Benedetta Canestrelli

Ghrelin system in alcohol‐dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving

Animal studies suggest that the gut‐brain peptide ghrelin plays an important role in the neurobiology of alcohol dependence (AD). Human studies show an effect of alcohol on ghrelin levels and a correlation between ghrelin levels and alcohol craving in alcoholics.

Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression.

Experimental data suggest that the endogenous cannabinoid system is involved in mood regulation, but no study has been performed so far to investigate the role of endocannabinoid genes in the susceptibility to major depression (MD) and/or bipolar disorder (BD). We assessed the CB1 receptor gene (CNR1) single nucleotide polymorphism (SNP) rs1049353 (1359 G/A) and the fatty acid amide hydrolase (FAAH) gene rs324420 SNP (cDNA 385C to A) for their associations with MD and/or BD in 83 Caucasian patients with recurrent MD, 134 Caucasian individuals with BD, and 117 Caucasian healthy subjects. The distribution of the CNR1 1359 G/A genotypes and alleles significantly differed among the groups (chi(2)=12.595; df=4, P=0.01 for genotypes; chi(2)=13.773; df=2, P=0.001 for alleles) with MD patients showing a higher frequency of both AG, GG genotypes and A allele as compared to healthy controls. The distribution of the FAAH cDNA 385C to A genotypes, according to the CC dominant model (AA+AC vs. CC), significantly differed among the groups (chi(2)=6.626; df=2, P=0.04), with both BD patients and MD patients showing a non-significant slightly higher frequency of the AC genotype. These findings, although preliminary, suggest that the CNR1 1359 G/A and the FAAH cDNA 385C to A gene variants may contribute to the susceptibility to mood disorders.

Investigation of 3111T/C polymorphism of the CLOCK gene in obese individuals with or without binge eating disorder: Association with higher body mass index

Loss of circadian patterning of metabolism-related functions seems to play a role in the pathogenesis of obesity; therefore, it is reasonable to hypothesize that the functional 3111T/C single nucleotide polymorphism (SNP) of the (Circadian locomotor output cycles kaput) CLOCK gene may have a part in the genetic susceptibility to obesity. The aim of this study was to assess the frequencies of 3111T/C CLOCK gene SNP in overweight/obese subjects with or without binge eating disorder (BED) as compared to normal weight healthy controls. A total of 284 Caucasian subjects, including 92 normal weight healthy subjects and 192 overweight/obese patients (107 with BED) participated into the study. Genotype and allele frequencies did not significantly differ between normal weight controls and overweight/obese patients with and/or without BED. However, overweight/obese patients carrying the CC genotype had significantly higher values of body mass index (BMI) as compared to those carrying the CT and/or TT genotypes. Moreover, obese class III individuals had a significantly higher frequency of both the CC genotype and the C allele as compared to individuals with BMI<40 kg/m(2). Present findings show for the first time that the 3111T/C SNP of the CLOCK gene is not associated to human obesity and/or BED, but it seems to predispose obese individuals to a higher BMI.

Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects

Endocannabinoids modulate eating behavior; hence, endocannabinoid genes may contribute to the biological vulnerability to eating disorders. The rs1049353 (1359 G/A) single nucleotide polymorphism (SNP) of the gene coding the endocannabinoid CB1 receptor (CNR1) and the rs324420 (cDNA 385C to A) SNP of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, have been suggested to have functional effects on mature proteins. Therefore, we explored the possibility that those SNPs were associated to anorexia nervosa and/or bulimia nervosa. The distributions of the CNR1 1359 G/A SNP and of the FAAH cDNA 385C to A SNP were investigated in 134 patients with anorexia nervosa, 180 patients with bulimia nervosa and 148 normal weight healthy controls. Additive effects of the two SNPs in the genetic susceptibility to anorexia nervosa and bulimia nervosa were also tested. As compared to healthy controls, anorexic and bulimic patients showed significantly higher frequencies of the AG genotype and the A allele of the CNR1 1359 G/A SNP. Similarly, the AC genotype and the A allele of the FAAH cDNA 385C to A SNP were significantly more frequent in anorexic and bulimic individuals. A synergistic effect of the two SNPs was evident in anorexia nervosa but not in bulimia nervosa. Present findings show for the first time that the CNR1 1359 G/A SNP and the FAAH cDNA 385C to A SNP are significantly associated to anorexia nervosa and bulimia nervosa, and demonstrate a synergistic effect of the two SNPs in anorexia nervosa.

The 196G/A (val66met) polymorphism of the BDNF gene is significantly associated with binge eating behavior in women with bulimia nervosa or binge eating disorder

The brain-derived neurotrophic factor (BDNF) is involved not only in promoting neuronal outgrowth and differentiation, synaptic connectivity and neuronal repair, but also in modulating eating behavior. Since genetic factors likely contribute to the biological vulnerability to bulimia nervosa (BN) and binge eating disorder (BED), we investigated whether the functional 196G/A single nucleotide polymorphism (SNP) of the BDNF gene was associated to BN and/or BED or to some phenotypic aspects of the disordered eating. Two hundred and ten Caucasian women (126 with BN, 84 with BED and 121 healthy controls) participated into the study. No significant differences were found in the frequencies of the 196G/A variants of the BDNF gene among patients with BN or BED and healthy controls. In both BN and BED groups, subjects carrying the 196A/A genotype exhibited a weekly frequency of bingeing and a severity of binge eating (as assessed by the Bulimia Investigation Test Edinburgh) significantly higher than those with the 196A/G and 196G/G genotypes. These results suggest that the 196G/A SNP of the human BDNF gene does not contribute to the genetic susceptibility to BN and BED, but may predispose those patients to a more severe binge eating behavior.

The cDNA 385C to A missense polymorphism of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH) is associated with overweight/obesity but not with binge eating disorder in overweight/obese women

Endocannabinoids are involved in the modulation of eating behavior; hence, alterations of this system may play a role in obesity. Recently, a single nucleotide polymorphism (cDNA 385C to A) of the gene coding for fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, has been found to be associated with obesity. However, the possibility that the FAAH gene cDNA 385C to A single nucleotide polymorphism (SNP) is associated to binge eating disorder (BED), a condition that frequently occurs in obese individuals, has not been investigated. In order to address this issue, we assessed the distribution of the cDNA 385C to A SNP in 115 overweight/obese subjects with BED, 74 non-BED patients with obesity and 110 normal weight healthy controls. As compared to healthy controls, the whole group of overweight/obese BED and non-BED patients had a significantly higher frequency of the CA genotype and the A allele of the FAAH gene cDNA 385C to A SNP. Moreover, the SNP resulted significantly correlated to the presence of overweight/obesity (F(2, 296)=3.58, P=0.02), but not to the occurrence of BED (F(2, 296)=0.98; P=0.3). The present study confirms previously published significant over-representations of the FAAH 385 A allele in overweight/obese subjects and presents new data in BED patients that the 385 mutation is not significantly associated with BED-related obesity.

Asymmetry of salivary cortisol and α-amylase responses to psychosocial stress in anorexia nervosa but not in bulimia nervosa

BACKGROUND The stress response involves the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). As a role for stress in determining of the onset and the natural course of eating disorders (EDs) has been proposed, the study of the psychobiology of the stress response in patients with anorexia nervosa (AN) and bulimia nervosa (BN) should be helpful in understanding the pathophysiology of these disorders. The two neurobiological components of the stress response can be easily explored in humans by the measurement of salivary cortisol and α-amylase response to a stressor. Therefore, we assessed salivary cortisol and α-amylase responses to the Trier Social Stress Test (TSST) in symptomatic patients with AN and BN compared to healthy controls. METHOD Seven AN women, eight BN women and eight age-matched healthy females underwent the TSST between 1530 and 1700 h. Salivary cortisol and α-amylase levels were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS Compared to healthy women, AN patients showed a normal cortisol response to the TSST, although this occurred at significantly increased hormone levels, and an almost complete absence of response of α-amylase. BN women, however, exhibited enhanced pre-stress levels of salivary α-amylase but a normal response of the enzyme and cortisol to the TSST. CONCLUSIONS These findings demonstrate, for the first time, the occurrence of an asymmetry between the HPA axis and SNS components of the stress response in the acute phase of AN but not in BN. The pathophysiological significance of this asymmetry remains to be determined.

Endocannabinoid Pro129Thr FAAH Functional Polymorphism But Not 1359G/A CNR1 Polymorphism Is Associated With Antipsychotic-Induced Weight Gain

Several candidate genes have been associated with antipsychotic-induced body weight (BW) gain. Because the endocannabinoid system is deeply involved in BW regulation, endocannabinoid genes may have a role in the antipsychotic-induced weight gain. Therefore, we investigated the 1359 G/A (rs1049353) single nucleotide polymorphisms (SNP) of the cannabinoid receptor 1 (CNR1) gene, which codes the endocannabinoid CB1 receptor, and the complementary DNA (cDNA) 385C/A (rs324420) SNP of the FAAH gene, which codes the endocannabinoid degrading enzyme, for their role in BW changes induced by antipsychotic drugs. Eighty-three white psychotic patients who underwent a naturalistic treatment with different antipsychotics (clozapine, olanzapine, risperidone, quetiapine, and haloperidol) and completed a 24-week treatment period were included into the study together with 80 age- and sex-matched white healthy controls. At the 24th week of treatment, 41 patients gained more than 7% of their baseline BW. No significant differences between patients and controls emerged in genotype and allele frequencies of both SNPs. Genotype and allele frequencies of the FAAH cDNA 385C/A SNP but not of the CNR1 1359 G/A SNP significantly differed between subjects who gained more than 7% of BW and those who did not, with both AC and AA genotypes and the A allele being significantly more frequent in patients who gained more than 7% of their baseline BW. Present findings, although obtained in a small population and in a naturalistic setting, suggest that the cDNA 385C/A SNP of the FAAH gene may predispose subjects to get a clinically meaningful weight gain after antipsychotic exposure.

Gastroenteric hormone responses to hedonic eating in healthy humans.

Hedonic eating differentiates from homeostatic eating on two main aspects: the first one is that eating occurs when there is no need for calorie ingestion and the second one is that the food is consumed exclusively for its gustatory and rewarding properties. Gastroeneteric hormones such as ghrelin, colecystokinin-33 (CCK) and peptide YY3-36 (PYY3-36) are known to play a pivotal role in the homeostatic control of food intake. To the contrary, their role in hedonic eating has been never investigated. Here we report peripheral responses of CCK, PYY3-36 and ghrelin to the consumption of food for pleasure in well-nourished satiated healthy subjects. Plasma levels of CCK, PYY3-36 and ghrelin were measured in 7 satiated healthy subjects before and after ad libitum consumption of both a highly pleasurable food (hedonic eating) and an isoenergetic non-pleasurable food (non-hedonic eating). The consumption of food for pleasure was associated to a significantly increased production of the hunger hormone ghrelin and a significantly decreased secretion of the satiety hormone CCK. No significant changes in plasma PYY3-36 levels occurred in the two eating conditions. These preliminary data demonstrate that in hedonic eating the peripheral hunger signal represented by ghrelin secretion is enhanced while the satiety signal of CCK production is decreased. This could be responsible for the persistence of peripheral cues allowing a continued eating as well as for the activation of endogenous reward mechanisms, which can drive food consumption in spite of no energy need, only for reward.