Role of Endocannabinoids on Sweet Taste Perception, Food ...

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Chemical Senses, 2018, Vol 43, 3–16doi:10.1093/chemse/bjx062

Review ArticleAdvance Access publication October 9, 2017

Review Article

Role of Endocannabinoids on Sweet Taste Perception, Food Preference, and Obesity-related DisordersErnesto Tarragon1 and Juan José Moreno2,3

1Department of Neurobehavioral Genetics, Institute of Psychobiology, University of Trier, Universitätsring 15, 54296 Trier, Germany, 2Department of Nutrition, Food Sciences and Gastronomy, Institute of Nutrition and Food Safety, University of Barcelona, Gran Via de les Corts Catalanes, 585, 08007 Barcelona, Spain. 3CIBEROBN Fisiopatologia de la Obesidad y Nutricion, Instituto de Salud Carlos III, C/ Monforte de Lemos 3-5, Pabellon 11. Planta 0, 28029 Madrid, Spain.

Correspondence to be sent to: Ernesto Tarragon Cros, PhD, University of Trier, Institute of Psychobiology, Department of Neurobehavioral Genetics, Johanniterufer 15, D54290 Trier, Germany. e-mail: [email protected]

Editorial Decision 27 September 2017.

Abstract

The prevalence of obesity and obesity-related disorders such as type 2 diabetes (T2D) and metabolic syndrome has increased significantly in the past decades, reaching epidemic levels and therefore becoming a major health issue worldwide. Chronic overeating of highly palatable foods is one of the main responsible aspects behind overweight. Food choice is driven by food preference, which is influenced by environmental and internal factors, from availability to rewarding properties of food. Consequently, the acquisition of a dietary habit that may lead to metabolic alterations is the result of a learning process in which many variables take place. From genetics to socioeconomic status, the response to food and how this food affects energy metabolism is heavily influenced, even before birth. In this work, we review how food preference is acquired and established, particularly as regards sweet taste; towards which flavors and tastes we are positively predisposed by our genetic background, our early experience, further lifestyle, and our surroundings; and, especially, the role that the endocannabinoid system (ECS) plays in all of this. Ultimately, we try to summarize why this system is relevant for health purposes and how this is linked to important aspects of eating behavior, as its function as a modulator of energy homeostasis affects, and is affected by, physiological responses directly associated with obesity.

Key words: 2-arachidonoylglycerol, anandamide, inflammation, natural reinforcers/reward, sweet taste, type 2 diabetes

Introduction

Eating behavior is influenced by taste perception. Humans tend to flavor pleasurable tastes and avoid those that are perceived as unpleasant. Thus, the processing of taste information and the growth a hedonic experience is essential for mediating food preference, cre-ate familiar dietary habits (Kral and Rauh 2010), and, ultimately, weight maintenance (Dotson et al. 2012).

Sweet, umami, and salty tastes have an evolutionary role in nutri-tion as a selective source of calories, proteins, and minerals; whereas bitter and sour tastes are involved in the avoidance of harmful and/or spoiled foods (Breslin and Spector 2008). Further, emerging evidence suggests that lipids can be detected by specific receptors in taste cells, leading to the development of a new taste quality (Gaillard et al. 2008; Cartoni et al. 2010).

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The prevalence of obesity and obesity-related disorders such as type 2 diabetes (T2D) and metabolic syndrome has increased sig-nificantly in the past decades, reaching epidemic levels and therefore becoming a major health issue worldwide (Ng et al. 2014). Access to large amounts of highly palatable foods containing fat and added sugars is easy in modern society. Consequently, the traditional view of obesity etiopathogenesis states that this disorder occurs mainly as a result of a chronic, high caloric food overconsumption through-out life. However, regardless the unquestionable role of overeating in weight gain, it cannot account for all variation observed in this phenotype. Directly influencing this outcome, social context (Siegel et al. 2016), hormonal environment (Bowen et al. 2014; Poddar et al. 2017), and psychological factors such as reward processes by natural reinforcers (Rolls 2016; van Strien et al. 2016) contribute as well to the appearance and maintenance of obesity.

Thus, understanding the role of taste in food selection and eating behavior is important for expanding our knowledge of the elements involved in body weight maintenance and the development of obes-ity and related diseases such as T2D.

Sweet taste, hedonic response, and food preference

The acquisition of a dietary habit that sets the path to metabolic alterations is a learning process that occurs through time, and food preference undoubtedly has a saying in this. Conveniently, humans show unconditioned appetence for certain organoleptic features, like sweetness (Berridge et al. 2010). Sweet taste is perceived through the activation of seven-transmembrane G-protein-coupled heterodimers of T1R2-T1R3 receptors, responsible for the perception of all sweet-tasting molecules, including carbohydrates and noncaloric sweeten-ers (Laffitte et al. 2014). Together with caloric density, the perception of taste and texture is notably relevant in relation to feeding, as physicochemical attributes affect the orosensory response (i.e., pal-atability) to food (Prindiville et al. 1999, 2000) and can, therefore, play a key role in modulating motivational (approach, consumption) and affective (hedonic response) constituents of eating behavior (Berthoud 2011).

After detection, T1R2-T1R3 in the tongue initiate the signal trans-mission to the nucleus of the solitary tract, from where afterward projects to the thalamus and then to the brain region responsible for processing gustatory information, also densely interconnected with the anterior insula (Oberndorfer et al. 2013). This structure is of interest when linking taste experience and food processing, since its connections with the amygdala, the anterior cingulate cortex (ACC), and the orbitofrontal cortex (OFC) make it an essential part of the limbic system. Connections from cortical structures involved in emo-tional and cognitive processing are redirected to different areas of the brain in which emotional and cognitive aspects of taste create a uni-fied experience. Further, taste can be perceived differently according to expectations and previous exposure (Sarinopoulos et al. 2006). Then, salience acquires significance, as the properties attributed to one or another food will certainly affect its motivational meaning, presenting it in the future as more or less desirable; more or less likely to be approached to and consumed.

These aspects are then integrated and influence the decision of eating that particular food or not. The involvement of prefrontal structures and processing opens the possibility of taking over the more emotional approach towards food (i.e., emotional eating), as it has been suggested for people suffering from anorexia nervosa. In these individuals, switching the automatic reinforcing response of

eating into a more conscious and rational strategy may disrupt the normal, functional reinforcement response of taste (Kaye et al. 2009). If true, this system could be operating just the opposite in overeat-ing, obesity, or other eating behavior derived disorders. Processing of the hedonic properties of food is key to develop and maintain dietary habits, and taste perception is one of the first steps in the learning process to establish such habits. It is no surprise then that hyperpalatable foods (i.e., rich in added sugar) are the most craved among people reporting food craving (White and Grilo 2005). What is more, experimental research shows that food and drug cravings share features in terms of both behavioral outcome and brain acti-vation patterns (Pelchat et al. 2004; Tang et al. 2012). This suggests that palatability, a key characteristic of a wide variety of frequently consumed and advertised products, is able to artificially affect motiv-ational and emotional responses to food in vulnerable individuals in a similar fashion as drugs of abuse do in drug abusers. Given that the behavioral response to reinforces (whether natural or artificial) is governed by the same neuronal pathways, hyperpalatable foods, in overstimulating these reinforce and reward pathways, present an increased associative power and appear as a relevant element when considering obesity-related disorders.

Interestingly, recent studies have identified sweet receptors other than in the tongue. More concretely, T1R2-T1R3 have been described within the gastrointestinal tract, in adipose tissues, and in the brain, where are also expressed and influence many physiological functions, like insulin secretion, and glucose and fat metabolism (Behrens and Meyerhof 2011; Masubuchi et al. 2013; Smith et al. 2016). This implies that sweet foods are evolutionarily predisposed to be processed as desirable and may not only influence motivated behavior but also activate specific receptors that participate in the regulation of energy metabolism (Kojima et al. 2015). Nevertheless, as others previously stated, additional factors besides physiological activity of T1R2-T1R3 are key to create a complete experience of taste (Noel and Dando 2015). In addition to this, the genetic back-ground appears to be remarkably relevant.

Genetics of sweet taste perception and food preference

Many single nucleotide polymorphisms (SNP) have been identified in the genes encoding taste receptors. SNPs in these genes result in variable sensitivity to different tastings and, therefore, personal food preference. T1R genes present multiple polymorphisms, particularly in comparison with other human genes. Indeed, T1R2 is within the top 5–10% of all human genes with regard to the reported number of polymorphisms, which was hypothesized to be associated with variations in sweet taste perception (Kim 2006).

Human genetic studies have identified a polymorphism in the GNAT3 gene, coding for α-gustducin, a protein involved in the sig-nal transduction cascade for sweet taste, which explains 13% of dif-ferences in (sweet) taste sensitivity (Fushan et al. 2010; Reed and Margolskee 2010). Concretely, it seems that the presence of the C allele in TAS1R3, the gene coding for the T1R3 receptor, facilitates the perception of sweet taste in a concentration-related fashion. Hence, individuals with the CC variant are more accurate identify-ing sweet concentration scales than those with only one (TC) allele or no C (TT) allele at all (Fushan et al. 2009; 2010). Subjects with the TT genotype display greater preference for higher sweet levels, compared with those carrying the CC variants (Mennella et al. 2014; 2015), probably to reach the same hedonic response. Preference for sweet seems related to these polymorphisms, suggesting a direct link

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between genetic variations related to sweet perception and eating behavior (Dias et al. 2015). In this way, many studies linked gen-etic variation in TAS1R with habitual consumption of sugar in over-weight and obese individuals (Table 1).

Evidence supporting this idea is also found in several studies with children and adolescents. Infants that were frequently exposed to sweetened water early in life later displayed markedly increased pref-erence for this beverage (Pepino and Mennella 2005a). In accord-ance, when testing genetic differences in sweet preference, TAS1R3 variations can be related to preference levels in adults, but not in children (Mennella et al. 2012, 2014, 2015, 2016). Notably, this has been demonstrated further than in laboratory context. How much sweetness is preferred is observed as well in food choices. Coherently, preference for greater sweetened concentrations is associated with (added) sugar content in most preferred foods (Olson and Gemmill 1981; Liem and Mennella 2002; Mennella et al. 2005). Mennella et al. demonstrated that children preference was associated with intake reports of both salt and sugar, but not to added sugar alone (Mennella et al. 2011). This particularity is of relevance given that daily, real-life food choices include most of the times a combination of nutrients (i.e., salt and sugar) instead one nutrient alone. Indeed, changes in taste perception and preference occur from infancy to teenage years and are related to the reinforcing (sweet, fat, and salty) and aversive (bitterness) properties of food (Joseph et al. 2016). Genetic variances thus seem remarkably relevant as regards modu-lating behavior, although this response is susceptible to the impact of early experiences despite the strong biological basis (Table 1). It may be possible that an early life overexposure to sweet foods influences the associative processes mentioned above (Mennella and Trabulsi 2012). In a time when high-processed food and added sugar have proved relevant for increased obesity risk, individual susceptibility

is not to be forgotten. Polymorphisms in the TAS2R38 gene have been linked to the content of added sugar as a proportion of the total amount of calories consumed by children, but not with the total amount of calories consumed alone. Further, when exploring rele-vant obesity measures, adiposity levels, and anthropometric values (i.e., waist to hip ratio) but not body mass index were inversely cor-related with sweet sensibility. This suggests that dietary habits may also impact on sweet taste perception through modifications in gene expression (Lipchock et al. 2013) and supports the idea that food quality (whole, fresh food vs. highly processed food) rather than food quantity (Kcal alone) could be an additional determinant risk factor for developing metabolic problems.

Endocannabinoid system

The endocannabinoids (eCBs) are derivatives of arachidonic acid (AA), resembling other lipid mediators such as prostaglandins and leukotrienes. AA is conjugated with ethanolamine to form fatty acid amides or with glycerol to form monoacylglycerols. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the best studied and most active members of each class, respectively (Devane et al. 1992; Mechoulam et al. 1995).

AEA biosynthesis occurs in two steps: first, a calcium-dependent transacylase transfers an acyl group from a membrane phospho-lipids to the N-position of phosphatidylethanolamine to generate N-acylphosphatidylethanolamines that selective phospholipase D hydro-lyzes to release AEA and phosphatidic acid (Okamoto et al. 2004). 2-AG is mainly synthesized from AA-containing membrane phospholipids through the action of phospholipase C, leading to the formation of dia-cylglycerol, and then through diacylglycerol lipase (DAGL) isoforms α or β (Bisogno et al. 2003; 2005) (Figure 1).

Table 1. Sweet receptors variants and effect on sweet perception and preference

Reference Target gene Variant Population Preference on sugar/sweet

Eny et al. 2010 TAS1R2 Ille191Val Overweight and obese Increased consumptionRamos-Lopez et al. 2016 Val191Val Adult men and women Higher carbohydrate intake and

hypertriglyceridemia.Haznedaroglu et al. 2015 TAS1R2, TAS1R3 rs35874116

rs307355Children from 7 to 12 Moderate (rs307355) and severe

(rs35874116) risk of caries experience in T allele variant carriers

Nie et al. 2005 TAS1R3 shows higher affinity to su-crose than TAS1R2

Fushan et al. 2009 TAS1R3 rs307355rs35744813

Caucasian, Asian, AfricanAmerican men and women

T allele carriers (CT, TT) show de-creased sensitivity to sucrose

Mennella et al. 2012 rs35744813 Children and mothers Differences in sweet preference in mothers (CC/CT, more sensitive), but not children

Mennella et al. 2014 Children and mothers Greater preference to lower sucrose concentrations in no T allele carriers

Joseph et al. 2016 TAS1R3, TAS2R38 rs35744813rs713598

Children and adults Sucrose is able to mask bitterness in CC and CT allele carriers, but not in TT allele carriers.

Pawellek et al. 2016 TAS2R38 rs713598 Children PP/PA genotype consume more sweet foods

Mennella et al. 2005 AP, PP Children and mothers AP/PP genotype show greater prefer-ence in children, not in adults

Fushan et al. 2010 GNAT3 rs2012380rs7792845

Caucasian, Asian, AfricanAmerican men and women

Regulation of sucrose sensitivity

Keskitalo et al. 2007 Chromosome 16p11.2 Normal weight adults Differences in perception of sweetness

The table shows some research made on the genetic variances of the T1R2, T1R3, and other sweet-related taste perception receptors and their influence on sweet perception and preference.

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eCBs rapid diffusion is mediated by a selective and saturable transporter (Di Marzo et al. 1994). Moreover, AEA can be accumu-lated in intracellular stores as adiposomes (Oddi et al. 2008), whereas 2-AG might be sequestered in distinct intracellular pools (Alger and Kim 2011). Finally, AEA is degraded by fatty acid amide hydro-lase (FAAH), whereas 2-AG is degraded by monoacylglycerol lip-ase (MGL) and the serine hydrolase α/β hydrolase (ABHD) domain 6 (and possibly domain 12) (Thomas et al. 2013). In the end, this breakdown leads to the release AA (AEA, 2-AG) and ethanolamide (AEA) or glycerol (2-AG) (Cravatt et al. 1996). Degradation-derived byproducts are then recycled into the phospholipid membrane, where the two eCBs are synthesized de novo (Bisogno et al. 2005).

AEA, 2-AG, and other eCBs activate two well-characterized seven-transmembrane G-protein-coupled cannabinoid (CB) receptor subtypes: CB1 (Herkenham et al. 1991) and CB2 (Munro et al. 1993). CB1 is expressed in a larger extent in the central and peripheral ner-vous system. Interestingly, CB2 is also expressed in the brain (Chen et al. 2017), where it seems to be upregulated upon stressing condi-tions (Viscomi et al. 2009). However, both receptors can be local-ized ubiquitously in the organism (Maccarrone et al. 2001; Nong et al. 2001; Klein et al. 2003), including heart, uterus, testis, liver, and immune cells (Roche et al. 2006; Liu et al. 2009).

Regulation of hedonic response of sweet taste and food preference/intake by eCBs

The role of the endocannabinoid system (ECS) on the hedonic response of eating has been recently described (Monteleone et al. 2015, 2016). As mentioned before, palatability is a key feature in establishing food preference, and sweet foods commonly pre-sent this attribute. Accordingly, eCBs have been shown to enhance sweet taste sensitivity both in vivo and in vitro (Higgs et al. 2003;

Yoshida et al. 2010). Additionally, the administration of physio-logical doses of 2-AG and AEA increase human taste cell response to sweeteners in more than 120% (Yoshida et al. 2010). This effect was also observed in mice and rats, as 2-AG and AEA potentiated the behavioral gustatory response to sweeteners in a concentration-dependent manner. Importantly, this potentiation occurred with-out affecting the response to other taste profiles. Even more, the enhanced response to sweeteners was blocked in CB1-knockout mice or when CB1 antagonists were administered (Higgs et al. 2003). This suggests that the modulatory function of the ECS on sweet taste takes place via CB1 activity.

Nevertheless, it is to be considered that (sweet) taste is a com-plex perception that can be modulated by paracrine and endocrine hormones through taste receptor sensibility modulation and conse-quently affect palatability and, eventually, food intake. Thus, lep-tin, cholecystokinin, neuropeptide Y, oxytocin, insulin, ghrelin, or galanin have important and diverse effects on taste function (Loper et al. 2015). It is worth mentioning that eCBs have been shown to oppose the effect of leptin on sweet taste sensitivity (Yoshida et al. 2013; Niki et al. 2015), suggesting a cross talk between the ECS and leptin on eating behavior and energy homeostasis via central and peripheral mechanisms.

Effect of polymorphism of CB receptors on sweet taste and food preferences

Genetic variations of various elements within the ECS also influence food preference (de Luis et al. 2016b), together with other processes related to eating behavior, such as reward sensitivity (Hariri et al. 2009), binging (Monteleone et al. 2009), and cravings (Haughey et al. 2008). For instance, Argueta and Di Patrizio recently showed that chronic exposure to a cafeteria-style diet (high in fat and sucrose) is

Figure 1. Scheme of eCBs biosynthesis from phospholipids of biomembranes. Phospholiases C (PLC) and DAG lipase are involved in 2-AG synthesis whereas MAGL and ABHD6 (and possibly ABDH12) hydrolyze 2-AG to release glycerol and AA. N-acyl transferases and phospholipases D (PLD) are involved in AEA synthesis whereas FAAH hydrolyzes AEA to release ethanolamine and AA.


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able to dysregulate the expression of genes coding for cannabinoid receptor (CBRs), and endocannabinoid biosynthetic and degradative enzymes (Argueta and DiPatrizio 2017). Also, it has been described that carriers of the rs2023239 CNR1 polymorphism show increased reactivity to drug-related cues in the OFC and ACC in comparison with the more common variant of the gene (Haughey et al. 2008; Filbey et al. 2010). As mentioned in a previous section, the OFC and ACC are two key components for processing reward. Considering the importance of the ECS in the hedonic response to natural and artificial reinforcers, and given the similarities between food and drug cravings, it is reasonable to think that this polymorphism could play a role as well in sweet-related cravings. Unfortunately, no stud-ies have explored the effect of this particular polymorphism on sweet taste preference or sensitivity yet. Table 2 compiles a brief summary of relevant research regarding ECS and food preference.

Further work explored the impact of the G1422A variant (rs1049353) on abdominal adiposity (Peeters et al. 2007), body mass index (Gazzerro et al. 2007), intermuscular fat mass (Frost et al. 2010), and longitudinal changes from healthy to metabolic syndrome occurrence (Kvaløy et al. 2015). However, the literature has been inconsistent with respect to CNR1 polymorphisms and obesity-related markers, with as many studies not finding any rele-vant association with this or other CNR1 gene variants (Müller et al. 2007; de Luis et al. 2010; Łaczmański et al. 2011).

Another frequently studied CNR1 polymorphism is the (AAT)n repeat allele. This variant has been associated not only with a pre-disposition to cocaine addiction (Ballon et al. 2006) but also with sweet taste threshold and preference in obese females (Umabiki et al. 2011). Concretely, the sweetness threshold of (AAT)n carriers obese women was significantly lower compared with those without the (AAT)n repeat. Also, the C allele at the rs806365 polymorphism was associated with increased insulin resistance, greater risk of T2D, and coronary heart disease (de Miguel-Yanes et al. 2011). This brings attention to the relationship between genetic variants of the CNR1 and consumptions of simple carbohydrates. However, research focusing on CNR1 polymorphisms and preference for a specific macronutrient or taste is, unfortunately, surprisingly scarce (de Luis et al. 2010, 2013, 2016b).

Stress exposure modulates ECS, hedonic response, and sweet intake

A considerable amount of experimental evidence supports the involvement of the ECS in the neurobehavioral effects of stress on hypothalamic-pituitary axis (HPA) (Hill and McEwen 2010; Akirav 2013). It is known that glucocorticoids (GCs) induce the synthesis of eCBs in the paraventricular nucleus of the hypothalamus, a region with a vast presence of CB1 (Cota et al. 2006; Hill and Tasker 2012). Interestingly, various studies describe how the ECS-GC modula-tion is affected by insulin, as this hormone reduces circulating eCBs (Romero-Zerbo and Bermúdez-Silva 2014).

More evidence supporting the potentiation effect of stress on the ECS comes from studies showing that exposure to the Trier Social Stress Test elevates circulating levels of 2-AG (Hill et al. 2013) and AEA (Dlugos et al. 2012; Hill et al. 2013). Moreover, it has been shown that the HPA axis activity varies in relation to changes in circulating eCBs (Chouker et al. 2010). Concretely, minor changes in stress response were observed in individuals with increments in cir-culating 2-AG after exposure to parabolic stress, whereas individuals with no increase in 2-AG displayed a dramatic increase in cortisol levels. This indicates an inverse relationship between the ability to

mobilize eCBs in response to stress and the magnitude of HPA axis activation. Indeed, the impairment of the eCB signaling may result in an increased sensitivity to the stress response and, therefore, an enhanced vulnerability to develop stress-related psychiatric illnesses, including depression and anhedonia (Rademacher and Hillard 2007; Juhasz et al. 2009; Agrawal et al. 2012).

Effect of food consumed on the ECS

The type of food consumed can, for its part, influence ECS. A recent study showed that chronic supplementation with docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids decrease AEA plasma lev-els (Berge et al. 2013). In accordance to this, diets rich in ω-6 poly-unsaturated fatty acids (PUFA) and poor in ω-3 PUFA enhanced the levels of AEA (Berger et al. 2001) or 2-AG (Watanabe et al. 2003) in the postnatal and adult brain. It has been proposed that these events can be a consequence of impaired AA amounts of the phospholipids (Nieves and Moreno 2006; Petersen et al. 2006). This is actually relevant since high ω-6/ω-3 PUFA ratio is characteristic of a high-fat Western-type diet (Simopoulos 2016).

Interestingly, consumption of a favorite food, usually high in fat and sugar, was recently shown to be related with elevated plasmatic 2-AG in healthy volunteers, which in turn correlated with elevated ghrelin levels in plasma (Monteleone et al. 2005). Also, it has been recently described that rats with chronic access to a diet rich in fat and sucrose (both characteristics of the “Western diet”) presented increased levels of AEA and 2-AG in plasma and the jejunum but also greater portion intake and weight gain (Argueta and DiPatrizio 2017). Furthermore, these diet-induced effects were no longer vis-ible when a CB1 antagonist was administered peripherally. This and other studies exploring the effect of diet on the ECS in the intestinal tract indicate that both directly and indirectly, palatable food con-sumption has an effect on central and peripheral eCB levels, which suggest a role for peripheral eCBs in hyperphagia associated with Western-style diet (DiPatrizio et al. 2011, 2013).

In addition, Monteleone et al. found that 2-AG levels were ele-vated 5 min before consuming the favorite food, suggesting an antici-patory response. Monteleone et al. (2016) recently demonstrated that food palatability can influence plasma eCBs concentrations during the cephalic phase and demonstrated that 2-AG can be used as a biomarker of food liking in humans (Monteleone et al. 2016). Remarkably, they showed that sweet, palatable food facilitated an increasing trend for AEA and 2-AG levels in plasma and was associ-ated with the liking score of the food. Interestingly, such results were not obtained when a bitter food was presented. Taken together, these observations demonstrate that anticipatory mechanisms involved in cephalic (i.e., motivational and rewarding/sensory) aspects of palat-able food can modulate the ECS response.

Inflammation as a landmark in obesity and T2D

Today, 9 out of 10 cases of diabetes are T2D, and the numbers are rising. Intervention studies have conclusively demonstrated that diet-induced hyperglycemia is a major contributor to develop T2D and related pathology (Varga et al. 2015). However, the mechanism of action behind these adaptations has not been fully described. Foods that facilitate hyperglycemia have been associated with an increased risk of developing obesity, have shown to promote inflammatory processes, and to increase oxidative stress (Bray et al. 2014). Indeed, a recent review concluded that it is the reactive oxygen species (ROS)


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Table 2. Summary of relevant research focusing of the influence of ECS (gene variants and pharmacological manipulation) on food pref-erence

Reference Target Intervention Sample Effect on sweet preference

de Luis et al. 2016a, 2016b CNR1 rs1049353 (GG/GA/AA) Obese women GA/AA carriers presented lower intake of saturated fat and cholesterol in a 3-day self-report food intake

de Miguel-Yanes et al. 2011 rs806365 (CC/CT) Adult men and women C allele variant associated with increased insulin resistance, risk of T2D, and coronary heart disease

Umabiki et al. 2011 (AAT)n repeat allele Obese women Reduced sweet taste thresholdSiegfried et al. 2004 (AAT)n repeat allele Women with AN 14 but not 13 repeat allele associated with binge

eating/purging behaviorWard and Dykstra 2005 CB1 Deletion/antagonism/agonism Mice Effect on reinforced learning for Ensure® (sweet)

but not corn oil (fat)Mathes et al. 2008 Antagonism Rats Reduced consumption of palatable (sugar/fat)

foods, but not sweet aloneMcLaughlin et al. 2006 Antagonism Mice Reduced food intake (sweet, fat, and standard lab

chow)Wierucka-Rybak et al. 2014 Leptin + agonist/antagonist Mice Leptin + antagonist reduced fat but not high-

sucrose food intake. Leptin + agonist did not affect food preference or intake

Dore et al. 2014 Inverse agonist Rats Reduced the excessive intake of palatable food with higher potency and the body weight

Niki et al. 2015 Antagonism db/db mice Modulation of sweet taste sensitivity in a leptin deficiency situation

Escartín-Pérez et al. 2009 Agonism Rats Increased intake of carbohydrate, but not fats or protein

DiPatrizio et al. 2013 Antagonism Rats Blocked preference for linoleic acid emulsion in a two-bottle choice paradigm

Méndez-Díaz et al. 2012 Agonism/antagonism Rats CB1 antagonism inhibits CPP for palatable food (fat and sugar) and regular food. CB1 agonism strengthens the CPP for regular food

Argueta and DiPatrizio 2017 Peripheral blockade Mice Reduction in Western diet but not standard diet food intake

Deshmukh and Sharma 2012 Agonism (noladin ether and 2-AG into nACC shell)

Rats Increased preference for high fat vs. high carbohy-drate or standard chow in dose dependent manner

Rademacher and Hillard 2007

Agonism/antagonism Mice CB1 agonist inhibited, whereas CB1 antagonist enhanced stress-induced decreases in sucrose pref-erence

Higuchi et al. 2010 CB1/CB2 Antagonism Mice CB1, but not CB2 antagonist reduced conditioned place preference for high-fat diet

Verty et al. 2015 CB2 Agonism Mice Reduction in food intake and significant reduc-tion in fat mass and adipocyte cell size. Anxiolytic response in the elevated plus maze while having no effect on immobility time in the forced swim test

Rademacher and Hillard 2007

FAAH Blockade Mice Inhibited stress-induced decreases in sucrose prefer-ence

Dipatrizio and Simansky 2008

Blockade Rats Increased intake of high-fat/sucrose pellets

Wei et al. 2016 ECS MGL-Tg mutant (reduced levels of 2-AG in brain)

Mice Impaired conditioning place preference for high-fat food

Ramírez-López et al. 2015 AEA, 2-AG, OEA, and PEA reduced at birth

Rats Offspring of mothers under hypercaloric-hypopro-teic palatable diet during pregestational, gesta-tional, and lactation periods showed anxiety-like behavior in the elevated plus maze and open field test and a low preference for a chocolate diet in a food preference test

Mahler et al. 2007 AEA microinjection into medial nACC

Rats Increased the number of positive “liking” reactions elicited by intraoral sucrose, without altering nega-tive “disliking” reactions to bitter quinine

DiPatrizio and Simansky 2008

Microinfusions of 2-AG into the pontine parabrachial nucleus

Rats Increased intake of fat and sucrose, fat, and sucrose foods; but not standard chow foods

CNR, cannabinoid receptor gene; CB cannabinoid receptor; FAAH, fatty acid amide hydrolase; ECS, endocannabinoid system.


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through which added sugars induce most of its deleterious effects, including atherosclerosis, hypertension, cardiomyopathy, and heart failure (Prasad and Dhar 2014). Furthermore, there is evidence that, compared with a heart-healthy meal, a fast-food-style meal increase biomarkers of oxidative stress and inflammation, including lower levels of high density lipoprotein, and increased total triglyceride and interleukin-1β levels (Devaraj et al. 2008). Despite the limitations of a reduced sample size and the acute design of this study, the results obtained by Devaraj et al. would partially explain the promising results obtained with dietary interventions aiming to reduce oxida-tive stress in patients with metabolic disturbances (Vendrame et al. 2016).

Importantly, there is evidence that persistent subacute inflamma-tion and lipid disturbances may also be present in subjects within a healthy weight range. The inflammatory profile of these metabolic-ally obese individuals typically displays excessive inflamed, visceral adipose tissue, and deranged fat deposition, together with reduced skeletal muscle mass and impaired cardiorespiratory performance (Ding et al. 2016). However, chronic low-grade inflammation has also been linked to various mental disorders with notorious impact on the emotional response (Das 2016; Halaris 2017). This indicates that diet-induced metabolic disruption is possible under a healthy weight and has consequences that extend further than those related to energy homeostasis.

Role of eCBs in obesity and T2D inflammation

Fatty acid metabolites have been suggested to participate in the obesity-induced insulin resistance promoted by chronic low-grade inflamma-tion (Gruden et al. 2016). Of particular interest are those related to the ECS, as an increased ECS activity directly impairs insulin sensitivity and glucose metabolism in peripheral organs (Di Marzo 2008). In adipose tissue, activation of the CB1 enhances glucose uptake to increase energy storage as de novo lipogenesis, downregulates adiponectin thus affect-ing insulin sensitivity, and even favors local inflammation (Murumalla et al. 2011; Ge et al. 2013). In addition, the ECS has proved to indir-ectly contribute to the inflammatory and apoptotic processes promoting β-cell loss in T2D (Rohrbach et al. 2012). Specifically, the activation of the CB1 in macrophages seem to induce both activation and release of the inflammatory factors IL-1β and IL-18, which leads to β-cell apop-tosis (Jourdan et al. 2016) and consequently to insulin resistance and diabetes development (Figure 2).

Cytokines and chemokines play a significant role in the abnor-malities of metabolic disorder, but bioactive lipids such as those derived from fatty acids may be also of relevance. In accordance to this, targeting the ECS seems efficient in alleviating some of the obe-sity-related symptomatology of metabolic disorder (Witkamp 2016). The mechanism behind this interaction is still unknown, although was suggested that this effect is mediated by the proinflammatory

Figure 2. Main effects of eCBs on macrophages and β-cells. Hyperglycemia and dyslipidemia and eCBs are related in ROS and inflammatory mediators release by macrophages and β-cells, events that are involved in insulin resistance and consequently diabetes development.


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properties of eicosanoids like AA, a byproduct of ω-6 fatty acid metabolism (Bradshaw et al. 2009). Thus, the degradation of fatty acids can lead to the biosynthesis of various metabolites with pro and anti-inflammatory properties. Recent studies show that in addition to absolute amounts of PUFA intake, the ratio specifically between ω-6 and ω-3 fatty acids is associated with an increased risk of devel-oping obesity (Simopoulos 2016). Interestingly, dietary intake of ω-3 eicosanoid metabolites (EPA and DHA) show anti-inflammatory properties capable of reversing AA deleterious effects (Simopoulos 2016).

Therefore, eicosanoids may provide a common link between inflammation and metabolic abnormalities, with their different pathways serving perhaps as a target for potential pharmacological treatment (Hardwick et al. 2013). Unfortunately, no studies yet have looked into the ratio of these fatty acid metabolites and its relation with other inflammation biomarkers involved in T2D and obesity, or how, if at all, the ratio of ω-6/ω-3 eicosanoid metabolites shows the same predictive risk than the absolute ω-6/ω-3 ratio.

T1R2-T1R3, inflammation, and the ECS

In exploring the relationship between sweet uptake and ECS, the coexistence of T1R2-T1R3 receptors with endocannabinoid and lep-tin receptors (CB1 and Ob-Rb, respectively) in sweet-sensitive taste

cells is a relevant finding (Yoshida et al. 2010). The role of the ECS in the regulation of food intake and palatability is mainly studied through its effects on the central nervous system, but this evidence adds support to the hypothesis of a modulatory function of taste at peripheral level (Jager and Witkamp 2014). This suggests that sweet taste sensitivity could be altered peripherally by factors engaged in other metabolically relevant processes, as it is the case of the ECS in inflammation an emotional regulation (Jyotaki et al. 2010) (Figure 3). Interestingly, Pepino and Mennella showed that the sugar effect on alleviating pain is tempered in individuals with overweight (Pepino and Mennella 2005b), which is worth considering since the ECS is a major player in modulating emotional and physical response to pain.

Unfortunately, despite that the physiological consequences of activating T1R2-T1R3 are fairly well-known (Smith et al. 2016), experimental research studying the potential effect on metabolism after the blockade of these receptors is not abundant (Kochem and Breslin 2017). Similarly, to the best of our knowledge, there is no research on how the GNAT3 polymorphism affects the ECS activ-ity in the context of eating behavior or how is this gene related to inflammatory processes. It would be therefore of interest to explore how the manipulation of these receptors and related systems affect physiologically and psychologically relevant factors in obesity, as well as exploring whether individuals carrying genetic variants pre-sent significant differences in their ECS functioning.

Figure 3. ECS and sweet receptors (T1R2, T1R3) are involved in the development of a chronic low-grade inflammation that it is implicated in the pathogenesis of overweight/obesity and T2D.


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Modulation of ECS as a novel strategy for the treatment of “Western diet” induced obesity/diabetes

Since the discovery of the CB1 and its role in energy homeostasis, many attempts have been made to target this receptor in order to influence eating behavior. The evidence gathered so far supports that the use of agonists and antagonists to modulate the ECS shows enor-mous potential. For instance, the uses of CB1 antagonists have proved highly efficient at reducing body weight and other parameters of the metabolic syndrome (Pi-Sunyer et al. 2006; Scheen et al. 2006).

Unfortunately, the blockade of CB1 as the target for obesity treatment has shown inviable due to its severe side effects on mood (Bermudez-Silva et al. 2010). Luckily, an alternative approach has been adopted in the last years with promising results. Concretely, recent preclinical and clinical evidence suggest that the metabolic action of the CB1 antagonism can be effective as well by reaching metabolically relevant peripheral tissue (Shrinivasan et al. 2012; O’Keefe et al. 2014). Avoiding pharmacological action at the central nervous system would presumably restrict adverse psychiatric conse-quences (Nogueiras et al. 2008; Tam et al. 2012). In this regard, the results obtained on impairing overeating of cafeteria-style diet with peripheral CB1 antagonism in animal models are a reason to be opti-mistic (Argueta and DiPatrizio 2017).

Redox state homeostasis, ECS, and food preference/intake

A fair amount of research interested in exploring the therapeutic effects of the ECS is focused on its neuroprotective properties. Particularly, a crucial link between the ECS and redox homeo-stasis has been identified, as supported by in vitro studies show-ing a protective role of CB treatment on astrocytes (Carracedo et al. 2004). Concretely, long-term Δ9-tetrahydrocannabinol (Δ9-THC) incubation prevented H2O2-induced loss of cell viability. Moreover, this effect seems to occur in a CB1 receptor-dependent manner. In addition, Ribeiro et al. (2013) demonstrated that a CB2 agonist is able to block ROS production in response to lipopoly-saccharides by microglial cells (Ribeiro et al. 2013). Further, it was shown that the manipulation of both CB1 and CB2 inhibited microglial activation through independent mechanisms. In this way, the pharmacological inhibition of CBRs appears to lead to the suppression of oxidative stress and associated inflammation (Cao et al. 2013).

In addition to these results, animal studies demonstrated that the treatment with Δ9-THC increased pancreatic glutathione levels, antioxidant enzymatic activities of superoxide dismutase, and cata-lase (Coskun and Bolkent 2014). Furthermore, CB1 inhibition has shown to ameliorate diabetes-induced retinal oxidative stress and inflammation, as well as to improve oxidative stress in nonalcoholic fatty acid disease model (Jorgačević et al. 2015). Interestingly, and in accordance with other studies, CB1 and CB2 receptors have been reported to differentially regulate ROS production within the same cell (Han et al. 2009).

In addition to the effects of ECS on cellular redox state, it should be highlighted that changes in cellular redox homeostasis can also affect ECS as consequence of phospholipid hydrolysis (Martínez and Moreno 2001). For instance, Batkai et al. (2007) reported the increase of hepatic AEA and 2-AG levels following oxidative stress/inflammation (Bátkai et al. 2007). Furthermore, oxidative stress mediated the upregulation of CB1 and CB2 expression (Wei et al. 2009; Wang et al. 2014), as well as the downregulation of FAAH (Wei et al. 2009). This last study also suggests that ECS may con-tribute to ameliorating the damaging action of ROS in these experi-mental conditions.

Conclusions

The information here presented gathers the following evidence: first, that the frequent intake of palatable, high in sugar, foods causes hyperglycemia and can stimulate brain regions associated with appetitive behavior and reward, processes partially modulated by the ECS. Second, that hyperglycemia is a major risk factor to develop T2D, a metabolic disorder to which the ECS contributes through promoting insulin dysregulation and inflammatory processes. Third, that T1R2-T1R3 receptors are responsible for sweet perception in the bud tastes, where coexist with CB1 and Ob-Rb receptors. Fourth, that a significant amount of variance to sweet perception can be explained by genetic differences and that this response can be also affected by lifestyle and experience. Also, that T1R2-T1R3 are expressed in peripheral tissue as well, from where influence metabolic processes relevant to T2D physiopathology. Lastly, that antioxidant and anti-inflammatory food sources can ameliorate T2D-related symptomatology, presumably through the participation of molecular mechanisms form the ECS. Nevertheless, this review provides only a small view of the importance of sweet taste percep-tion in the pathogenesis of obesity and T2D, particularly as regards the role of the ECS (Figure 4). Future studies on these matters would

Figure 4. Sweet receptor polymorphisms and the modulation of sweet taste sensitivity by ECS are involved in the regulation of sweet preference and consequently in the regulation of sweet food consumption.


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be of interest, especially those to explore potential therapeutic effects of dietary interventions focusing on hedonic response to food.

Funding

This work was supported in part by Spanish Ministry of Economy and Innovation (AGL2013-49083-C3-1-R and AGL2016-75329R) and by the Autonomous Government of Catalonia (2009SGR0438 and 2014SGR0773). Dr Ernesto Tarragon Cros was funded by the Alexander von Humboldt Foundation under the Alexander von Humboldt Postdoctoral Fellowship program.

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