrients reach the intestine and are absorbed, a number of hormonal signals that are again integrated in the brain to induce satiety are released. In addition to these episodic signals, satiety is also affected by fluctuations in hormones, such as leptin and insulin, which indicate the level of fat storage in the body.Satiation and satiety can be measured directly via food intake or indirectly via ratings of subjective sensations of appetite. The most common study design when measuring satiation or satiety over a short period is using a test preload in which the variables of interest are carefully controlled. This is followed by subjects rating aspects of their appetite sensations, such as fullness or hunger, at intervals and then, after a predetermined time interval, a test meal at which energy intake is measured. Longer-term studies may provide foods or drinks of known composition to be consumed ad libitum and use measures of energy intake and/or appetite ratings as indicators of satiety. The measurement of satiation and satiety is complicated by the fact that many factors besides these internal signals may influence appetite and energy intake, for example, physical factors such as bodyweight, age or gender, or behavioural factors such as diet or the influence of other people present. For this reason, the majority of studies on satiation and satiety take place in a laboratory, where confounders can be controlled as much as possible, and are, therefore, of short duration.It is possible for any food or drink to affect appetite, and so it is important to determine whether, for a given amount of energy, particular variables have the potential to enhance or reduce satiation or satiety. A great deal of research has been conducted to investigate the effect of different foods, drinks, food components and nutrients on satiety. Overall, the characteristic of a food or drink that appears to have the most impact on satiety is its energy density. That is the amount of energy it contains per unit weight (kJ/g, kcal/g). When energy density is controlled, the macronutrient composition of foods does not appear to have a major impact on satiety. In practice, high-fat foods tend to have a higher energy density than high-protein or high-carbohydrate foods, and foods with the highest water content tend to have the lowest energy density. Some studies have shown that energy from protein is more satiating than energy from carbohydrate or fat. In addition, certain types of fibre have been shown to enhance satiation and satiety. It has been suggested that energy from liquids is less satiating then energy from solids. However, evidence for this is inconsistent, and it may be the mode of consumption (i.e. whether the liquid is perceived to be a food or drink) that influences its effect on satiety. Alcohol appears to stimulate energy intake in the short-term, and consuming energy from alcohol does not appear to lead to a subsequent compensatory reduction in energy intake.The consumption of food and drink to provide energy is a voluntary behaviour, and, despite the existence of sophisticated physiological mechanisms to match intake to requirements, humans often eat when sated and sometimes refrain from eating when hungry. Thus, there are numerous influences on eating behaviour beyond satiation and satiety. These include: the portion size, appeal, palatability and variety of foods and drinks available; the physiological impact on the body of physical activity and sleep; and other external influences such as television viewing and the effect of social situations.Because satiation and satiety are key to controlling energy intake, inter-individual differences in the strength of these signals and responsiveness to their effects could affect risk of obesity. Such differences have been observed at a genetic, physiological and behavioural level and may be important to consider in strategies to prevent or treat obesity.Overall, it is clear that, although the processes of satiation and satiety have the potential to control energy intake, many individuals override the signals generated. Hence, in such people, satiation and satiety alone are not sufficient to prevent weight gain in the current obesogenic environment. Knowledge about foods, ingredients and dietary patterns that can enhance satiation and satiety is potentially useful for controlling bodyweight. However, this must be coupled with an understanding of the myriad of other factors that influence eating behaviour, in order to help people to control their energy intake.
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Despite intensive investigation, a clear understanding of the metabolic disturbances in diabetes mellitus and their temporal relationship to each other during disease development has still not emerged. With emphasis on non-insulin-dependent diabetes (NIDDM), three possibilities are explored here: (1) that the insulin resistance characteristic of obesity/NIDDM syndromes is the result rather than the cause of hyperinsulinemia, as is widely held, (2) that the linkage between hyperactivity of the pancreatic β-cell and peripheral insulin resistance is vested in excessive delivery of lipid substrate from liver to the muscle bed, and (3) that conceivably hyperamylinemia works in concert with hyperinsulinemia in promoting overproduction of very-low-density lipoproteins by the liver, and thus in the etiology of muscle insulin resistance. © 1994 Wiley-Liss, Inc.
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Recent studies indicate that aldosterone/mineralocorticoid receptor (MR) is a major contributor of chronic kidney disease (CKD) progression. Aldosterone/MR induces glomerular podocyte injury, causing the disruption of the glomerular filtration barrier and proteinuria. Conversely, MR antagonists substantially reduce proteinuria, which can be partly attributable to the protective effects on podocytes. Aldosterone excess, caused by adipocyte-derived aldosterone-releasing factors and other mechanisms, can be pathologically important in the renal complication of metabolic syndrome. A rat model of metabolic syndrome exhibits podocyte injury and proteinuria with serum aldosterone elevation, and the renal damage is prevented by MR blockade. Accumulating data also indicate that MR inhibition can confer renoprotection in a subgroup with low or normal aldosterone levels. We have recently identified the cross-talk between MR and small GTPase Rac1, providing one theoretical basis for the renoprotective effects of MR antagonists in non-high-aldosterone subjects. MR blockade can be a promising strategy for preventing CKD progression, and future clinical trials will conclusively determine the efficacy and tolerability of selective MR inhibition in CKD and metabolic syndrome.