Recent studies in adult and weanling rats show that dietary fat, in close association with circulating lipids, can stimulate expression of hypothalamic peptides involved in controlling food intake and body weight. In the present study, we examined the possibility that a fat-rich diet during pregnancy alters the development of these peptide systems in utero, producing neuronal changes in the offspring that persist postnatally in the absence of the diet and have long-term consequences. The offspring of dams on a high-fat diet (HFD) versus balanced diet (BD), from embryonic day 6 to postnatal day 15 (P15), showed increased expression of orexigenic peptides, galanin, enkephalin, and dynorphin, in the paraventricular nucleus and orexin and melanin-concentrating hormone in the perifornical lateral hypothalamus. The increased density of these peptide-expressing neurons, evident in newborn offspring as well as P15 offspring crossfostered at birth to dams on the BD, led us to examine events that might be occurring in utero. During gestation, the HFD stimulated the proliferation of neuroepithelial and neuronal precursor cells of the embryonic hypothalamic third ventricle. It also stimulated the proliferation and differentiation of neurons and their migration toward hypothalamic areas where ultimately a greater proportion of the new neurons expressed the orexigenic peptides. This increase in neurogenesis, closely associated with a marked increase in lipids in the blood, may have a role in producing the long-term behavioral and physiological changes observed in offspring after weaning, including an increase in food intake, preference for fat, hyperlipidemia, and higher body weight.

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Neuropeptide Y (NPY) was injected directly Into the paraventricular nucleus of the hypothalamus (PVN) of satiated, brain-cannulated rats, and food and water intake were measured 0.5, 1, 2, 4, and 22 hr postinjection. NPY (24, 78, 235, 783, and 2351 pmol/0.3 pl) produced a large, dosedependent increase in food intake as well as a small increase in water intake. The latency to eat was about 10 min, with substantial feeding occurring in the first 30 min. At doses below 78 pmol, the eating generally occurred only within the first hour. At doses above 235 pmol, however, the subjects' food intake continued to increase such that by 4 hr postinjection they had consumed the equivalent of normal 22-hr intake, and 22 hr postinjection they had also eaten significantly more than control subjects. Previous studies have shown that norepinephrine injected into the PVN stimulates feeding through aadrenergic receptors. To investigate a possible interaction, subjects were given PVN injections of phentolamine (60 nmol) prior to injections of either NPY (78 pmol) or norepinephrine (20 nmol). Phentolamine pretreatment significantly decreased feeding elicited by norepinephrine without affecting feeding elicited by NPY. This suggests that NPY does not stimulate feeding through the release of endogenous norepinephrine. The powerful stimulation of feeding elicited by this neuropeptide suggests an important role for hypothalamic NPY, or a structurally related peptide, in the regulation of feeding behavior.Neuropeptide Y (NPY), a 36-amino acid member of the pancreatic polypeptide family, was discovered in porcine brain by Tatemoto et al. in 1982 (1, 2). Subsequently, the concentration of NPY in the brain was found to exceed the concentration of any other peptide (3). Our interest in a possible role for NPY in the control of feeding behavior was stimulat ed by the recent reports that it is colocalized with norepinephrine (NE) and epinephrine in brainstem catecholamine cell groups, which send afferent fibers to the paraventricular nucleus of the hypothalamus (PVN) (4, 5; however, see ref.32), and also by reports that it is found within numerous presynaptic terminals in the PVN (3, 6, 7). Experiments investigating brain mechanisms of feeding behavior have demonstrated that central injections of several putative neurotransmitters, including NE, y-aminobutyric acid, acetylcholine, and opiate agonists, can selectively stimulate feeding behavior (8-11). The most intensely studied of these is NE. It has been shown that PVN injection of exogenous NE, or drug-induced release of endogenous NE from brainstem catecholamine neurons that ascend to the PVN, elicits feeding behavior through stimulation of a2-adrenergic receptors (12-15). The feeding response appears to be mediated through the PVN, since this is the brain region that is most sensitive to NE and since NE-induced feeding is severely attenuated by PVN lesions (12, 16). A role for this system in natural (deprivation-induced) feeding was suggested by the findings that PVN a-adrenergic r...

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