Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction?

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.

A potential role for the secretogranin II‐derived peptide EM66 in the hypothalamic regulation of feeding behaviour

“…We have subsequently investigated whether EM66 expression within the hypothalamus is influenced by the energy status of the animal, and we have compared it with the gene expression of POMC and NPY in diet‐induced obesity and in fasting conditions. Our results reveal that long‐term HFD exposure is associated with an important decrease in POMC mRNA levels and no significant change in NPY gene expression, in agreement with previous studies . Concurrently, we show that expression of SgII (the EM66 precursor) is down‐regulated in HFD mice to a similar extent as POMC, suggesting that EM66 is a major anorexigenic factor playing a crucial role in the maintenance of the obese status, acting in synergy with α‐MSH (the anorexigenic POMC‐derived peptide).…”

Diet‐induced DNA methylation within the hypothalamic arcuate nucleus and dysregulated leptin and insulin signaling in the pathophysiology of obesity

“…In the studies evaluated herein, no methylation changes were observed for NPY, MC4R, or PPAR-γ when investigated (Cifani et al, 2015;Zheng et al, 2015), while the methylation status of POMC was consistently found to be altered and positively associated with increased levels of leptin and insulin and the development of the obesity phenotype and symptoms of MeS (Cifani et al, 2015;Gali Ramamoorthy et al, 2018;Marco et al, 2013;Andreas Plagemann et al, 2009;Wang et al, 2014;Zhang et al, 2014;Zheng et al, 2015).…”

“…In the studies evaluated herein, no methylation changes were observed for NPY , MC4R, or PPAR‐ γ when investigated (Cifani et al, ; Zheng et al, ), while the methylation status of POMC was consistently found to be altered and positively associated with increased levels of leptin and insulin and the development of the obesity phenotype and symptoms of MeS (Cifani et al, ; Gali Ramamoorthy et al, ; Marco et al, ; Andreas Plagemann et al, ; Wang et al, ; Zhang et al, ; Zheng et al, ). With POMC‐mediated leptin and insulin function playing a major role in the pathological development of obesity and MeS, the methylation status of POMC thus represents a pivotal therapeutic target.…”

“…After 21 weeks of HFD‐feeding, no changes in NPY or AgRP expression level between the respective groups were observed, while a reduced expression of POMC within the DIO group was reported when compared to the diet resistant group. Furthermore, no changes in NPY methylation were observed, while POMC promoter methylation was reduced in diet resistant group compared with the DIO group (Cifani et al, ). These studies provide evidence for obesogenic diet‐induced alteration in DNA methylation of arcuate nucleus genes, such as POMC , which were associated with raised leptin and insulin levels and the development of obesity and MeS (Cifani et al, ; Marco et al, ).…”

POMC and NPY mRNA expression during development is increased in rat offspring brain from mothers fed with a high fat diet

“…The increase in POMC and NPY expression detected in the brains of E18 pups taken from dams fed a high fat diet is somewhat paradoxical. Indeed, one would expect that POMC expression would be decreased as it does in adult animals that are chronically exposed to high fat diets (Cifani et al, 2015; Desai et al, 2016). Nevertheless, our data are consistent with data of others showing that rat pups whose mother was exposed to a high fat diet showed increased POMC and NPY mRNA expression in the ARC twenty days after birth (Chen and Morris, 2009).…”