Hostname: page-component-cd9895bd7-q99xh Total loading time: 0 Render date: 2024-12-25T03:14:17.511Z Has data issue: false hasContentIssue false

The maternal endocrine environment in the low-protein model of intra-uterine growth restriction

Published online by Cambridge University Press:  09 March 2007

D. S. Fernandez-Twinn*
Affiliation:
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, UK
S. E. Ozanne
Affiliation:
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, UK
S. Ekizoglou
Affiliation:
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, UK
C. Doherty
Affiliation:
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, UK
L. James
Affiliation:
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, UK
B. Gusterson
Affiliation:
Department of Pathology, Western Infirmary, University of Glasgow, Glasgow G11 6NT, Scotland, UK
C. N. Hales
Affiliation:
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QR, UK
*
*Corresponding author: Dr D. S. Fernandez-Twinn, fax +44 1223 330598, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Many adult diseases, including type 2 diabetes, hypertension and cardiovascular disease, are related to low birth weight. The mechanistic basis of this relationship is not known. To investigate the role of fetal undernutrition, we used a rat model of maternal protein restriction in which dams were fed a diet containing 80 g protein/kg (v. 200 g/kg in the control group) throughout gestation and lactation. Offspring were born smaller than controls and in adulthood developed diabetes, hyperinsulinaemia and tissue insulin resistance. To determine possible mechanisms of fetal programming, circulating levels of several hormones were measured in maternal plasma at gestational days 14, 17 and 21 and fetal plasma at gestational day 21. Several differences were noted at day 14, when glucose concentrations in maternal and feto–placental blood were raised significantly (P=0·04 and P=0·0001 respectively); insulin levels in the low-protein (LP) dams were raised (P=0·04), prolactin levels were raised (P=0·047) and progesterone levels were reduced (P=0·02). Circulating 17β-oestradiol in the LP dams was raised by 35% over those of the controls from day 17 to day 21 (P=0·008). A significant decrease in maternal leptin levels (P=0·004) was observed at gestation on day 21. Neither oestradiol nor leptin levels were altered in the fetal circulation at day 21. Maternal and fetal corticosterone levels were comparable with control levels, suggesting that they do not initiate the programming effects in this model. Our present results suggest that maternal protein restriction imposes changes in maternal levels of glucose, insulin, prolactin, progesterone, oestradiol and leptin; these changes could influence the programming of eventual adult disease in the developing fetus.

Type
Research Article
Copyright
Copyright © The Nutrition Society 2003

References

Alvarez, JJ, Montelongo, A, Iglesias, A, Lasuncion, MA & Herrera, E (1996) Longitudinal study on lipoprotein profile, high density lipoprotein subclass, and postheparin lipases during gestation in women. J Lipid Res 37, 299308.CrossRefGoogle ScholarPubMed
Boileau, P, Mrejen, C, Girard, J & Hauguel-de Mouzon, S (1995) Overexpression of GLUT3 placental glucose transporter in diabetic rats. J Clin Invest 96, 309317.CrossRefGoogle ScholarPubMed
Blondeau, B, Lesage, J, Czernichow, P, Dupouy, JP & Breant, B (2001) Glucocorticoids impair fetal β-cell development in rats. Am J Physiol Endocrinol Metab 281, E592E599.CrossRefGoogle ScholarPubMed
Cherif, H, Reusens, B, Ahn, MT, Hoet, JJ & Remacle, C (1998) Effects of taurine on the insulin secretion of rat islets from dams fed a low-protein diet. J Endocrinol 159, 341348.CrossRefGoogle ScholarPubMed
Christou, H, Connors, JM, Ziotopoulou, M, et al. (2001) Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth. J Clin Endocrinol Metab 86, 935938.CrossRefGoogle ScholarPubMed
Cinaz, P, Sen, E, Bodeci, A, Ezgu, FS, Atalay, Y & Koca, E (1999) Plasma leptin levels of large for gestational age and small for gestational age infants. Acta Pediatr 88, 753755.CrossRefGoogle ScholarPubMed
Clark, PM (1998) Programming of the hypothalamo-pituitary-adrenal axis and the fetal origins of adult disease hypothesis. Eur J Pediatr 157, Suppl. 1, S7S10.CrossRefGoogle ScholarPubMed
Freemark, M, Avril, I, Fleenor, D, et al. (2002) Targeted deletion of the PRL receptor: Effects on islet development, insulin production, and glucose tolerance. Endocrinology 143, 13781385.CrossRefGoogle ScholarPubMed
Hales, CN, Barker, DJP, Clark, PMS, Cox, LJ, Fall, C & Winter, PD (1991) Fetal and infant growth and impaired glucose tolerance at age 64 years. Br Med J 303, 10191022.CrossRefGoogle Scholar
Hales, CN & Barker, DJ (2001) The thrify phenotype hypothesis. Br Med Bull 60, 520.CrossRefGoogle ScholarPubMed
Hassink, SG, de Lancey, E, Sheslow, DV, et al. (1997) Placental leptin: an important new growth factor in intrauterine and neonatal development? Pediatrics 100, E1E6.CrossRefGoogle ScholarPubMed
Herrera, E, Palacin, M, Martin, A & Lasuncion, MA (1985) Relationship between maternal and fetal fuels and placental glucose transfer in rats with maternal diabetes of varying severity. Diabetes 34, Suppl. 2, 4246.CrossRefGoogle Scholar
Herrera, E, Lasuncion, MA, Gomes Coronado, D, Aranda, P, Lopez-Luna, P & Maier, I (1988) Role of lipoprotein lipase activity on lipoprotein metabolism and the fate of circulating triglycerides in pregnancy. Am J Obstet Gynecol 158, 15751583.CrossRefGoogle ScholarPubMed
Herrera, E (2002) Implications of dietary fatty acids during pregnancy on placental, fetal and postnatal development–A review. Placenta 23, Suppl. A, S9S19.CrossRefGoogle Scholar
Karabulut, AK, Layfield, R & Pratten, MK (1999) The mechanism of growth-promoting effects of prolactin in embryogenesis-links to growth factors. Cells Tissues Organs 164, 213.CrossRefGoogle ScholarPubMed
Kaijser, M, Granath, F, Jacosen, G, Cnattingius, S & Ekbom, A (2000) Maternal pregnancy estriol levels in relation to anamnestic and fetal anthropometric data. Epidemiology 11, 315319.CrossRefGoogle ScholarPubMed
Langley-Evans, SC, Phillips, GJ, Benediktsson, R, et al. (1996) Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 17, 169172.CrossRefGoogle ScholarPubMed
Langley-Evans, SC (1997) Maternal carbenoxolone treatment lowers birthweight and induces hypertension in the offspring of rats fed a protein-replete diet. Clin Sci 93, 423429.CrossRefGoogle ScholarPubMed
Lesage, J, Hahn, D, Leonhardt, M, Blondeau, B, Breant, B & Dupouy, JP (2002) Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels. J Endocrinol 174, 3743.CrossRefGoogle Scholar
Lewandowski, K, Horn, R, O'Callaghan, CR, et al. (1999) Free leptin, bound leptin, and soluble leptin receptor in normal and diabetic pregnancies. J Clin Endocrinol Metab 84, 27552758.CrossRefGoogle ScholarPubMed
Linnemann, K, Malek, A, Sager, R, Blum, WF, Schneider, H & Fusch, C (2000) Leptin production and release in the dually in vitro perfused human placenta. J Clin Endocrinol Metab 85, 42984301.Google ScholarPubMed
Martin-Hidalgo, A, Holm, C, Belfrage, P, Schotz, MC & Herrera, E (1994) Lipoprotein lipase and hormone sensitive lipase activity and mRNA in adipose tissue during pregnancy. Am J Physiol 266, E930E935.Google ScholarPubMed
Miller, RK, Heckmann, ME & McKenzie, RC (1982) Diethylstilbestrol: placental transfer, metabolism, covalent binding and fetal distribution in the Wistar rat. J Pharmacol Exp Ther 220, 358365.Google ScholarPubMed
Montelongo, A, Lasuncion, MA, Pallardo, LF & Herrera, E (1992) Longitudinal study of plasma lipoproteins and hormones during pregnancy in normal and diabetic women. Diabetes 41, 16511659.CrossRefGoogle ScholarPubMed
Nathanielsz, PW (1978) Parturition in rodents. Semin Perinatol 2, 223234.Google ScholarPubMed
Ozanne, SE, Martensz, ND, Petry, CJ, Loizou, CL & Hales, CN (1998) Maternal low protein diet in rats programmes fatty acid desaturase activities in the offspring. Diabetologia 41, 13371342.CrossRefGoogle ScholarPubMed
Ozanne, SE (2001) Metabolic programming in animals. Brit Med Bull 60, 143152.CrossRefGoogle ScholarPubMed
Phillips, DIW, Barker, DJP, Fall, CHD, et al. (1998) Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 83, 757760.Google ScholarPubMed
Seckl, JR (1997) Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 62, 8994.CrossRefGoogle Scholar
Sivan, E, Whittaker, PG, Sinha, D, et al. (1998) Leptin in human pregnancy: the relationship with gestational hormones. Am J Obstet Gynecol 179, 11281132.CrossRefGoogle ScholarPubMed
Snoeck, A, Remacle, C, Reusens, B & Hoet, JJ (1990) Effect of a low protein diet during pregnancy on the foetal rat endocrine pancreas. Biol Neonate 57, 107118.CrossRefGoogle ScholarPubMed
Sorenson, RL, Brelje, TC & Roth, C (1993) Effects of steroid and lactogenic hormones on islets of Langerhans: A new hypothesis for the role of pregnancy steroids in the adaptation of islets to pregnancy. Endocrinology 133, 22272234.CrossRefGoogle ScholarPubMed
Symonds, ME, Budge, H, Stephenson, T & McMillen, IC (2001) Fetal endocrinology and development-manipulation and adaptation to long-term nutritional and environmental challenges. Reproduction 121, 853862.CrossRefGoogle ScholarPubMed
Varvarigou, A, Mantzoros, CS & Beratis, NG (1999) Cord blood leptin concentrations in relation to intrauterine growth. Clin Endocrinol (Oxf) 50, 177183.CrossRefGoogle ScholarPubMed
Wasfi, I, Weinstein, I & Heimberg, M (1980) Increased formation of triglycerides from oleate in perfused livers from pregnant rats. Endocrinology 10, 584596.CrossRefGoogle Scholar
Wauters, M, Considine, RV & van Gaal, LF (2000) Human leptin: from an adipocyte hormone to an endocrine mediator. Eur J Endocrinol 143, 293311.CrossRefGoogle Scholar