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Trans Fat Intake and Behavior
Chapter 14
Trans Fat Intake and Behavior Camila Simonetti Pase1, 2 and Marilise Escobar Bu¨rger1 1
Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, Brazil; 2Universidade Federal do Pampa,
Uruguaiana, Brazil
1. INTRODUCTION Fatty acids are considered one of the most important constituents in living organisms due to their structural role in cell membranes and as sources of metabolic energy. Most natural unsaturated fatty acids in eukaryotes typically occur as cis configuration, which is strictly controlled by the stereoselectivity of desaturase enzymes. Trans double bonds of unsaturated fatty acids only exist naturally in some bacteria or ruminants. Most trans fatty acids (TFAs) are formed from partially hydrogenated vegetable oils, which is a process of hardening liquid vegetable oils and fats. These FAs are used to improve durability, palatability, and texture in industrialized products. Hence, the major dietary sources of trans fatty acids include margarine and shortening, being used in fast foods, frying fat, bakery products, and crackers (Mozaffarian et al., 2006). Changes in dietary habits, including the increased consumption of industrialized products, have led to the intake of large amounts of partially hydrogenated vegetable oils and fats, hence, of TFAs. Several nutritional and epidemiological studies have indicated that the high consumption of trans fats may cause adverse effects on human health (Mozaffarian et al., 2006; Thompson et al., 2011). Over the last few years, numerous studies have identified that the consumption of TFAs is related to multiple cardiovascular risks, contributing to an increased risk of coronary heart disease. Specifically, TFA intake increases low-density lipoprotein cholesterol concentrations, decreases high-density lipoprotein cholesterol concentrations, and can also cause systemic inflammation as well as endothelial dysfunction (Lopez et al., 2005). Alteration of insulin sensitivity and higher risk of type 2 diabetes have also been reported to follow the long-term intake of TFAs (Ibrahim et al., 2009). In addition, dietary TFAs can be incorporated into membrane phospholipids, thus decreasing membrane fluidity and altering the biochemical properties and functionality of membrane proteins (Larqué et al., 2003). TFAs from foods are quickly metabolized and then incorporated into plasma phospholipids. The occurrence of TFAs in cell membrane phospholipids may alter cell membrane asymmetry and fluidity. Overall, the same findings support the notion that trans fat consumption is related to an increased vulnerability to the development of neuropsychiatric conditions. This hypothesis has been extensively supported by experimental studies, when the chronic supplementation of trans fat was related to movement disorders (Teixeira et al., 2012), memory impairments (Teixeira et al., 2011), increased preference for addictive drugs (Kuhn et al., 2013, 2015a,b), besides stress-induced anxiety and fear behavior (Pase et al., 2013). Interestingly, studies regarding Western societies have shown a growing incidence of neuropsychiatric diseases (Innis, 2007), raising concerns about their etiology, which include dietary habits. The presence of TFAs in the Western diet has been the focus of attention due to the escalating consumption of processed foods, making it of vital importance to evaluate the impact of this consumption on the behavior and pathophysiology of diseases that affect the new generations. In this sense, this chapter is a review about the nutritional aspects of TFAs, collectively considering the outcomes of clinical and preclinical trials that are relevant to understanding dietary trans fat in relation to behavioral disturbances.
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2. TRANS FATTY ACIDS: CHEMICAL AND DIETARY ASPECTS It is well known that there are two distinct sources of TFAs that can be found in the diet: industrial TFA (iTFA) and ruminant TFA (rTFA). These different TFAs may have opposite effects on the metabolic health. On the one hand, iTFAs are the most common in the diet and are found in partially hydrogenated vegetable oils. This process is used by the food industry because it allows longer shelf life, thermodynamic stability, and enhanced palatability of the food product. Thus, iTFAs are widely used in the production of baked goods, deep-fried foods, and packaged snacks. In chemical terms, elaidic acid, the isomer of oleic acid, is the major iTFA, while trans isomers of linoleic acid appear in smaller amounts. On the other hand, rTFA can be mainly found in dietary products derived from the milk and meat of ruminants. TFAs from natural ruminant products such as dairy and beef have been shown to display neutral to beneficial health effects, suggesting that natural TFAs have a different bioactivity compared to industrially produced TFA. rTFAs are produced during the natural bacterial hydrogenation of unsaturated fatty acids that occurs in the rumen of polygastric animals such as cattle, sheep, and goats. Main rTFAs are trans-vaccenic acids, trans-palmitoleic acids, and conjugated linoleic acids (CLAs). In summary, these are the two distinct sources of TFA, each having their specific chemical composition.
2.1 Industrial Trans Fat The synthesis of TFA first started in 1890 through the hydrogenation process, which consists of changing an original cis configuration of a remaining double bond into a trans configuration, thereby resulting in a more linear fatty acid chain. TFAs are, therefore, similar in conformation and behavior to saturated fatty acids. TFAs are formed during the partial hydrogenation of liquid polyunsaturated oils, forming semisolid fats such as margarine and shortening. The majority of trans fats in a typical Western diet come from margarines, processed cheeses, commercially fried foods, and bakery products. Margarines are produced by a process known as partial hydrogenation. During partial hydrogenation, some of the cis isomers found in the aliphatic chain become trans isomers as the hydrogenation process leaves the double bond intact. Therefore, the aliphatic tail is no longer kinked, causing distinct conformational changes. Partial hydrogenation is mainly used to remove unstable fatty acids; MUFA and PUFA are generally unstable, however, when partially hydrogenated, these fatty acids are no longer unstable. Partial hydrogenation increases the shelf life of foods such as margarine. The process of partial hydrogenation is, therefore, a hallmark identifier for iTFA. Fried foods, fast foods, pastries, margarines, shortenings, cake mixes, and many frozen meals and packaged foods contain industrially produced trans fats. iTFAs are found primarily as elaidic acid (18:1 trans-9), which is one of the main TFA isomers formed during the commercial hydrogenation of vegetable oils. Oleic acid (18:1) is a naturally occurring fatty acid found in many vegetable oils. Upon partial hydrogenation, it becomes elaidic acid and changes conformation. Although elaidic acid is the primary form of iTFA, 18:2, 18:3, and 16:2 fatty acid moieties can also be found in a trans form in industrially produced foods. Therefore, elaidic acid is elevated in products containing partially hydrogenated margarines or vegetable shortening such as fried foods, cookies, donuts, and crackers. North Americans consume between 5 and 10 g/day of iTFA with an upper limit of 20 g/day. Five to 10 g of iTFA/day constitutes approximately 2%e5% of total energy in our diets.
2.2 Trans Fat From Ruminants TFAs also occur naturally in ruminant meat and dairy products. Typically, we consume 2%e9% of our total fatty acid content as rTFA. Furthermore, a study has estimated that as much as half of all trans fats consumed in specialty diets such as the Mediterranean diet will be in the form of rTFA (van de Vijver et al., 2000). The major contributor in the category of rTFA is vaccenic acid. Vaccenic acid (18:1 trans-11) constitutes 50%e80% of all ruminant-derived trans fats and is naturally produced by bacterial fermentation of dietary unsaturated fatty acids in ruminants (cattle, goats, and sheep). It is present at low concentrations in milk, yoghurt, cheese, butter, and meat of ruminant species. CLAs complete the rest of the category. Briefly, CLAs are also found in products from ruminants and are identified by two double bonds within the aliphatic chain that are separated by a single bond in between. Rumenic acid (c9t11-CLA) is an example of conjugated linoleic acids. Vaccenic acid consists of only one double bond. It is the isomer of oleic acid (18:1 trans-11) and although similar to elaidic acid, the position of the double bond in vaccenic acid (position 11 vs. position 9 in elaidic acid) plays an integral role in determining the differences between the two fatty acids. Vaccenic acid is derived from a complete biohydrogenation of the PUFA, linoleic acid, and linolenic acid, within the gut of ruminants. It is therefore imperative that the differences between iTFA and rTFA are acknowledged in terms of their detrimental or positive health effects.
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3. TRANS FAT CONSUMPTION: INFLUENCES ON OFFSPRING BEHAVIOR Mammals encounter two environments during neural development: the intrauterine and early postnatal environments, and adverse environments may have negative influences on childhood and adult life. Lipids correspond to about 50%e60% of the dry weight of the brain, in which approximately 35% is in the form of LC-PUFA (Innis, 2007). In fact, the influence of the intake of specific types of lipids during early stages of life on the health of adult offspring has been documented (deVelasco et al., 2012; Ibrahim et al., 2009). Thus, several studies have indicated that the development and maturation of the brain can be influenced by diet, especially in early stages of life, when the events of synaptic plasticity and neural reorganization occur at a higher intensity (de Velasco et al., 2012; Murphy et al., 2014). Therefore, the maternal diet during these critical periods (pregnancy and lactation) can impact the developing brain, functioning as an epigenetic factor that could influence the offspring to metabolic alterations in adulthood. Animal models provide strong evidence that the perinatal nutrition has an enduring impact on numerous aspects of offspring physiology and behavior, including a higher likelihood to develop mental health disorders, impairments in social behaviors, decreased cognitive abilities, and altered reward-based behaviors (Sullivan et al., 2010; Yu et al., 2010). Experimentally, rodent models have shown that a high-fat consumption was related to increased nursing and grooming (Purcell et al., 2011). Higher grooming rates in rodents can influence offspring behavior (Weaver et al., 2006). Furthermore, evidence from studies on overfeeding suggests that higher rates of nursing favor hyperphagia behavior, increased body weight, and reprogramming of the hypothalamic pathways that regulate energy balance (Glavas et al., 2010). Another way that diet can affect the maternal behavior in a rodent model is when a high-energy diet disrupts the maternal hippocampal function, consequently affecting learning and memory parameters (Kanoski et al., 2010). Evidence has shown that intake of trans fatty acids may have adverse effects on fetal growth and development, interfering with essential fatty acid metabolism, having direct effects on membrane structures or metabolism. Several studies have shown that dietary trans fatty acids are transferred from mother to fetus and disturb fetal growth and birth weight (Elias and Innis, 2001). Stender and Dyerberg (2004) agree that the concentration of trans fatty acids in newborns is inversely proportional to the concentration of longer-chain, more-unsaturated derivatives of essential fatty acids, the LCPUFAs. Thus, a newborn with a high concentration of trans fatty acids appeared to have correspondingly lower concentrations of arachidonic (AA) and docosahexaenoic acid (DHA), which are important for fetal growth, and development of the central nervous system. It has been already demonstrated that maternal diet with TFAs induces inflammatory processes that could generate brain dysfunctions and lead to neurodegenerative diseases. Offspring from dams that received saturated or trans fat diets during pregnancy and lactation showed increased expression of brain cytokines in adult life that could impair brain development (Bolton and Bilbo, 2014). TFAs provided during the perinatal period were able to modify the brain oxidative status and facilitated the development of emotionality and anxiety symptoms in offspring (Pase et al., 2013). Additionally, it has been demonstrated that maternal intake of dietary trans fat was able to induce memory impairments in the adult offspring (Pase et al., 2017). Furthermore, Albuquerque et al. (2006) observed that the intake of partially hydrogenated vegetable oil, which is rich in TFAs, during pregnancy and lactation modified the food intake central control, whose role is exerted by both insulin and serotonin in adult animals. TFAs also led to changes in the homeostasis of these animals, suggesting that early adaptations induced by the trans diet may have deleterious consequences in later life. These relationships exemplify the interconnectivity of maternal diet and behavior as well as demonstrate pathways in humans through which maternal diet affects maternal behavior, thus indirectly influencing the behavior of the next generation.
4. TRANS FAT AND DEPRESSION Depressive disorders are a leading cause of disability worldwide, affecting approximately 350 million people (Vermeulen et al., 2016). According to statistics from the World Health Organization (2012), depression is the fourth most common global burden of disease, and will be the second leading cause of disease, coming only after cardiovascular disease, by 2020. In Europe and North America, the lifetime prevalence of depression is estimated between 10% and 20%, and two times higher in women than in men (Le Port et al., 2012). In China, the incidence of depression in elderly people ranged from 4% to 26.5%, and it has become a substantial burden (Gao et al., 2009). It is well known that diet is related to inflammation, oxidative stress, and brain plasticity and function; all these physiological factors are potentially involved in depression (Jacka et al., 2011). In the past several decades, many epidemiological studies have pointed out that diet plays an important role in mental health, and investigated the relation between the intake of individual foods or nutrients and the risk of depression (Lucas et al., 2011).
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The potential effect of specific nutrients on physiologic pathways that lead to depression, allied to the observation that diet is a modifiable behavior, has prompted a series of studies that examined the potential etiologic role of dietary factors in the development of this mental health problem. It was postulated nearly 2 decades ago that the sharp rises in the rate of depression in the 20th century could be associated with the increased consumption of vegetable oils and decreased consumption of omega-3 fats (Hibbeln and Salem, 1998). Evidence indicates that Western dietary patterns are associated with negative mental health states, including depression and anxiety (Jacka et al., 2011), whereas a higher adherence to the Mediterranean food pattern (rich in fruit, vegetables, fish, and cereals) was found to be inversely related to the risk of depression (Akbaraly et al., 2013). In addition to evidence linking trans fat to depression, some data suggest an association between trans fat consumption and behaviors of irritability and aggression (Golomb et al., 2012). From different experimental evidence, researchers have suggested the development of neuroinflammation to the pathophysiology of depression and other neuropsychiatric diseases, whose etiology may be also linked to trans fat consumption, since it has been related to proinflammatory events (Mozaffarian et al., 2009; Lang and Borgwardt, 2013). In line with this, a subgroup of depression characterized by high C-reactive protein levels has been recently found to respond to antiinflammatory treatment (Raison, 2014). Diet may influence inflammatory processes through the modulation of sympathetic activity, oxidative stress, and proinflammatory cytokine production (Kiecolt-Glaser, 2010). Proinflammatory cytokines may also interfere with neurotransmitter metabolism, decrease plasma tryptophan levels, alter messenger RNA neurotransmitters, and inhibit brain-derived-neurotrophic-factor (BDNF) expression, which is a peptide that is critical for axonal growth, neuronal survival, and synaptic plasticity and function. BDNF levels have been reported to be reduced in patients with depression, and antidepressants seem to upregulate BDNF and other neurotrophic and growth factors (Jacka et al., 2011). According to Sánchez-Villegas et al. (2011), TFA intake, a well-known risk factor for cardiovascular disease (CVD), might also have a detrimental effect on the development of depression. The adverse effects of TFA on CVD are thought to be mediated by increases in plasma concentrations of low-density lipoprotein (LDL) cholesterol, reductions in highdensity lipoprotein (HDL) cholesterol, proinflammatory changes, endothelial dysfunction, and possibly insulin resistance and displacement of essential fatty acids from membranes. Thus, since depression is associated with modifications in proinflammatory cytokines as well as in endothelial cellesignaling cascades, some detrimental biological modifications caused by TFA with respect to CVD risk could also be responsible for a harmful effect of TFA on the risk of depression. A longitudinal study in Spain has also found a detrimental relationship between trans fatty acid intake and risk of depression (Sánchez-Villegas et al., 2011). Furthermore, the Whitehall II Study found that trans fat intake was associated with recurrent depressive symptoms in women (Akbaraly et al., 2013). Negative affective states such as depression, anxiety, and psychological distress have long been associated with disease, and studies have associated well-being with reduced mortality (Chida and Steptoe, 2008). In contrast, Western dietary patterns are associated with negative mood states (Brinkworth et al., 2009), and the intake of trans fatty acids was associated with negative affect and inversely associated with positive affect (Ford et al., 2016).
5. TRANS FAT AND DEMENTIA Cognitive disorders in later life are potentially devastating and several studies have identified an association between saturated or trans fat intake and risk of dementia (Morris et al., 2003). Alzheimer’s disease (AD), the most common form of adult onset dementia, is a progressive and neurodegenerative disorder characterized by the reduction of cognitive and functional abilities of the brain. The two hallmarks of AD are the presence of senile plaques and neurofibrillary tangles in the brain (Kim et al., 2015). The senile plaques are extracellular amyloid b-peptide (Ab) protein deposits derived from amyloid precursor protein. Many studies have shown that Ab-mediated oxidative stress plays an important role, causing neurotoxicity in the pathogenesis of AD (Mattson, 2004). A recent study indicates that mono-trans arachidonic acids were found in the hippocampus of 9-month-old human amyloid precursor protein (hAPP) mice (Hsu et al., 2015). The Chicago Health and Aging Project, which studied a group of 815 individuals aged 65 years and older at baseline, have identified positive associations between saturated and trans fat intake and risk of developing AD. In this large prospective study of age-related cognitive change in a community, high intake of saturated and trans unsaturated fat was associated with a greater decline in cognitive score over a 6-year followup. The intake of monounsaturated fat was inversely associated with cognitive changes among people with good cognitive function at baseline, and among those with stable long-term consumption of margarine, a major food source (Morris et al., 2003).
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Several possible mechanisms link trans fat intake to the risk of dementia. TFAs tend to elevate total plasma and LDL cholesterol concentrations, which, in turn, may be associated with risk of AD. In a clinical study, serum cholesterol levels drawn in midlife (average 42 years old) were associated with AD risk nearly 3 decades later (average 69 years old) (Solomon et al., 2009). Moreover, cholesterol may play a key role in beta-amyloid production and deposition (Puglielli et al., 2003). Although it may be intracellular cholesterol distribution, not circulating cholesterol concentrations, that regulates beta-amyloid generation, the boundaries between the roles of cholesterol in the plasma and in the brain are not clear. In a postmortem study of 64 individuals with AD, total serum and LDL cholesterol concentrations were associated with the quantity of beta-amyloid N-42, but not with the less pathogenic beta-amyloid N-40, in the cerebral cortex (Kuo et al., 1998). In fact, these prospective studies indicate relationships between saturated and trans fat intake and risk of cognitive problems.
6. TRANS FAT AND RISK FACTORS FOR DRUG ADDICTION Drug abuse is a relevant issue of public health. Drug addiction represents a dramatic dysregulation of motivational circuits and is defined primarily based on behavior toward substances and activities, together with reports of associated cognitions, emotions, and other experiences. These behavioral tendencies and experiences are represented in the brain, modifying its neurochemical aspects in ways that may perpetuate and potentially escalate drug consumption. Of particular importance, drug-induced neural changes in cortical and basal ganglia structures, involving dopaminergic, GABAergic, and opioid peptidergic neurocircuits, are thought to be critical in the development of drug addiction. These changes characterize a significant transition from occasional and voluntary drug use to habitual use, compulsion and chronic addiction, together with heightened stress, underlying what is described as the three-stage recurring cycle of addiction, namely binge/ intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving) (Koob and Volkow, 2016), caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. There has been evidence derived mostly from the animal literature that fatty acids from dietary fats could play a role in substance abuse through their action on the central serotonergic and dopaminergic systems, both known to play a role in reward mechanisms. It has been demonstrated that dietary fats exert influences on male binge drinking frequency, as well as the loss of PUFA tissue due to alcohol use (Kim et al., 2007). Interestingly, human studies have associated n-3 PUFA deficiencies with increased vulnerability to affective disorders and aggression, besides the addiction to psychostimulant drugs (Buydens-Branchey et al., 2008). One observational study performed with heroin addicts has shown that the ratio of n-6 to n-3 PUFA was higher in red blood cells of addicted individuals than in volunteer nondrug abusers (Wannasirindr et al., 2000). Besides, there is the existence of a causal relationship between PUFA status and relapse vulnerability in cocaine addicts (Buydens-Branchey et al., 2003). The relation between trans fat consumption and addiction has not been much studied. Experimental studies have shown that trans fat-supplemented animals are more susceptible to amphetamine self-administration in relation to control group (Kuhn et al., 2015a). Indeed, trans fat consumption across generations could also modify behavioral and biochemical parameters related to emotionality and stress (Pase et al., 2013), thus facilitating the preference for psychostimulant drugs (Kuhn et al., 2013, 2015b). Moreover, trans fat consumption during the perinatal period is able to modify parameters of opioid preference in female rats (Roversi et al., 2016). This relation is of relevant interest, given the potential role of trans fat in targeting fatty acids in the brain. Additional evidence has shown TFA incorporation into neural brain membranes, affecting their fluidity and biochemical properties, that can affect the reward mesocorticolimbic system (Larqué et al., 2003; Acar et al., 2003). In fact, this system is responsible for the rewarding effects of addictive drugs. The oxidative status and neurotransmission in dopaminergic brain areas are significantly affected by drug addiction, possibly due to TFA incorporation into neural phospholipid membranes.
7. TRANS FAT AND BIPOLAR DISORDER Bipolar disorder (BD) is a debilitating psychiatric condition, which can be related to disabling impairment of social and occupational functions (Magalhães et al., 2012). Many hypotheses have been postulated to explain the exact neurochemical mechanism underlying this pathophysiology, which is related to different signaling pathways, abnormalities in neural plasticity, and body neurochemical systems (Martinowich et al., 2007). There has been preliminary evidence for a role of diet in BD. As with major depression, seafood consumption has been inversely associated with prevalence rates of BD in epidemiological studies (Parker et al., 2006). There may be a correlation between decreased omega-3 consumption and increased prevalence of mood disorders. This is possibly linked to
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the effect of Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on certain aspects of physiology that have been seen as key in BD. Both EPA and DHA have been shown to reduce proinflammatory cytokines and increase BDNF as well as glutathione, possibly countering relevant peripheral changes in BD (Ross et al., 2007). Postmortem studies have shown abnormalities in n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) and in phospholipid metabolism of individuals with schizophrenia and mood disorders (Hamazaki and Maekawa, 2015). According to Kummerow et al. (2004), TFAs from hydrogenated fat were able to inhibit D6-desaturase activity, which is essential for the synthesis of LC-PUFA in phospholipid membranes. Different human studies have shown an inverse correlation between LC-PUFA plasma and TFA, as well as a significant negative correlation between 18-carbon TFA and intelligence quotients in schizophrenia patients (Lohner et al., 2014). Furthermore, experimental studies have shown that trans fat supplementation of two sequential generations of rats from mating to adulthood was able to modify FA profile in the hippocampus, exacerbating behavioral and biochemical parameters related to mania development (Dias et al., 2015a). Indeed, prolonged consumption of trans fat has also allowed TFA incorporation, which was related to increased oxidative damage in the striatum, impairing the functionality of enzymes and affecting molecular targets closely related to neuropsychiatric diseases such as bipolar disorder (Dias et al., 2015b; Trevizol et al., 2015a). In addition, the predominance of trans fat in the diet was interestingly related to amphetamine-induced hyperactivity (Trevizol et al., 2013), while trans fat consumption from weaning until adulthood for two generations was related to increased locomotor activity, impulsiveness, and agitation (Pase et al., 2015), which are indicative of spontaneous hyperactivity. These behavioral abnormalities can be linked to manic and attention deficit hyperactivity disorder symptoms, which are involved in neuropsychiatric disorders. As a whole, these results indicate that the molecular signaling cascade suffers influences from TFA incorporation in brain membranes. According to Trevizol et al. (2015b), TFA can reduce BDNF mRNA expression following amphetamine administration. This finding reinforces the hypothesis related to mania development, since reduced BDNF levels have been related to BD development. Additional evidence suggests that BDNF is involved in BD (Frey et al., 2006), since clinical studies have shown significant negative correlation between serum lipid peroxidation markers and BDNF levels in BD patients. These studies have also shown that TFA incorporation in brain membranes may be related to behavioral and biochemical changes, being reflected on molecular neuroadaptations following an animal model of mania. These findings reinforce impairments due to prolonged consumption of foods rich in trans fat, especially during early life periods, whose consequences may be reflected through neuropsychiatric vulnerabilities in adulthood.
8. CONCLUSION Recent studies have provided strong evidence that the chronic consumption of trans fats may facilitate the development of impairments in human health. These literature outcomes indicate that the consumption of processed foods, which are rich in trans fats, can modify the plasticity and permeability of brain neural membranes, impairing cellular and molecular pathways, facilitating the development of neuropsychiatric diseases. Thus, the current study contributes to a warning for public health authorities, since it shows the harmful influence of trans fats on the development of behavioral disturbances.
LIST OF ABBREVIATIONS AA Arachidonic acid AD Alzheimer’s disease BD Bipolar disease BDNF Brain-derived neurotrophic factor CLA Conjugated linoleic acids CNS Central nervous system CVD Cardiovascular disease DHA Docosahexaenoic acid EPA Eicopentaenoic acid FA Fatty acids LCPUFA Long-chain polyunsaturated fatty acid MUFA Monounsaturated fatty acid PUFA Polyunsaturated fatty acid SFA Saturated fatty acid TFA Trans fatty acid
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SUMMARY POINTS l l
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Fatty acids have an important structural role in cell membranes. Natural fatty acids typically occur as cis configuration, while trans fatty acids are formed from partially hydrogenated vegetable oils. Changes in dietary habits, including the increased consumption of industrialized products, have led to the intake of large amounts of trans fatty acids. Several nutritional and epidemiological studies have indicated that the high consumption of trans fats may cause adverse effects on human health. Trans fatty acids are related to multiple cardiovascular risks, alteration of insulin sensitivity, and higher risk of type 2 diabetes. Trans fat may have adverse effects on fetal growth and development. Trans fatty acids can be incorporated into membrane phospholipids, altering the biochemical properties and functionality of membrane proteins, increasing the vulnerability to the development of neuropsychiatric conditions. It is necessary to alert public health authorities about the harmful influence of trans fatty acids on the development of behavioral disorders.
KEY FACTS OF TRANS FATTY ACIDS l
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Trans fats are unsaturated fatty acids with at least one double bond in the trans configuration where the two hydrogen atoms are on opposite sides of the double bond. Ruminant TFA (rTFA) and industrial TFA (iTFA) and are the two distinct sources of TFA that can be found in the diet. Main rTFA are trans-vaccenic acids, trans-palmitoleic acids and conjugated linoleic acids (CLA). Elaidic acid, the isomer of oleic acid, is the major iTFA. rTFA occur naturally in small amounts in foods produced from ruminant animals such as milk, beef, and lamb. Most of the trans fatty acids (iTFAs) are found in margarines, fast foods, frying fat, bakery products, and crackers. Trans fat in diet increases risk for heart disease and many other health problems.
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Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3, 760e773. Kuhn, F.T., Roversi, K., Antoniazzi, C.T.D., Pase, C.S., Trevizol, F., Barcelos, R.C.S., Dias, V.T., Roversi, K., Boufleur, N., Benvegnú, D.M., Piccolo, J., Emanuelli, T., Bürger, M.E., 2013. Influence of trans fat and omega-3 on the preference of psychostimulant drugs in the first generation of young rats. Pharmacol. Biochem. Behav. 110, 58e65. Kuhn, F.T., Dias, V.T., Roversi, K., Vey, L., De Freitas, D.L., Pase, C.S., Roversi, K., Veit, J.C., Emanuelli, T., Burger, M.E., 2015a. Cross-generational trans fat consumption favors self-administration of amphetamine and changes molecular expressions of BDNF, DAT, and D1/D2 receptors in the cortex and hippocampus of rats. Neurotoxic Res. 28, 319e331. Kuhn, F.T., Trevizol, F., Dias, V.T., Barcelos, R.C.S., Pase, C.S., Roversi, K., Antoniazzi, C.T.D., Roversi, K., Boufleur, N., Benvegnú, D.M., Emanuelli, T., Bürger, M.E., 2015b. 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Dietary trans fatty acids alter the compositions of microsomes and mitochondria and the activities of microsome n6-fatty acid desaturase and glucose-6-phosphatase in livers of pregnant rats. J. Nutr. 133, 2526e2531. Le Port, A., Gueguen, A., Kesse-Guyot, E., Melchior, M., Lemogne, C., Nabi, H., Goldberg, M., Zins, M., Czernichow, S., 2012. Association between dietary patterns and depressive symptoms over time: a 10-year follow-up study of the GAZEL cohort. PLoS One 7, 51593. Lohner, S., Vágási, J., Marosvölgyi, T., Tényi, T., Decsi, T., 2014. Inverse association between 18-carbon trans fatty acids and intelligence quotients in smoking schizophrenia patients. Psychiatry Res. 215, 9e13. Lopez, G.E., Schulze, M.B., Meigs, J.B., Manson, J.E., Rifai, N., Stampfer, M.J., Willett, W.C., Hu, F.B., 2005. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J. Nutr. 135 (3), 562e566. Lucas, M., Mirzaei, F., O’Reilly, E.J., Pan, A., Willett, W.C., Kawachi, I., Koenen, K., Ascherio, A., 2011. Dietary intake of n-3 and n-6 fatty acids and the risk of clinical depression in women: a 10-y prospective follow-up study. Am. J. Clin. Nutr. 93, 1337e1343. Magalhães, P.V., Kapczinski, F., Nierenberg, A.A., Deckersbach, T., Weisinger, D., Dodd, S., Berk, M., 2012. Illness burden and medical comorbidity in the systematic treatment enhancement program for bipolar disorder. Acta Psychiatr. Scand. 125 (4), 303e308. Martinowich, K., Manji, H.K., Lu, B., 2007. New perspective of BDNF cell biology and its implications in depression. Nat. Neurosci. 10, 1089e1093. Mattson, M.P., 2004. Pathways towards and away from Alzheimer’s disease. Nature 430 (7000), 631e639. Morris, M.C., Evans, E.A., Bienias, J.L., Tangney, C.C., Bennett, D.A., Aggarwal, N., Schneider, J., Wilson, R.S., 2003. Dietary fats and the risk of incident Alzheimer’s disease. Arch. Neurol. 60, 194e200. Murphy, T., Dias, G.P., Thuret, S., 2014. Effects of diet on brain plasticity in animal and human studies: mind the gap. Neural Plast., 563160
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Mozaffarian, D., Katan, M.B., Ascherio, A., Stampfer, M.J., Willett, W.C., 2006. Trans fatty acids and cardiovascular disease. N. Engl. J. Med. 354 (15), 1601e1613. Mozaffarian, D., Aro, A., Willett, W., 2009. Health effects of trans-fatty acids: experimental and observational evidence. Eur. J. Clin. Nutr. 63, S5eS21. Parker, G., Gibson, N.A., Brotchie, H., Heruc, G., Rees, A.M., Hadzi-Pavlovic, D., 2006. Omega-3 fatty acids and mood disorders. Am. J. Psychiatry 163, 969e978. Pase, C.S., Roversi, K., Trevizol, F., Roversi, K., Kuhn, F.T., Schuster, A.J., Vey, L.T., Dias, V.T., Barcelos, R.C.S., Piccolo, J., Emanuelli, T., Bürger, M.E., 2013. Influence of perinatal trans fat on behavioral responses and brain oxidative status of adolescent rats acutely exposed to stress. Neuroscience 247, 242e252. Pase, C.S., Roversi, K., Trevizol, F., Kuhn, F.T., Dias, V.T., Roversi, K., Vey, L.T., Antoniazzi, C.T., Barcelos, R.C.S., Burguer, M.E., 2015. Chronic consumption of trans fat can facilitate the development of hyperactive behavior in rats. Physiol. Behav. 139, 344e350. Pase, C.S., Roversi, K., Roversi, K., Vey, L.T., Dias, V.T., Veit, J., Maurer, L.H., Duarte, T., Emanuelli, T., Duarte, M., Bürger, M.E., 2017. Maternal trans fat intake during pregnancy or lactation impairs memory and alters BDNF and TrkB levels in the hippocampus of adult offspring exposed to chronic mild stress. Physiol. Behav. 169, 114e123. Puglielli, L., Tanzi, R.E., Kovacs, D.M., 2003. Alzheimer’s disease: the cholesterol connection. Nat. Neurosci. 6, 345e351. Purcell, R.H., Sun, B., Pass, L.L., Power, M.L., Moran, T.H., Tamashiro, K.L., 2011. Maternal stress and high-fat diet effect on maternal behavior, milk composition, and pup ingestive behavior. Physiol. Behav. 104, 474e479. Raison, C.L., 2014. Inflammatory depression: a trifecta of trouble. J. Clin. Psychiatry 75, 663e664. Ross, B.M., Seguin, J., Sieswerda, L.E., 2007. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis. 6, 21. Roversi, K., Pase, C.S., Roversi, K., Vey, L.T., Dias, V.T., Metz, V.G., Bürger, M.E., 2016. Trans fat intake across gestation and lactation increases morphine preference in females but not in male rats: behavioral and biochemical parameters. Eur. J. Pharmacol. 788, 210e217. Sánchez-Villegas, A., Verberne, L., De Irala, J., Ruiz-Canela, M., Toledo, E., Serra-Majem, L., Martínez-González, M.A., 2011. Dietary fat intake and the risk of depression: the SUN project. PLoS One 6, 16268. Solomon, A., Kivipelto, M., Wolozin, B., Zhou, J., Whitmer, R.A., 2009. Midlife sérum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement. Geriatr. Cogn. Disord. 28, 75e80. Stender, S., Dyerberg, J., 2004. Influence of trans fatty acids on health. Ann. Nutr. Metab. 48, 61e66. Sullivan, E.L., Grayson, B., Takahashi, D., Robertson, N., Maier, A., Bethea, C.L., Smith, M.S., Coleman, K., Grove, K.L., 2010. Chronic consumption of a high-fat diet during pregnancy causes perturbations in the serotonergic system and increased anxiety-like behavior in nonhuman primate offspring. J. Neurosci. 30, 3826e3830. Teixeira, A.M., Pase, C.S., Boufleur, N., Roversi, K., Barcelos, R.C.S., Benvegnú, D.M., Segat, H.J., Dias, V.T., Reckziegel, P., Trevizol, F., Dolci, G.S., Carvalho, N.R., Soares, F.A., Rocha, J.B., Emanuelli, T., Bürger, M.E., 2011. Exercise affects memory acquisition, anxiety-like symptoms and activity of membrane bound enzyme in brain of rats fed with different dietary fats: impairments of trans fat. Neuroscience 195, 80e88. Teixeira, A.M., Dias, V.T., Pase, C.S., Roversi, K., Boufleur, N., Barcelos, R.C.S., Benvegnú, D.M., Trevizol, F., Dolci, G.S., Carvalho, N.R., Quatrin, A., Soares, F.A., Reckziegel, P., Segat, H.J., Rocha, J.B., Emanuelli, T., Bürger, M.E., 2012. Could dietary trans fatty acids induce movement disorders? Effects of exercise and its influence on NaþKþ-ATPase and catalase activity in rat striatum. Behav. Brain Res. 226, 504e510. Thompson, A.K., Minihane, A.M., Williams, C.M., 2011. Trans fatty acids, insulin resistance and diabetes. Eur. J. Clin. Nutr. 65 (5), 553e564. Trevizol, F., Roversi, K., Dias, V.T., Roversi, K., Pase, C.S., Barcelos, R.C.S., Benvegnu, D.M., Kuhn, F.T., Dolci, G.S., Ross, D.H., Veit, J.C., Piccolo, J., Emanuelli, T., Bürger, M.E., 2013. Influence of lifelong dietary fats on the brain fatty acids and amphetamine-induced behavioral responses in adult rat. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 45, 215e222. 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Trans Fat Intake and Behavior Camila Simonetti Pase1, 2 and Marilise Escobar Bu¨rger1 1
Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Santa Maria, Brazil; 2Universidade Federal do Pampa,
Uruguaiana, Brazil
1. INTRODUCTION Fatty acids are considered one of the most important constituents in living organisms due to their structural role in cell membranes and as sources of metabolic energy. Most natural unsaturated fatty acids in eukaryotes typically occur as cis configuration, which is strictly controlled by the stereoselectivity of desaturase enzymes. Trans double bonds of unsaturated fatty acids only exist naturally in some bacteria or ruminants. Most trans fatty acids (TFAs) are formed from partially hydrogenated vegetable oils, which is a process of hardening liquid vegetable oils and fats. These FAs are used to improve durability, palatability, and texture in industrialized products. Hence, the major dietary sources of trans fatty acids include margarine and shortening, being used in fast foods, frying fat, bakery products, and crackers (Mozaffarian et al., 2006). Changes in dietary habits, including the increased consumption of industrialized products, have led to the intake of large amounts of partially hydrogenated vegetable oils and fats, hence, of TFAs. Several nutritional and epidemiological studies have indicated that the high consumption of trans fats may cause adverse effects on human health (Mozaffarian et al., 2006; Thompson et al., 2011). Over the last few years, numerous studies have identified that the consumption of TFAs is related to multiple cardiovascular risks, contributing to an increased risk of coronary heart disease. Specifically, TFA intake increases low-density lipoprotein cholesterol concentrations, decreases high-density lipoprotein cholesterol concentrations, and can also cause systemic inflammation as well as endothelial dysfunction (Lopez et al., 2005). Alteration of insulin sensitivity and higher risk of type 2 diabetes have also been reported to follow the long-term intake of TFAs (Ibrahim et al., 2009). In addition, dietary TFAs can be incorporated into membrane phospholipids, thus decreasing membrane fluidity and altering the biochemical properties and functionality of membrane proteins (Larqué et al., 2003). TFAs from foods are quickly metabolized and then incorporated into plasma phospholipids. The occurrence of TFAs in cell membrane phospholipids may alter cell membrane asymmetry and fluidity. Overall, the same findings support the notion that trans fat consumption is related to an increased vulnerability to the development of neuropsychiatric conditions. This hypothesis has been extensively supported by experimental studies, when the chronic supplementation of trans fat was related to movement disorders (Teixeira et al., 2012), memory impairments (Teixeira et al., 2011), increased preference for addictive drugs (Kuhn et al., 2013, 2015a,b), besides stress-induced anxiety and fear behavior (Pase et al., 2013). Interestingly, studies regarding Western societies have shown a growing incidence of neuropsychiatric diseases (Innis, 2007), raising concerns about their etiology, which include dietary habits. The presence of TFAs in the Western diet has been the focus of attention due to the escalating consumption of processed foods, making it of vital importance to evaluate the impact of this consumption on the behavior and pathophysiology of diseases that affect the new generations. In this sense, this chapter is a review about the nutritional aspects of TFAs, collectively considering the outcomes of clinical and preclinical trials that are relevant to understanding dietary trans fat in relation to behavioral disturbances.
The Molecular Nutrition of Fats. https://doi.org/10.1016/B978-0-12-811297-7.00014-7 Copyright © 2019 Elsevier Inc. All rights reserved.
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2. TRANS FATTY ACIDS: CHEMICAL AND DIETARY ASPECTS It is well known that there are two distinct sources of TFAs that can be found in the diet: industrial TFA (iTFA) and ruminant TFA (rTFA). These different TFAs may have opposite effects on the metabolic health. On the one hand, iTFAs are the most common in the diet and are found in partially hydrogenated vegetable oils. This process is used by the food industry because it allows longer shelf life, thermodynamic stability, and enhanced palatability of the food product. Thus, iTFAs are widely used in the production of baked goods, deep-fried foods, and packaged snacks. In chemical terms, elaidic acid, the isomer of oleic acid, is the major iTFA, while trans isomers of linoleic acid appear in smaller amounts. On the other hand, rTFA can be mainly found in dietary products derived from the milk and meat of ruminants. TFAs from natural ruminant products such as dairy and beef have been shown to display neutral to beneficial health effects, suggesting that natural TFAs have a different bioactivity compared to industrially produced TFA. rTFAs are produced during the natural bacterial hydrogenation of unsaturated fatty acids that occurs in the rumen of polygastric animals such as cattle, sheep, and goats. Main rTFAs are trans-vaccenic acids, trans-palmitoleic acids, and conjugated linoleic acids (CLAs). In summary, these are the two distinct sources of TFA, each having their specific chemical composition.
2.1 Industrial Trans Fat The synthesis of TFA first started in 1890 through the hydrogenation process, which consists of changing an original cis configuration of a remaining double bond into a trans configuration, thereby resulting in a more linear fatty acid chain. TFAs are, therefore, similar in conformation and behavior to saturated fatty acids. TFAs are formed during the partial hydrogenation of liquid polyunsaturated oils, forming semisolid fats such as margarine and shortening. The majority of trans fats in a typical Western diet come from margarines, processed cheeses, commercially fried foods, and bakery products. Margarines are produced by a process known as partial hydrogenation. During partial hydrogenation, some of the cis isomers found in the aliphatic chain become trans isomers as the hydrogenation process leaves the double bond intact. Therefore, the aliphatic tail is no longer kinked, causing distinct conformational changes. Partial hydrogenation is mainly used to remove unstable fatty acids; MUFA and PUFA are generally unstable, however, when partially hydrogenated, these fatty acids are no longer unstable. Partial hydrogenation increases the shelf life of foods such as margarine. The process of partial hydrogenation is, therefore, a hallmark identifier for iTFA. Fried foods, fast foods, pastries, margarines, shortenings, cake mixes, and many frozen meals and packaged foods contain industrially produced trans fats. iTFAs are found primarily as elaidic acid (18:1 trans-9), which is one of the main TFA isomers formed during the commercial hydrogenation of vegetable oils. Oleic acid (18:1) is a naturally occurring fatty acid found in many vegetable oils. Upon partial hydrogenation, it becomes elaidic acid and changes conformation. Although elaidic acid is the primary form of iTFA, 18:2, 18:3, and 16:2 fatty acid moieties can also be found in a trans form in industrially produced foods. Therefore, elaidic acid is elevated in products containing partially hydrogenated margarines or vegetable shortening such as fried foods, cookies, donuts, and crackers. North Americans consume between 5 and 10 g/day of iTFA with an upper limit of 20 g/day. Five to 10 g of iTFA/day constitutes approximately 2%e5% of total energy in our diets.
2.2 Trans Fat From Ruminants TFAs also occur naturally in ruminant meat and dairy products. Typically, we consume 2%e9% of our total fatty acid content as rTFA. Furthermore, a study has estimated that as much as half of all trans fats consumed in specialty diets such as the Mediterranean diet will be in the form of rTFA (van de Vijver et al., 2000). The major contributor in the category of rTFA is vaccenic acid. Vaccenic acid (18:1 trans-11) constitutes 50%e80% of all ruminant-derived trans fats and is naturally produced by bacterial fermentation of dietary unsaturated fatty acids in ruminants (cattle, goats, and sheep). It is present at low concentrations in milk, yoghurt, cheese, butter, and meat of ruminant species. CLAs complete the rest of the category. Briefly, CLAs are also found in products from ruminants and are identified by two double bonds within the aliphatic chain that are separated by a single bond in between. Rumenic acid (c9t11-CLA) is an example of conjugated linoleic acids. Vaccenic acid consists of only one double bond. It is the isomer of oleic acid (18:1 trans-11) and although similar to elaidic acid, the position of the double bond in vaccenic acid (position 11 vs. position 9 in elaidic acid) plays an integral role in determining the differences between the two fatty acids. Vaccenic acid is derived from a complete biohydrogenation of the PUFA, linoleic acid, and linolenic acid, within the gut of ruminants. It is therefore imperative that the differences between iTFA and rTFA are acknowledged in terms of their detrimental or positive health effects.
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3. TRANS FAT CONSUMPTION: INFLUENCES ON OFFSPRING BEHAVIOR Mammals encounter two environments during neural development: the intrauterine and early postnatal environments, and adverse environments may have negative influences on childhood and adult life. Lipids correspond to about 50%e60% of the dry weight of the brain, in which approximately 35% is in the form of LC-PUFA (Innis, 2007). In fact, the influence of the intake of specific types of lipids during early stages of life on the health of adult offspring has been documented (deVelasco et al., 2012; Ibrahim et al., 2009). Thus, several studies have indicated that the development and maturation of the brain can be influenced by diet, especially in early stages of life, when the events of synaptic plasticity and neural reorganization occur at a higher intensity (de Velasco et al., 2012; Murphy et al., 2014). Therefore, the maternal diet during these critical periods (pregnancy and lactation) can impact the developing brain, functioning as an epigenetic factor that could influence the offspring to metabolic alterations in adulthood. Animal models provide strong evidence that the perinatal nutrition has an enduring impact on numerous aspects of offspring physiology and behavior, including a higher likelihood to develop mental health disorders, impairments in social behaviors, decreased cognitive abilities, and altered reward-based behaviors (Sullivan et al., 2010; Yu et al., 2010). Experimentally, rodent models have shown that a high-fat consumption was related to increased nursing and grooming (Purcell et al., 2011). Higher grooming rates in rodents can influence offspring behavior (Weaver et al., 2006). Furthermore, evidence from studies on overfeeding suggests that higher rates of nursing favor hyperphagia behavior, increased body weight, and reprogramming of the hypothalamic pathways that regulate energy balance (Glavas et al., 2010). Another way that diet can affect the maternal behavior in a rodent model is when a high-energy diet disrupts the maternal hippocampal function, consequently affecting learning and memory parameters (Kanoski et al., 2010). Evidence has shown that intake of trans fatty acids may have adverse effects on fetal growth and development, interfering with essential fatty acid metabolism, having direct effects on membrane structures or metabolism. Several studies have shown that dietary trans fatty acids are transferred from mother to fetus and disturb fetal growth and birth weight (Elias and Innis, 2001). Stender and Dyerberg (2004) agree that the concentration of trans fatty acids in newborns is inversely proportional to the concentration of longer-chain, more-unsaturated derivatives of essential fatty acids, the LCPUFAs. Thus, a newborn with a high concentration of trans fatty acids appeared to have correspondingly lower concentrations of arachidonic (AA) and docosahexaenoic acid (DHA), which are important for fetal growth, and development of the central nervous system. It has been already demonstrated that maternal diet with TFAs induces inflammatory processes that could generate brain dysfunctions and lead to neurodegenerative diseases. Offspring from dams that received saturated or trans fat diets during pregnancy and lactation showed increased expression of brain cytokines in adult life that could impair brain development (Bolton and Bilbo, 2014). TFAs provided during the perinatal period were able to modify the brain oxidative status and facilitated the development of emotionality and anxiety symptoms in offspring (Pase et al., 2013). Additionally, it has been demonstrated that maternal intake of dietary trans fat was able to induce memory impairments in the adult offspring (Pase et al., 2017). Furthermore, Albuquerque et al. (2006) observed that the intake of partially hydrogenated vegetable oil, which is rich in TFAs, during pregnancy and lactation modified the food intake central control, whose role is exerted by both insulin and serotonin in adult animals. TFAs also led to changes in the homeostasis of these animals, suggesting that early adaptations induced by the trans diet may have deleterious consequences in later life. These relationships exemplify the interconnectivity of maternal diet and behavior as well as demonstrate pathways in humans through which maternal diet affects maternal behavior, thus indirectly influencing the behavior of the next generation.
4. TRANS FAT AND DEPRESSION Depressive disorders are a leading cause of disability worldwide, affecting approximately 350 million people (Vermeulen et al., 2016). According to statistics from the World Health Organization (2012), depression is the fourth most common global burden of disease, and will be the second leading cause of disease, coming only after cardiovascular disease, by 2020. In Europe and North America, the lifetime prevalence of depression is estimated between 10% and 20%, and two times higher in women than in men (Le Port et al., 2012). In China, the incidence of depression in elderly people ranged from 4% to 26.5%, and it has become a substantial burden (Gao et al., 2009). It is well known that diet is related to inflammation, oxidative stress, and brain plasticity and function; all these physiological factors are potentially involved in depression (Jacka et al., 2011). In the past several decades, many epidemiological studies have pointed out that diet plays an important role in mental health, and investigated the relation between the intake of individual foods or nutrients and the risk of depression (Lucas et al., 2011).
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The potential effect of specific nutrients on physiologic pathways that lead to depression, allied to the observation that diet is a modifiable behavior, has prompted a series of studies that examined the potential etiologic role of dietary factors in the development of this mental health problem. It was postulated nearly 2 decades ago that the sharp rises in the rate of depression in the 20th century could be associated with the increased consumption of vegetable oils and decreased consumption of omega-3 fats (Hibbeln and Salem, 1998). Evidence indicates that Western dietary patterns are associated with negative mental health states, including depression and anxiety (Jacka et al., 2011), whereas a higher adherence to the Mediterranean food pattern (rich in fruit, vegetables, fish, and cereals) was found to be inversely related to the risk of depression (Akbaraly et al., 2013). In addition to evidence linking trans fat to depression, some data suggest an association between trans fat consumption and behaviors of irritability and aggression (Golomb et al., 2012). From different experimental evidence, researchers have suggested the development of neuroinflammation to the pathophysiology of depression and other neuropsychiatric diseases, whose etiology may be also linked to trans fat consumption, since it has been related to proinflammatory events (Mozaffarian et al., 2009; Lang and Borgwardt, 2013). In line with this, a subgroup of depression characterized by high C-reactive protein levels has been recently found to respond to antiinflammatory treatment (Raison, 2014). Diet may influence inflammatory processes through the modulation of sympathetic activity, oxidative stress, and proinflammatory cytokine production (Kiecolt-Glaser, 2010). Proinflammatory cytokines may also interfere with neurotransmitter metabolism, decrease plasma tryptophan levels, alter messenger RNA neurotransmitters, and inhibit brain-derived-neurotrophic-factor (BDNF) expression, which is a peptide that is critical for axonal growth, neuronal survival, and synaptic plasticity and function. BDNF levels have been reported to be reduced in patients with depression, and antidepressants seem to upregulate BDNF and other neurotrophic and growth factors (Jacka et al., 2011). According to Sánchez-Villegas et al. (2011), TFA intake, a well-known risk factor for cardiovascular disease (CVD), might also have a detrimental effect on the development of depression. The adverse effects of TFA on CVD are thought to be mediated by increases in plasma concentrations of low-density lipoprotein (LDL) cholesterol, reductions in highdensity lipoprotein (HDL) cholesterol, proinflammatory changes, endothelial dysfunction, and possibly insulin resistance and displacement of essential fatty acids from membranes. Thus, since depression is associated with modifications in proinflammatory cytokines as well as in endothelial cellesignaling cascades, some detrimental biological modifications caused by TFA with respect to CVD risk could also be responsible for a harmful effect of TFA on the risk of depression. A longitudinal study in Spain has also found a detrimental relationship between trans fatty acid intake and risk of depression (Sánchez-Villegas et al., 2011). Furthermore, the Whitehall II Study found that trans fat intake was associated with recurrent depressive symptoms in women (Akbaraly et al., 2013). Negative affective states such as depression, anxiety, and psychological distress have long been associated with disease, and studies have associated well-being with reduced mortality (Chida and Steptoe, 2008). In contrast, Western dietary patterns are associated with negative mood states (Brinkworth et al., 2009), and the intake of trans fatty acids was associated with negative affect and inversely associated with positive affect (Ford et al., 2016).
5. TRANS FAT AND DEMENTIA Cognitive disorders in later life are potentially devastating and several studies have identified an association between saturated or trans fat intake and risk of dementia (Morris et al., 2003). Alzheimer’s disease (AD), the most common form of adult onset dementia, is a progressive and neurodegenerative disorder characterized by the reduction of cognitive and functional abilities of the brain. The two hallmarks of AD are the presence of senile plaques and neurofibrillary tangles in the brain (Kim et al., 2015). The senile plaques are extracellular amyloid b-peptide (Ab) protein deposits derived from amyloid precursor protein. Many studies have shown that Ab-mediated oxidative stress plays an important role, causing neurotoxicity in the pathogenesis of AD (Mattson, 2004). A recent study indicates that mono-trans arachidonic acids were found in the hippocampus of 9-month-old human amyloid precursor protein (hAPP) mice (Hsu et al., 2015). The Chicago Health and Aging Project, which studied a group of 815 individuals aged 65 years and older at baseline, have identified positive associations between saturated and trans fat intake and risk of developing AD. In this large prospective study of age-related cognitive change in a community, high intake of saturated and trans unsaturated fat was associated with a greater decline in cognitive score over a 6-year followup. The intake of monounsaturated fat was inversely associated with cognitive changes among people with good cognitive function at baseline, and among those with stable long-term consumption of margarine, a major food source (Morris et al., 2003).
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Several possible mechanisms link trans fat intake to the risk of dementia. TFAs tend to elevate total plasma and LDL cholesterol concentrations, which, in turn, may be associated with risk of AD. In a clinical study, serum cholesterol levels drawn in midlife (average 42 years old) were associated with AD risk nearly 3 decades later (average 69 years old) (Solomon et al., 2009). Moreover, cholesterol may play a key role in beta-amyloid production and deposition (Puglielli et al., 2003). Although it may be intracellular cholesterol distribution, not circulating cholesterol concentrations, that regulates beta-amyloid generation, the boundaries between the roles of cholesterol in the plasma and in the brain are not clear. In a postmortem study of 64 individuals with AD, total serum and LDL cholesterol concentrations were associated with the quantity of beta-amyloid N-42, but not with the less pathogenic beta-amyloid N-40, in the cerebral cortex (Kuo et al., 1998). In fact, these prospective studies indicate relationships between saturated and trans fat intake and risk of cognitive problems.
6. TRANS FAT AND RISK FACTORS FOR DRUG ADDICTION Drug abuse is a relevant issue of public health. Drug addiction represents a dramatic dysregulation of motivational circuits and is defined primarily based on behavior toward substances and activities, together with reports of associated cognitions, emotions, and other experiences. These behavioral tendencies and experiences are represented in the brain, modifying its neurochemical aspects in ways that may perpetuate and potentially escalate drug consumption. Of particular importance, drug-induced neural changes in cortical and basal ganglia structures, involving dopaminergic, GABAergic, and opioid peptidergic neurocircuits, are thought to be critical in the development of drug addiction. These changes characterize a significant transition from occasional and voluntary drug use to habitual use, compulsion and chronic addiction, together with heightened stress, underlying what is described as the three-stage recurring cycle of addiction, namely binge/ intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving) (Koob and Volkow, 2016), caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. There has been evidence derived mostly from the animal literature that fatty acids from dietary fats could play a role in substance abuse through their action on the central serotonergic and dopaminergic systems, both known to play a role in reward mechanisms. It has been demonstrated that dietary fats exert influences on male binge drinking frequency, as well as the loss of PUFA tissue due to alcohol use (Kim et al., 2007). Interestingly, human studies have associated n-3 PUFA deficiencies with increased vulnerability to affective disorders and aggression, besides the addiction to psychostimulant drugs (Buydens-Branchey et al., 2008). One observational study performed with heroin addicts has shown that the ratio of n-6 to n-3 PUFA was higher in red blood cells of addicted individuals than in volunteer nondrug abusers (Wannasirindr et al., 2000). Besides, there is the existence of a causal relationship between PUFA status and relapse vulnerability in cocaine addicts (Buydens-Branchey et al., 2003). The relation between trans fat consumption and addiction has not been much studied. Experimental studies have shown that trans fat-supplemented animals are more susceptible to amphetamine self-administration in relation to control group (Kuhn et al., 2015a). Indeed, trans fat consumption across generations could also modify behavioral and biochemical parameters related to emotionality and stress (Pase et al., 2013), thus facilitating the preference for psychostimulant drugs (Kuhn et al., 2013, 2015b). Moreover, trans fat consumption during the perinatal period is able to modify parameters of opioid preference in female rats (Roversi et al., 2016). This relation is of relevant interest, given the potential role of trans fat in targeting fatty acids in the brain. Additional evidence has shown TFA incorporation into neural brain membranes, affecting their fluidity and biochemical properties, that can affect the reward mesocorticolimbic system (Larqué et al., 2003; Acar et al., 2003). In fact, this system is responsible for the rewarding effects of addictive drugs. The oxidative status and neurotransmission in dopaminergic brain areas are significantly affected by drug addiction, possibly due to TFA incorporation into neural phospholipid membranes.
7. TRANS FAT AND BIPOLAR DISORDER Bipolar disorder (BD) is a debilitating psychiatric condition, which can be related to disabling impairment of social and occupational functions (Magalhães et al., 2012). Many hypotheses have been postulated to explain the exact neurochemical mechanism underlying this pathophysiology, which is related to different signaling pathways, abnormalities in neural plasticity, and body neurochemical systems (Martinowich et al., 2007). There has been preliminary evidence for a role of diet in BD. As with major depression, seafood consumption has been inversely associated with prevalence rates of BD in epidemiological studies (Parker et al., 2006). There may be a correlation between decreased omega-3 consumption and increased prevalence of mood disorders. This is possibly linked to
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the effect of Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on certain aspects of physiology that have been seen as key in BD. Both EPA and DHA have been shown to reduce proinflammatory cytokines and increase BDNF as well as glutathione, possibly countering relevant peripheral changes in BD (Ross et al., 2007). Postmortem studies have shown abnormalities in n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) and in phospholipid metabolism of individuals with schizophrenia and mood disorders (Hamazaki and Maekawa, 2015). According to Kummerow et al. (2004), TFAs from hydrogenated fat were able to inhibit D6-desaturase activity, which is essential for the synthesis of LC-PUFA in phospholipid membranes. Different human studies have shown an inverse correlation between LC-PUFA plasma and TFA, as well as a significant negative correlation between 18-carbon TFA and intelligence quotients in schizophrenia patients (Lohner et al., 2014). Furthermore, experimental studies have shown that trans fat supplementation of two sequential generations of rats from mating to adulthood was able to modify FA profile in the hippocampus, exacerbating behavioral and biochemical parameters related to mania development (Dias et al., 2015a). Indeed, prolonged consumption of trans fat has also allowed TFA incorporation, which was related to increased oxidative damage in the striatum, impairing the functionality of enzymes and affecting molecular targets closely related to neuropsychiatric diseases such as bipolar disorder (Dias et al., 2015b; Trevizol et al., 2015a). In addition, the predominance of trans fat in the diet was interestingly related to amphetamine-induced hyperactivity (Trevizol et al., 2013), while trans fat consumption from weaning until adulthood for two generations was related to increased locomotor activity, impulsiveness, and agitation (Pase et al., 2015), which are indicative of spontaneous hyperactivity. These behavioral abnormalities can be linked to manic and attention deficit hyperactivity disorder symptoms, which are involved in neuropsychiatric disorders. As a whole, these results indicate that the molecular signaling cascade suffers influences from TFA incorporation in brain membranes. According to Trevizol et al. (2015b), TFA can reduce BDNF mRNA expression following amphetamine administration. This finding reinforces the hypothesis related to mania development, since reduced BDNF levels have been related to BD development. Additional evidence suggests that BDNF is involved in BD (Frey et al., 2006), since clinical studies have shown significant negative correlation between serum lipid peroxidation markers and BDNF levels in BD patients. These studies have also shown that TFA incorporation in brain membranes may be related to behavioral and biochemical changes, being reflected on molecular neuroadaptations following an animal model of mania. These findings reinforce impairments due to prolonged consumption of foods rich in trans fat, especially during early life periods, whose consequences may be reflected through neuropsychiatric vulnerabilities in adulthood.
8. CONCLUSION Recent studies have provided strong evidence that the chronic consumption of trans fats may facilitate the development of impairments in human health. These literature outcomes indicate that the consumption of processed foods, which are rich in trans fats, can modify the plasticity and permeability of brain neural membranes, impairing cellular and molecular pathways, facilitating the development of neuropsychiatric diseases. Thus, the current study contributes to a warning for public health authorities, since it shows the harmful influence of trans fats on the development of behavioral disturbances.
LIST OF ABBREVIATIONS AA Arachidonic acid AD Alzheimer’s disease BD Bipolar disease BDNF Brain-derived neurotrophic factor CLA Conjugated linoleic acids CNS Central nervous system CVD Cardiovascular disease DHA Docosahexaenoic acid EPA Eicopentaenoic acid FA Fatty acids LCPUFA Long-chain polyunsaturated fatty acid MUFA Monounsaturated fatty acid PUFA Polyunsaturated fatty acid SFA Saturated fatty acid TFA Trans fatty acid
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SUMMARY POINTS l l
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Fatty acids have an important structural role in cell membranes. Natural fatty acids typically occur as cis configuration, while trans fatty acids are formed from partially hydrogenated vegetable oils. Changes in dietary habits, including the increased consumption of industrialized products, have led to the intake of large amounts of trans fatty acids. Several nutritional and epidemiological studies have indicated that the high consumption of trans fats may cause adverse effects on human health. Trans fatty acids are related to multiple cardiovascular risks, alteration of insulin sensitivity, and higher risk of type 2 diabetes. Trans fat may have adverse effects on fetal growth and development. Trans fatty acids can be incorporated into membrane phospholipids, altering the biochemical properties and functionality of membrane proteins, increasing the vulnerability to the development of neuropsychiatric conditions. It is necessary to alert public health authorities about the harmful influence of trans fatty acids on the development of behavioral disorders.
KEY FACTS OF TRANS FATTY ACIDS l
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Trans fats are unsaturated fatty acids with at least one double bond in the trans configuration where the two hydrogen atoms are on opposite sides of the double bond. Ruminant TFA (rTFA) and industrial TFA (iTFA) and are the two distinct sources of TFA that can be found in the diet. Main rTFA are trans-vaccenic acids, trans-palmitoleic acids and conjugated linoleic acids (CLA). Elaidic acid, the isomer of oleic acid, is the major iTFA. rTFA occur naturally in small amounts in foods produced from ruminant animals such as milk, beef, and lamb. Most of the trans fatty acids (iTFAs) are found in margarines, fast foods, frying fat, bakery products, and crackers. Trans fat in diet increases risk for heart disease and many other health problems.
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