This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator. This subproject evolved from the concept that the environment under which a ewe is selected alters the impacts of maternal malnutrition on fetal growth and offspring quality. Range ewes normally experiencing limited nutrition from Baggs, WY (Baggs ewes) maintained normal fetal weights when subjected to nutrient restriction (50% NRC requirements; NR) from day 28 to 78 of gestation. In contrast, ewes of similar breeding from the University of Wyoming flock (UW ewes), selected to a sedentary lifestyle and above adequate nutrition, exhibited a 30% decrease in fetal weight, under the same nutrient restriction. The growth restricted fetuses of UW ewes exhibited bilateral cardiac ventricular hypertrophy, reduced kidney nephron numbers, and fewer secondary myofibers and smaller fasciculi in skeletal muscle than fetuses from control fed (100% NRC requirements; C) UW ewes. The ability of NR Baggs ewes to maintain normal fetal weights was linked to an early placentomal conversion from Type A to more efficient Types B, C, or D by day 78 of gestation. When NR UW and Baggs ewes were re-alimented to 100% NRC requirements from day 79 to term, size, viability and birth weights were similar for lambs born to both NR and C UW ewes. At 2 months of age, however, lambs born to NR UW ewes exhibited increased baseline levels of circulating glucose and insulin than C UW lambs. Similarly, after an intravenous glucose tolerance test (IVGTT; 250 mg/kg glucose) both insulin and glucose levels remained higher longer in UW lambs from NR mothers, than UW lambs from C UW mothers. By 8 months of age, NR UW lambs exhibited elevated and prolonged blood glucose in response to an IVGTT, but exhibited a markedly reduced insulin release when compared to lambs from C UW ewes. These data suggest a reduction of pancreatic function in these NR lambs. These symptoms are similar the those Metabolic Syndrome X which afflicts significant numbers of human offspring born the women with compromised pregnancies. Further, lambs from NR UW ewes ate more, grew faster, remained fatter and had markedly higher blood pressures at 9 months of age when compared to lambs from C UW ewes. At necropsy on day 280 of age, carcasses from NR UW lambs had greater amounts of fat (kidney-pelvic and subcutaneous) and a reduced skeletal muscle mass as a percentage of empty body weight than lambs from C UW ewes. We have observed no differences in postpartum growth rate, insulin sensitivity, fatness or pancreatic function between lambs from NR and CF Baggs ewes. The abnormalities exhibited by the lambs born to NR UW ewes are consistent with a predisposition to health problems later in life such as obesity, type II diabetes, hypertension, and cardiovascular disease. These data also suggest that differences in pre-pregnancy environment can alter the sensitivity of ewes of similar breeding to a bout of maternal undernutrition during early gestation. This altered sensitivity is accomplished by alterations in the efficiency of fetal nutrient delivery. An understanding of the signal (s) which result in the advancement of placentomal type with associated increases in placentomal vascularity and efficiency of nutrient transport to the developing fetus will undoubtedly provide important clues to the mechanisms whereby placental efficiency is mediated in other species including man.
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