Newborn rat pups artificially raised on a high-carbohydrate (HC) milk formula are chronically hyperinsulinemic and develop adult-onset obesity. As HC rats display aberrations in body weight regulation, hypothalamic adaptations predisposing to obesity have been investigated in this study. The artificial rearing of neonatal rat pups on the HC milk formula resulted in significant increases in the mRNA levels of neuropeptide Y, agouti-related polypeptide, and galanin in the hypothalamus of 12-day-old HC rats. Simultaneously, decreases in the mRNA levels of POMC, melanocortin receptor-4, cocaine- and amphetamine-regulated transcript, and corticotrophin-releasing factor were observed in the hypothalamus of these rats. These changes persisted in 100-day-old HC rats despite weaning onto a rodent diet on postnatal day 24. Marked hyperphagia and increased body weight gain were observed in the post-weaning period. The mRNA levels and protein content of insulin receptor beta (IR-beta) and leptin receptor (long form) showed significant decreases in the hypothalamus of both 12- and 100-day-old HC rats. Further investigation of insulin signaling in the hypothalamus of HC rats indicated significant decreases in the proximal signaling components (insulin receptor substrate proteins 1 and 2 and phosphotidylinositol 3-kinase) in 100-day-old HC rats. These results suggest that hypothalamic neuropeptides respond to the increased carbohydrate availability with associated hormonal alterations during the period of dietary modulation and that these adaptations by persisting in the post-weaning period predispose the HC rats for adult-onset obesity.

. Maternal hyperinsulinemia predisposes rat fetuses for hyperinsulinemia, and adult-onset obesity and maternal mild food restriction reverses this phenotype. Am J Physiol Endocrinol Metab 290: E129 -E134, 2006. First published September 6, 2005 doi:10.1152/ajpendo.00248.2005We have previously shown that artificial rearing of newborn female rat pups on a high-carbohydrate (HC) milk formula resulted in chronic hyperinsulinemia and adultonset obesity (HC phenotype) and that the maternal HC phenotype was transmitted to their progeny (2-HC rats) because of fetal development in the HC female rat. The aims of this study were to investigate 1) the fetal adaptations that predisposed the progeny for the expression of the HC phenotype in adulthood and 2) whether the transfer of the HC phenotype to the progeny could be reversed by maternal food restriction. Fetal parameters such as plasma insulin and glucose levels, mRNA level of preproinsulin gene, pancreatic insulin content, and islet insulin secretory response in vitro were determined. On gestational day 21, 2-HC fetuses were hyperinsulinemic, had increased insulin content and mRNA level of the preproinsulin gene in their pancreata and demonstrated an altered glucose-stimulated insulin secretory response by isolated islets. Modification of the intrauterine environment in HC female rats was achieved by pair feeding them to the amount of diet consumed by age-matched control rats from the time of their weaning. This mild dietary restriction reversed their HC phenotype and also prevented the development of the HC phenotype in their progeny. These findings show that malprogramming of the progeny of the hyperinsulinemic-obese HC female for the expression of the HC phenotype is initiated in utero and that normalization of the maternal environment in HC female rats by mild food restriction resulted in the normal phenotype in their progeny. maternal intrauterine environment; fetal programming; fetal hyperinsulinemia; obesity; pair feeding EPIDEMIOLOGICAL DATA AND RESULTS from animal models indicate that the nutritional status of the mother during pregnancy impacts on the expression of metabolic diseases in adulthood of the progeny (2,3,7,11,12,18,21,30). Extensive organ development continues to occur in the immediate postnatal life of the rat, suggesting that this period, too, is vulnerable for metabolic programming effects. Earlier, we showed that the overlap of an altered nutritional experience in the form of a high-carbohydrate (HC) milk formula with the critical window of postnatal organ development in neonatal rat pups resulted in the establishment of the HC phenotype (chronic hyperinsulinemia and adult-onset obesity) in these rats (19,26). Because of fetal development in HC female rats, adult progeny demonstrated the same HC phenotype (29). Whether the adaptations that predispose the progeny for expression of the HC phenotype in adult life occur during fetal development in the HC intrauterine environment was not explored in the earlier study.The suckling period in the rat ...

Mitrani P, Srinivasan M, Dodds C, Patel MS. Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model. Am J Physiol Endocrinol Metab 292: E1364 -E1377, 2007. First published January 16, 2007; doi:10.1152/ajpendo.00672.2006.-Exposure to a high-carbohydrate (HC) milk formula during the suckling period results in permanent metabolic programming of hyperinsulinemia in HC rats. Previous studies have shown that hyperinsulinemia in HC rats involves a programmed hyperresponsiveness to glucose. However, the immediate onset and persistence of enhanced insulin secretion throughout life suggests a role for numerous factors that control insulin secretion. Present in vivo and in vitro studies have shown a role for altered autonomic activity, including increased parasympathetic and decreased sympathetic activities, in the maintenance of hyperinsulinemia in 100-day-old HC rats. HC rats were shown to be more sensitive to cholinergic-induced potentiation of glucose-stimulated insulin secretion (GSIS) in response to acetylcholine and showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic-type 3 receptor-specific antagonist 4-diphenylacetoxy-Nmethylpiperidine. In addition, HC rats were less sensitive to adrenergic-induced inhibition of insulin secretion by oxymetazoline, whereas treatment with yohimbine resulted in increased GSIS. Furthermore, HC rats showed greater reductions in plasma insulin levels after vagotomy, as well as an attenuation of yohimbine-induced potentiation of GSIS, suggesting that yohimbine-mediated changes are mediated by parasympathetic activity. Changes in autonomic regulation of GSIS are supported by increased mRNA levels of the parasympathetic signaling molecules muscarinic-type 3 receptor, phospholipase C␤1, and protein kinase C-␣ and decreased levels of ␣ 2a-adrenergic receptors in islets from adult HC rats. In conclusion, metabolic programming of hyperinsulinemia throughout adulthood of HC rats involves changes in autonomic activity in response to the HC dietary intervention in the suckling period.high-carbohydrate milk formula; parasympathetic nervous system; and sympathetic nervous system STUDIES OF THE RISING PREVALENCE of obesity, type 2 diabetes mellitus (48), and metabolic syndrome (19) suggest that the origins of these growing epidemics involve an acquired susceptibility to altered nutritional environments during critical periods of early development, including both the fetal and neonatal periods (9,47). This vulnerability manifests as a metabolic programming phenomenon in which a stimulus or insult during critical periods of organogenesis in early life induces permanent alterations in the development and function of affected organs at the cellular, biochemical, and molecular levels to increase the chance of survival in altered nutritional environments (52). These adaptations result in an increased susceptibility to metabolic diseases in adulthood, including obesity, type 2 diabetes mellitus, an...

Mitrani P, Srinivasan M, Dodds C, Patel MS. Role of the autonomic nervous system in the development of hyperinsulinemia by high-carbohydrate formula feeding to neonatal rats. Am J Physiol Endocrinol Metab 292: E1069 -E1078, 2007. First published December 12, 2006 doi:10.1152/ajpendo.00477.2006.-An early dietary intervention in the form of a high-carbohydrate (HC) milk formula in neonatal rat pups results in immediate onset of hyperinsulinemia. While increased insulin secretion in HC rats has been shown to be related to hypersensitivity to glucose, the immediate onset of hyperinsulinemia and its persistence throughout the suckling period suggest involvement of multiple systems that enhance insulin secretion in response to increased demand. Evidence presented here in 12-day-old HC rats indicates that altered activity of the autonomic nervous system contributes to enhanced insulin secretory responses to glucose stimulation through increased parasympathetic and decreased sympathetic signaling. Both in vivo and in vitro studies have shown that HC rats secrete significantly higher levels of insulin in response to glucose in the presence of acetylcholine, a cholinergic agonist, while sensitivity to inhibition of insulin secretion by oxymetazoline, an ␣ 2a-adrenergic receptor (␣2aAR) agonist, was reduced. In addition, HC rats showed increased sensitivity to blockade of cholinergicinduced insulin secretion by the muscarinic type 3 receptor (M3R) antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide, as well as increased potentiation of glucose-stimulated insulin secretion by treatment with yohimbine. Increases in islets levels of M3R, phospholipase C-␤1, and protein kinase C␣ mRNAs, as well as decreased ␣ 2aAR mRNA, in 12-day-old HC rats provide a mechanistic connection to the changes in insulin secretion seen in HC rats. In conclusion, altered autonomic regulation of insulin secretion, due to the HC nutritional intervention, contributes to the development of hyperinsulinemia in 12-day-old HC rats.high-carbohydrate milk formula; parasympathetic nervous system; sympathetic nervous system RECENT EVIDENCE SUGGESTS that changes in the quality of nutrition during critical periods of early development (fetal and neonatal) may play a decisive role in the metabolic programming of early adaptive responses into adulthood which result in metabolic disease (6). Metabolic programming is the phenomenon in which a stimulus or insult that occurs during a critical period of organogenesis in early life results in permanent alterations in the structure and function of affected organs and increased susceptibility to adult onset of diseases (6). The late fetal and early postnatal periods of rat development constitute a period during which the ontogeny of the endocrine pancreas is vulnerable to nutritional perturbations that result in permanent structural and functional adaptations (9).Studies from our laboratory found that an early high-carbohydrate (HC) dietary intervention during the immediate postnatal period (days 4-24) in rats r...

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