Hypothalamic alterations in fetuses of high fat diet-fed obese female rats

Abstract

The offspring of high fat (HF) diet-fed rats display increased body weight during adulthood. However, it is not known whether the changes in appetite regulation in these animals occur in utero or postnatally. We investigated the effects of maternal obesity induced by a HF diet prior to and during pregnancy on leptin and insulin signaling and the expression of orexigenic and anorexigenic peptides in term fetal hypothalami. The consumption of a HF diet prior to and during pregnancy resulted in obesity in HF female rats; additionally, HF female rats exhibited hyperinsulinemia and hyperleptinemia which were exaggerated in late gestation compared with control female rats that were fed a standard rodent laboratory chow (LC). Term fetuses of HF female rats (FHF) also had significantly higher serum leptin and insulin levels compared with control fetuses (FLC) while there was no difference in average fetal weight between the two groups.FHF hypothalami showed elevated levels of mRNA and proteins for leptin long receptor and insulin receptor bsubunit. However, the protein levels of signal transducers and activators of transcription-3 and insulin receptor substrate-2, the downstream signaling components of leptin and insulin signaling respectively were decreased. Also, FHF hypothalami had increased mRNA levels of neuropeptide Y and agoutirelated polypeptide indicating that orexigenic neuropeptides in HF progeny are already upregulated by term fetal stage. Additionally, the mRNA levels of pro-opiatemelanocortin and melanocortin receptor-4 were also increased in the HF fetal hypothalami. These findings indicate potential programming effects of an altered intrauterine environment induced by HF diet consumption on appetite-regulating neuropeptides and leptin and insulin signaling in the late fetal period.

Increased maternal fat consumption during pregnancy alters body composition in neonatal mice

“…Although leptin increases hypothalamic Pomc mRNA and reduces Agrp mRNA in adult rodents (43,63), the expression of these genes is not altered in neonatal mice that are chronically treated with leptin (1), a finding that is consistent with the results of the current experiment. In other studies in mice and rats, maternal HF diet consumption has been linked to decreased (44), increased (25,31), or unchanged (25) hypothalamic Pomc and Agrp gene expression in late embryonic (E19.5-E21) or neonatal (P1) offspring. Differences in the timing, duration, and fatty acid composition of the HF diets in the different studies might explain these disparate outcomes.…”

“…The programming effects of increased maternal fat consumption during pregnancy and lactation are typically exacerbated when the offspring are also fed an energy-rich diet postweaning, demonstrating that metabolic adaptations that are programmed during prenatal development can be modified by postnatal growth and nutrition (11,20,36,56). In contrast, other investigators have restricted their nutritional insult to the intrauterine environment by studying the offspring of high-fat (HF) diet-fed females during late fetal development or immediately after birth (25,31,37,44,56). For example, our laboratory and others have demonstrated that early third-trimester, nonhuman primate fetuses exhibit systemic inflammation, hepatic steatosis, increased hepatic oxidative stress with concurrent apoptotic cell death, and altered hypothalamic development in response to maternal consumption of a HF diet (26,27,42).…”

Nutritional manipulations in the perinatal period program adipose tissue in offspring

“…Models of maternal overnutrition and obesity rely on feeding the dams a high-fat (HF) or highenergy/cafeteria (fat and sugar) diet before (preconceptional period) and/or during gestation and/or lactation. In rodents, studies on maternal overfeeding have reported variable effects on birth weight, ranging from low to normal to high values (51,67,80). The discrepancy between these studies may be related to the complex interaction between maternal diet composition and genotypic susceptibility of individual rodent strains.…”

High-fat diet alters the dopamine and opioid systems: effects across development

“…31,32,34,35 Not all areas of the brain appear to be similarly sensitive to the effects of maternal consumption of a high-fat diet, as arcuate to paraventricular projections are not affected by maternal diet, 36 yet these projections are affected by maternal insulin status, 37 highlighting the complexity of the interactions between maternal environment (diet, obesity, diabetes) and the offspring outcome.…”

“…38 Changes in gene expression of neuropeptides that control homeostatic food intake (for example, melanocortins and neuropeptide Y) in the arcuate nucleus have also been documented in the offspring of dams fed a high-fat diet. 35,39,40 Importantly, a number of laboratories have identified changes in the reward circuitry in offspring from dams fed a high-fat diet, leading to an increased preference for high-fat or high-sugar foods in offspring from the affected pregnancies; in other words hedonically driven feeding. It has been shown that when pregnant rat dams are fed a 'junk-food diet' (for example, biscuits, pancakes, chocolate and cheese (high fat/high sugar)), the offspring have a significantly increased preference for fatty, sugary and salty foods.…”