Abstract

Fetal/neonatal insults can lead to adult-onset diseases (obesity, diabetes, etc.) but little is known about the mechanisms involved. We have demonstrated that newborn rats artificially reared on a high carbohydrate (HC) milk formula during their suckling period immediately develop hyperinsulinemia, which persists into adulthood and is accompanied by obesity. This proposal is based on our observation that HC female rats spontaneously transmit maternal traits (chronic hyperinsulinemia and adult-onset obesity) to the progeny due to the fetal experience of a hyperinsulinemic/obese HG pregnancy. To elucidate the mechanisms involved in this maternal-fetal transfer of phenotype three specific aims are proposed: (1) Investigate the maternal environmental factor(s) responsible for programming fetal B cells to develop hyperinsulinemia after weaning. It is hypothesized that hormonal and metabolic adaptations associate with such a pregnancy are responsible for programming of hyperinsulinemia in the progeny. (2) Investigate the biochemical and molecular mechanisms responsible for chronic hyperinsulinemia an adult-onset obesity in the progeny born to HG females. The hypothesis is that the intrauterine environment of the HG female programs molecular and biochemical changes in islets of the progeny facilitating the onset of hyperinsulinemia on weaning and its persistence into adulthood. (iii) Investigate the effects of maternal hyperinsulinemia on fetal and neonatal pancreatic ontogeny as influenced by alterations in the levels of specific growth factors (IGFs, FGFs, etc.) and transcription factors. Our hypothesis is that the H( intrauterine environment alters pancreatic cellular development in the progeny in response to the change in levels of specific growth factors and transcription factors. Experimental procedures include: artificial rearing of newborn rats, reciprocal embryo transfer, insulin secretion by isolated islets radioimmunoassays, semiquantitative RT-PCR assay, immunohistochemistry and in situ hybridization.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061518-03
Application #
6607540
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (21))
Program Officer
Laughlin, Maren R
Project Start
2001-09-01
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$339,000
Indirect Cost

  Institution

Name
State University of New York at Buffalo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260

  Publications

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
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
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
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
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
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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