Hypothalamic Nuclei Are Malformed in Weanling Offspring of Low Protein Malnourished Rat Dams

Abstract

Maternal low protein malnutrition during gestation and lactation (LP) is an animal model frequently used for the investigation of long-term deleterious consequences of perinatal growth retardation. Both perinatal malnutrition and growth retardation at birth are risk factors for diabetic and cardiovascular disturbances in later life. The pathophysiologic mechanisms responsible are unknown. Hypothalamic nuclei are decisively involved in the central nervous regulation of food intake, body weight and metabolism. We investigated effects of a low protein diet (8% protein; control diet, 17% protein) during gestation and lactation in rat dams on the organization of hypothalamic regulators of body weight and metabolism in the offspring at weaning (d 20 of life). LP offspring had significantly lower body weight than control offspring (CO; P: < 0.001), associated with hypoglycemia and hypoinsulinemia (P: < 0. 005) on d 20 of life. This was accompanied by a greater relative volume of the ventromedial hypothalamic nucleus (P: < 0.01) and a greater numerical density of Nissl-stained neurons in this nucleus (P: < 0.01) as well as in the paraventricular hypothalamic nucleus (PVN; P: < 0.001). In contrast, no significant differences in neuronal densities were observed generally in the lateral hypothalamic area, arcuate hypothalamic nucleus (ARC), and dorsomedial hypothalamic nucleus between LP offspring and CO offspring. On the other hand, LP offspring displayed fewer neurons immunopositive for neuropeptide Y in the ARC (P: < 0.05), whereas in the PVN, lower neuronal densities of neurons immunopositive for galanin were found in LP offspring compared with CO offspring (P: < 0.001). On the contrary, in the PVN, no significant group difference in the numerical density of cholecystokinin-8S-positive neurons was present. A long-term effect of these specific hypothalamic alterations on body weight and metabolism in LP offspring during later life is suggested.

Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats

“…For a tissue such as the hypothalamus, impaired nutrition at this time may alter the balance of neurones to glial cells, the density of neurones and the linkages they form, or the types of neurones that develop. 37 Our finding of effects or the LPL manipulation may not be surprising since Plagemann et al 38 have demonstrated that the suckling period is also a time when variation in nutrient supply can programme long-term changes in hypothalamic development, feeding behaviour and adiposity. Such studies have suggested that nutritional manipulations in the period of maximal fetal growth alter patterns of cell proliferation and differentiation and effectively remodel organ structure.…”

“…In the hypothalamus, for example, low protein feeding during gestation and lactation induced gross changes in the volume of the paraventricular nucleus and lateral hypothalamus and reduced the density of neurones staining for neuropeptide Y and other regulators of food intake. 37 In males, hyperphagia was noted in the aged LPM group. However, this was not associated with increased adiposity, and indeed at the time of measurement this group of rats was losing weight.…”

The hypothalamus–adipose axis is a key target of developmental programming by maternal nutritional manipulation

“…Weanling rat offspring from dams fed a LP diet presented nuclei morphometric alterations such as a greater volume of the VMN and PVN associated with higher neuronal densities (Plagemann et al 2000). Maternal nutrient restriction may also affect cell proliferation in the offspring.…”

A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat

“…The specific biological mechanisms underlying fetal/neonatal programming are largely unknown. It has been suggested that hypothalamic dysfunctions [12,13] and programming of relative leptin concentrations by early diet [14] are mechanisms that link early nutrition with later obesity. Several studies suggest the existence of alterations in the hypothalamic feeding-regulation systems in the postnatal overfeeding model.…”