Preclinical and clinical evidence for a distinct regulation of mu opioid and type 1 cannabinoid receptor genes expression in obesity

Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (<30 years old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of CNR1 and OPRM1 genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest CNR1 and OPRM1 epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention

Transcriptional regulation of the endocannabinoid system in a rat model of binge-eating behavior reveals a selective modulation of the hypothalamic fatty acid amide hydrolase gene.

OBJECTIVE: Binge-eating episodes are recurrent and are defining features of several eating disorders. Thus binge-eating episodes might influence eating disorder development of which exact underlying mechanisms are still largely unknown. METHODS: Here we focused on the transcriptional regulation of the endocannabinoid system, a potent regulator of feeding behavior, in relevant rat brain regions, using a rat model in which a history of intermittent food restriction and a frustration stress induce binge-like palatable food consumption. RESULTS: We observed a selective down-regulation of fatty acid amide hydrolase (faah) gene expression in the hypothalamus of rats showing the binge-eating behavior with a consistent reduction in histone 3 acetylation at lysine 4 of the gene promoter. No relevant changes were detected for any other endocannabinoid system components in any brain regions under study, as well as for the other epigenetic mechanisms investigated (DNA methylation and histone 3 lysine 27 methylation) at the faah gene promoter. DISCUSSION: Our findings suggest that faah transcriptional regulation is a potential biomarker of binge-eating episodes, with a relevant role in the homeostatic regulation of food intake

On the role of central type-1 Cannabinoid receptor gene regulation in food intake and eating behaviors

Different neuromodulatory systems are involved in long-  term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies

Epigenetic regulation of the cannabinoid receptor CB1 in an activity-based rat model of anorexia nervosa

Objective: Both environmental and genetic factors are known to contribute to the development of anorexia nervosa (AN), but the exact etiology remains poorly understood. Herein, we studied the transcriptional regulation of the endocannabinoid system, an interesting target for body weight maintenance and the control of food intake and energy balance. Method: We used two well-characterized animal models of AN: (a) the activity-based anorexia (ABA) model in which rats, housed with running wheels and subjected to daily food restriction, show reductions in body weight and increase in physical activity; (b) the genetic anx/anx mouse displaying the core features of AN: low food intake and emaciation. Results: Among the evaluated endocannabinoid system components, we observed a selective and significant down-regulation of the gene encoding for the type 1 cannabinoid receptor (Cnr1) in ABA rats' hypothalamus and nucleus accumbens and, in the latter area, a consistent, significant and correlated increase in DNA methylation at the gene promoter. No changes were evident in the anx/anx mice except for a down-regulation of Cnr1, in the prefrontal cortex. Discussion: Our findings support a possible role for Cnr1 in the ABA animal model of AN. In particular, its regulation in the nucleus accumbens appears to be triggered by environmental cues due to the consistent epigenetic modulation of the promoter. These data warrant further studies on Cnr1 regulation as a possible target for treatment of AN

The role of nutraceutical fruit drink on neurodegenerative diseases: a review

A changing lifestyle in food consumption due to the frequent taking of junk drinks based on the fastfood and ready-to-eat concept has brought about overloaded oxidative stress, thus weakening the body’s defence mechanism to scavenge free oxygen radicals by destroying antioxidants. Oxidative stress occurs as a result of an imbalance between pro and antioxidant levels in favour of pro-oxidants resulting in the pathogenesis of neurodegenerative diseases. Though researches on the probable cure for neurodegenerative diseases are ongoing, fruits have been found to play an important dietetic role in preventing neurodegenerative diseases and other physiological disorders. Most fruits have their own valuable, unique active ingredients, having tremendous nutraceutical potentials and therapeutic implications. Therefore, people are required to make rational choices on the correct type of food for consumption to engender proper growth and development. The role of fruits or fruit juice in ameliorating neurodegenerative diseases has created a reawakening in nutrition and human health research