The current obesity epidemic in the United States is a source of concern due to the clinical complications associated with obesity. Metabolic programming due to altered nutritional experiences in early periods of life is implicated in the etiology of obesity and related disorders. Our earlier results showed that a high carbohydrate (HC) dietary modification in new born rats results in chronic hyperinsulinemia and adult-onset obesity (HC phenotype) in first generation (1-HC) rats. Fetal development in the 1-HC female rats results in spontaneous transfer of the HC phenotype to the offspring (2-HC rats) (transgenerational effect). The focus of this grant proposal is to investigate mechanisms supporting the development of obesity in 1-HC and 2-HC rats. The hypothalamic melanocortin system is considered to play a critical role in the regulation of appetite and body weight homeostasis;it is hypothesized that aberrations in this system contribute significantly towards the development of obesity in 1-HC and 2-HC rats. Based on this rationale, Specific Aim 1 hypothesizes that the HC dietary modification in new born rat pups overlapping with the period of postnatal neuronal development in the rat will result in abnormalities in the melanocortin system and will predispose 1- HC rats for adult-onset obesity.
Specific Aim 2 hypothesizes that fetal development in the adverse intrauterine environment (a consequence of the metabolic phenotype of the 1-HC female rat) in the 1-HC female rat will result in malprogramming of the melanocortin system in the 2-HC offspring and predisposition to adult-onset obesity.
Specific Aim 3 hypothesizes that fetal development in the normalized 1-HC intrauterine environment, achieved by dietary or pharmacological interventions imposed on 1-HC female rats to reduce hyperphagia and body weight gain, will reverse the transgenerational effect for 2-HC offspring. To investigate the development of abnormalities in the melanocortin system, alterations in (i) the expression of the melanocortin genes, (ii) the development of arcuate nucleus projections and (iii) the functional responses to exogenous leptin will be determined in 1-HC and 2-HC rats. New born rat pups will be artificially reared on a high carbohydrate milk formula for generation of 1-HC rats. 2-HC rats will be generated by breeding 1-HC female rats with normal male rats. Pair-feeding and dietary supplementation with 1-lipoic acid will be enforced in the 1-HC female rats from the time of weaning and consequences for both the mother and the progeny will be monitored. For investigation of alterations in the melanocortin system, in situ hybridization and immunohistochemical analyses will be carried out in brain sections. The results from these studies are expected to provide valuable information on the mechanisms that support programming for adult-onset obesity in two generations of rats due to a high carbohydrate dietary modification imposed on the female rats in their immediate postnatal life and also on the possible reversal of the transgenerational effect. The results from the proposed studies may have implications for the altered dietary practices in humans during infancy.

Public Health Relevance

Early introduction of babies'first foods for infants and pregnancy complicated with obesity may independently contribute to the predisposition for development of obesity which is present in epidemic proportions in adults and children in the United States. Our rat model presents a unique opportunity to investigate the programming of the brain during the immediate postnatal and fetal periods for the development of obesity in adult life. Intervention measures proposed for the prevention of the malprogramming effects may lead to development of effective treatment options for curbing the human obesity epidemic.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Silva, Corinne M
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State University of New York at Buffalo
Schools of Medicine
United States
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Raychaudhuri, Nupur; Thamotharan, Shanthie; Srinivasan, Malathi et al. (2014) Postnatal exposure to a high-carbohydrate diet interferes epigenetically with thyroid hormone receptor induction of the adult male rat skeletal muscle glucose transporter isoform 4 expression. J Nutr Biochem 25:1066-76
Stachowiak, Ewa K; Srinivasan, Malathi; Stachowiak, Michal K et al. (2013) Maternal obesity induced by a high fat diet causes altered cellular development in fetal brains suggestive of a predisposition of offspring to neurological disorders in later life. Metab Brain Dis 28:721-5
Srinivasan, Malathi; Mahmood, Saleh; Patel, Mulchand S (2013) Metabolic programming effects initiated in the suckling period predisposing for adult-onset obesity cannot be reversed by calorie restriction. Am J Physiol Endocrinol Metab 304:E486-94
Liu, Hung-Wen; Srinivasan, Malathi; Mahmood, Saleh et al. (2013) Adult-onset obesity induced by early life overnutrition could be reversed by moderate caloric restriction. Am J Physiol Endocrinol Metab 305:E785-94
Stachowiak, Ewa K; Oommen, Saji; Vasu, Vihas T et al. (2013) Maternal obesity affects gene expression and cellular development in fetal brains. Nutr Neurosci 16:96-103
Liu, Hung-Wen; Mahmood, Saleh; Srinivasan, Malathi et al. (2013) Developmental programming in skeletal muscle in response to overnourishment in the immediate postnatal life in rats. J Nutr Biochem 24:1859-69
Patel, Mulchand S; Srinivasan, Malathi (2010) Metabolic programming due to alterations in nutrition in the immediate postnatal period. J Nutr 140:658-61
Gupta, Anshu; Srinivasan, Malathi; Thamadilok, Supaporn et al. (2009) Hypothalamic alterations in fetuses of high fat diet-fed obese female rats. J Endocrinol 200:293-300
Patel, M S; Srinivasan, M; Laychock, S G (2009) Metabolic programming: Role of nutrition in the immediate postnatal life. J Inherit Metab Dis 32:218-28
Srinivasan, Malathi; Mitrani, Paul; Sadhanandan, Gigani et al. (2008) A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity. J Endocrinol 197:565-74

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