Maternal High-Fat Diet and Fetal Programming: Increased Proliferation of Hypothalamic Peptide-Producing Neurons That Increase Risk for Overeating and Obesity

Abstract

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.

The early origins of food preferences: targeting the critical windows of development

“…Consistent with the findings of Gorski et al (49), we found that exposure to a maternal cafeteria diet during both the fetal and suckling periods or suckling period alone, but not fetal period alone, was associated with a higher intake of fat, carbohydrate, and total energy when offspring were given free access to both a control and cafeteria diet at 2 mo of age (46). The inconsistencies between the study conducted by Chang et al (43) and those conducted by Gorski et al (49) and in our laboratory could potentially be explained by differences in the composition of the diet and the length of high-fat/cafeteria diet exposure before pregnancy; however, further investigation is clearly required. Nevertheless, the results of the latter 2 studies suggest that the suckling period, rather than the prenatal period, plays the more important role in the programming of food preferences.…”

“…The findings of Chang et al (43) have not, however, been replicated in other cross-fostering studies. In one of these studies, Gorski et al (49) demonstrated that exposure to a high-fat diet during the suckling period alone was sufficient to increase the offspring's appetite for highenergy foods in adulthood.…”

“…This approach provides the opportunity to isolate the effects of exposure to the junk food diet during fetal and suckling periods without any carryover effects associated with switching the same dam from one diet to another, and is thus of considerable value in defining critical developmental windows. In one such study, Chang et al (43) demonstrated that offspring that had been exposed to a high-fat diet in utero exhibited an increased body weight, increased body fat mass, and increased fat preference, independent of whether they were suckled by a dam consuming a control or high-fat diet. This study went on to show that exposure to a high-fat diet before birth, but not during the suckling period, also resulted in significant increases in the proliferation of neuronal cells involved in regulating fat intake (e.g., galanin neurons) in the hypothalamic appetite regulatory center (43).…”

“…This study went on to show that exposure to a high-fat diet before birth, but not during the suckling period, also resulted in significant increases in the proliferation of neuronal cells involved in regulating fat intake (e.g., galanin neurons) in the hypothalamic appetite regulatory center (43). These results led the authors to conclude that exposure to a high-fat diet before birth was both necessary and sufficient to program a preference for high-fat foods and thereby predispose the offspring to diet-induced obesity (43).…”

“…The majority of studies to date that have focused on the critical windows of reward pathway development and the programming of food preferences have only considered male offspring or have failed to separate male and female animals in the analysis (7,43,45). Many researchers choose to focus only on male offspring to avoid any possible complications in the interpretation of results introduced by the hormonal fluctuations that accompany the estrous cycle in females (61).…”