ABSTRACT
Several factors play a role in obesity (i.e., behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down-regulation of the orexigenic neuropeptide Y (NPY) and peroxisome proliferator-activated receptor gamma (PPAR-γ) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-γ, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opio-melanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism.
ABSTRACT
The present study examined the effect of two A(2A) adenosine receptor (AR) agonists, CGS 21680 and VT 7, on high-palatability food (HPF) intake in a model of binge eating in sated rats and on low-palatability food (LPF) intake in food-deprived rats. Binge eating was induced in female rats by three 8-day cycles of food restriction/refeeding, followed by acute stress. Two groups of rats were used: NR+NS rats normally fed and not stressed and R+S rats exposed to cycles of food restriction/refeeding and then stressed. R+S rats had higher intake of HPF than the NR+NS controls. The two A(2A)AR agonists were tested at doses of 0.1 and 0.05 mg/kg intraperitoneally; VT 7 did not modify locomotor activity at either dose, whereas CGS 21680 only slightly reduced it at the higher dose tested. The injection of 0.1 mg/kg of both agonists markedly reduced HPF intake both in R+S and in NR+NS rats. The dose of 0.05 mg/kg was inactive. CGS 21680 and VT 7, 0.1 mg/kg, also reduced the standard LPF intake in 24 h food-deprived rats; however, they did not reduce water intake, indicating that their effect on food intake is selective. The dose of 0.05 mg/kg was inactive. Thus, A(2A)AR agonists exert a rather general effect on food intake, inhibiting both HPF intake in sated rats and LPF intake in food-deprived rats. They may potentially be useful pharmacological agents to control binge-related eating disorders and to reduce food overconsumption associated with obesity.
