Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y
International Journal of Obesity
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Stocker, C., Wargent, E., Martin, M., Cripps, R., O'Dowd, J., Zaibi, M., Cottrell, E., et al. (2012). Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y. International Journal of Obesity, 36 (8), 1040-1046. https://doi.org/10.1038/ijo.2011.226
BACKGROUND: Pups of normally nourished dams that are cross-fostered after birth to dams fed a low-protein (8% by weight) diet (postnatal low protein (PLP)) grow slower during the suckling period and remain small and lean throughout adulthood. At weaning, they have increased expression in the arcuate nucleus (ARC) of the hypothalamus of the orexigenic neuropeptide Y (NPY) and decreased expression of pro-opiomelanocortin, the precursor of anorexigenic melanocortins. OBJECTIVES AND METHODS: We investigated, using third ventricle administration, whether 3-month-old male PLP rats display altered sensitivity to leptin with respect to food intake, NPY and the melanocortin 3/4-receptor agonist MTII, and using in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR, whether the differences observed were associated with changes in the hypothalamic expression of NPY or the leptin receptor, NPY receptors and melanocortin receptors. RESULTS: PLP rats were smaller and had reduced percentage body fat content and plasma leptin concentration compared with control rats. Leptin (5 μg) reduced food intake over 0-48 h more in PLP than control rats (P<0.05). Submaximal doses of NPY increased the food intake less in PLP rats than in controls, whereas submaximal doses of MTII reduced the food intake more in PLP rats. Maximal responses did not differ between PLP and control rats. Leptin and melanocortin-3 receptor (MC3R) expression were increased in both ARC and ventromedial hypothalamic nuclei in PLP animals compared with the controls. MC4R, NPY Y1R, Y5R and NPY expression were unchanged. CONCLUSION: Postnatal undernourishment results in food intake in adult rats being more sensitive to reduction by leptin and melanocortins, and less sensitive to stimulation by NPY. We propose that this contributes to increased leptin sensitivity and resistance to obesity. Increased expression of ObRb and MC3R may partly explain these findings but other downstream mechanisms must also be involved.
Animals, Animals, Newborn, Arcuate Nucleus of Hypothalamus, Body Weight, Disease Susceptibility, Eating, Gene Expression Regulation, Leptin, Male, Neuropeptide Y, Obesity, Rats, Rats, Wistar, Receptor, Melanocortin, Type 3, Thinness, Time Factors, Weight Gain
We would like to thank David Hislop, Anita Roberts, Adrian Wayman and Delia Hawkes for their excellent technical support. This work was supported by an Industrial partnered BBSRC (from the Biotechnology and Biological Sciences Research Council, UK) research grant E007821/1 and E00797X/1. SEO is a British Heart Foundation Senior Fellow.
British Heart Foundation (FS/09/029/27902)
External DOI: https://doi.org/10.1038/ijo.2011.226
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266229