British Journal of Nutrition.  2014 March; 111 (05):924-932

Down-regulation of hypothalamic pro-opiomelanocortin (POMC) expression after weaning is associated with hyperphagia-induced obesity in JCR rats overexpressing neuropeptide Y. 

Abdoulaye Diane1, W. David Pierce2, James C. Russell 1, C. Donald Heth3, Donna F. Vine1, Denis Richard4, Spencer D. Proctor1

1Metabolic and Cardiovascular Diseases Laboratory, Alberta Institute for Human Nutrition, Alberta Diabetes Institute, University of Alberta, Edmonton, Canada; 2Department of Sociology, University of Alberta, Edmonton, Canada; 3Department of Psychology, University of Alberta, Edmonton, Canada; 4Institut Universitaire de Cardiologie et de Pneumologie de l’Université Laval, Quebec, Canada.

 

Abstract:

We hypothesized that hypothalamic feeding-related neuropeptides are differentially expressed in obese- and lean-prone rats and trigger overeating-induced obesity. To test this hypothesis, we measured energy balance, hypothalamic NPY and POMC mRNA expression in male JCR:LA-cp rats. We compared, in independent cohorts, free-feeding obese-prone (Obese-FF) and lean-prone (Lean-FF) rats at pre-weaning (10-day-old), weaning (21-25 days old) and early adulthood (8-12 weeks). A group of Obese-PF rats pair-fed to the Lean-FF animals was added to adult cohort. Body weights of Obese-FF and Lean-FF 10-day-old pups were not significantly different. However, when pups were shifted from dam’s milk to solid food (weaning), obese-prone rats showed more energy intake over days than lean-prone rats and higher body and fat pad weights, fasting plasma glucose, leptin, insulin and lipids. These differences were consistent with higher energy consumption and lower energy expenditure. In young-adult rats the differences between Obese-FF and Lean-FF became more pronounced, yielding significant age effects on most metabolic syndrome parameters, which were reduced in Obese-PF rats. Obese-prone animals displayed higher NPY expression than lean-prone rats at pre-weaning and weaning and the expression levels did not differ by age. In contrast, POMC expression showed significant age by genotype differences. At pre-weanling, there was no genotype difference on POMC expression, but within the weanling age group, obese-prone pups showed lower POMC expression than lean-prone rats. This genotype difference became more pronounced at adulthood. Overall, the development of hyperphagia-induced obesity in obese-prone JCR rats is related to POMC down-regulation in the presence of established NPY over-expression.

PMID: 24094067

 

Supplement :

Nutritional environment during early development is known to alter the expression of genes critical to regulation of energy balance. During the transition from dam’s milk to solid food at weaning, ‘a sensitive period’ of development, the feeding-related neuropeptide genes (NPY and POMC) may be altered in obese-prone animals, resulting in the early onset of energy imbalance and pre-disposition to obesity later in life.

Post-weaning and adult obese-prone Zucker (fa/fa) rats display higher NPY and lower POMC expressions in the arcuate nucleus of the hypothalamus compared to their lean-prone counterparts; however, no differences have been observed between the obese-prone and lean-prone genotypes during the pre-weaning or suckling period. The obese-prone Zucker (fa/fa) rat has a missense mutation in the leptin receptor gene, which diminishes but does not eliminate the response to leptin. Thus, leptin still can modulate the NPY and POMC pathways of Zucker (fa/fa) rats, making it difficult to draw simple conclusion about these eating neuropeptides for the early onset of energy imbalance. In contrast, our JCR rat model has a nonsense mutation on the leptin receptor gene that completely eliminates the leptin receptor in the obese-prone (cp/cp) rats but not in the lean-prone (+/?) animals—allowing an assessment of the developmental role of NPY and POMC expressions on energy imbalance and later life obesity without the confounding influence of leptin regulation.

In the current study, we hypothesized that NPY mRNA levels in the arcuate nucleus would be high and POMC mRNA levels low in suckling JCR obese-prone pups compared to lean-prone littermates. These pre-weaning differences would be exacerbated by the transition to solid food at weaning and then maintained until adulthood.

The results confirmed our hypothesis.  The JCR obese-prone animals displayed higher NPY expression in the arcuate nucleus than lean-prone rats at 10-days-old (pre-weaning) despite similar body weights, and the genotype difference for NPY expression also occurred in weanling and young adult animals; thus, differences in NPY expression levels by genotype did not differ by age group. In contrast, there was no genotype (obese-prone vs. lean-prone) difference in POMC expression for suckling pups, but obese-prone weanling pups showed lower POMC expression than their lean-prone counterparts. This genotype difference in POMC expression became more pronounced at adulthood. Unlike NPY, POMC expression showed significant age by genotype differences (Figure 1 supplement). For POMC, obese-prone rats have low expression levels across all age groups; lean-prone rats increase POMC expression levels over age cohorts (pre-weaning, weaning and adult). Within the context of elevated NPY expression, the lower POMC expression levels from pre-weaning to adulthood in the obese-prone compared to lean-prone rats is linked to higher energy intake, body weight, fasting plasma glucose, insulin and lipids levels and lower energy expenditure.

We concluded that, in our JCR rat model, NPY overexpression is established before weaning. Furthermore, the development of hyperphagia-induced obesity and metabolic syndrome is related to POMC down-regulation at weaning (transition to solid food) in the context of NPY overexpression.

 

Figure. 1 change

Supplement figure 1 : Arcuate nucleus neuropeptide expression levels for NPY and POMC of pre-weanling (panel A), weanling (panel B) and young-adult (panel C) lean-prone (+/?) and obese-prone (cp/cp)  JCR:LA-cp rats.

 

Multiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier SchönmannMultiselect Ultimate Query Plugin by InoPlugs Web Design Vienna | Webdesign Wien and Juwelier Schönmann