Leanness in postnatally nutritionally programmed rats is associated with increased sensitivity to leptin and a melanocortin receptor agonist and decreased sensitivity to neuropeptide Y

Abstract

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.

Figure. 1

Food intake following central administration of NPY. Food intake was measured 2, 4 and 6 hours after administering NPY to three-month-old control (■) and PLP (▲) rats (n = 13 to 18). ED₅₀ values are given in Table 3 n=16-20 per group. *P<0.05; **P<0.01 for absolute food intake differences between control and PLP rats.

Figure. 2

Food intake following central administration of MTII. Food intake was measured 2, 4 and 24 hours after administering MTII to three-month-old control (■) and PLP (▲) rats. ED₅₀ values are given in Table 3 n=13-18 per group. *P<0.05; **P<0.01; ***P<0.001 for absolute food intake differences between control and PLP rats.

Figure. 3

Gene expression of ObRb, MC3R and MC4R and SOCS3 in hypothalamic nuclei. Gene expression was measured in serial brain sections from overnight fasted animals by in situ hybridisation. Data expressed as means ± SEM. n = 6-8 per group, *P<0.05; **P<0.01 for absolute differences between control and PLP rats.

Figure. 4

Gene expression of NPY, NPY Y1R and NPY Y5R in hypothalamic nuclei. Gene expression was measured in laser capture microdisssected arcuate nuclei from overnight fasted animals by quantitative PCR. Data expressed as means ± SEM. n = 6-8 per group