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.
Highlights
Obesity is the consequence of an imbalance between energy intake and expenditure
Several evidences have been accumulated on the effects of a large number of hypothalamic neuropeptides on food intake, including neuropeptide Y (NPY), galanin, cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), agouti-related protein (AgRP), and pro-opio-melanocortin (POMC)-derived peptides, such as α-melanocyte-stimulating hormone (α-MSH) and β-endorphin (Woods et al, 1998)
In particular we evaluated the hypothalamic gene expression and possible epigenetic regulation of selected neuropeptides involved in the control of energy balance in rats that develop obesity, or do not develop obesity, when fed with a high fat diet
Summary
Obesity is the consequence of an imbalance between energy intake and expenditure. The prevalence of obesity all over the world suggests that there is a fundamental weakness in the regulation of appetite and energy homeostasis. Short- and long-term hormonal and neural signals regulate food intake and energy expenditure through the modulation of orexigenic and anorexigenic neuropeptides expression in the hypothalamus and in other brain regions involved in the control of the homeostasis (Woods et al, 1998; Schwartz et al, 2000). Critical elements of this control system are hormones secreted in proportion to body adiposity, including leptin and insulin, and the CNS targets upon which they act (Hewson et al, 2002). The activation of NPY/AGRP neurons has an orexigenic effect, promoting food intake, whereas the activation of POMC/CART neurons evoke an anorexigenic effect (Barsh and Schwartz, 2002)
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