Abstract
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.
Highlights
Obesity is a growing public health threat, potentially affecting emotional, and physical health with a relevant mortality rate and a high burden of disease for Western societies
The first outcome of this study is the selective up-regulation of the expression of Cnr1, the gene coding for cannabinoid receptor type 1 (CB1), and of Oprm1, the gene coding for mu opioid receptor (MOP), in the hypothalamus of rats exposed to high fat diet for 5 and 21 weeks
These alterations were present at both time-points analyzed for CB1, that appeared to be engaged in long-lasting effects, and only at the beginning of obesity development for MOP, that appeared to be engaged in obesity onset only
Summary
Obesity is a growing public health threat, potentially affecting emotional, and physical health with a relevant mortality rate and a high burden of disease for Western societies. Several preclinical studies reported that both opioid and cannabinoid receptor agonists stimulate food intake (Reid, 1985; Foltin et al, 1988; Williams et al, 1998; Glass et al, 1999; Williams and Kirkham, 1999), that is instead reduced by antagonists (Recant et al, 1980; Marks-Kaufman et al, 1984; Colombo et al, 1998; Di Marzo et al, 2001; Glass et al, 2002; Hildebrandt et al, 2003; Ravinet Trillou et al, 2003; Statnick et al, 2003; Vickers et al, 2003) with suppression of body weight gain in rodents It has been observed in human trials that opioid antagonists (naloxone, naltrexone, or nalmefene) may be helpful in the short term to suppress appetite, even though caution should be taken for possible long term use because of side effects and limited weight loss (Nathan and Bullmore, 2009). It should be recalled that rimonabant, a selective type 1 cannabinoid receptor (CB1) antagonist able to reduce body weight (Rinaldi-Carmona et al, 1995; Di Marzo and Despres, 2009), was an approved drug on the European market, but was withdrawn because of an increased risk of psychiatric disorders (Johansson et al, 2009)
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