We evaluated the effects of preconception and gestational obesity in the ewe on offspring growth, metabolism, and glucose homeostasis. From 60 d before conception through parturition, multiparous ewes were fed 100% (control; n = 8) or 150% (obese, OB; n = 10) of NRC (1985) recommendations. Ewes on the OB diet increased BW by 30% from diet initiation to mating (P = 0.03) and by 52% by d 135 of gestation (P = 0.04), whereas control ewes increased BW by 7% (P = 0.65) from diet initiation to d 135 of gestation. Lambs were weaned at 120 d of age and were maintained as a group. At 19.5 ± 0.5 mo of age, offspring from control and OB ewes were individually penned and subjected to a 12-wk ad libitum feeding challenge. At the beginning and end of the feeding challenge, dual x-ray absorptiometry was used to determine percentage of body fat, and a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis was used to assess insulin and glucose homeostasis. At the beginning of the feeding challenge, BW and percentage of body fat were similar for control and OB offspring, averaging 69.0 ± 1.5 kg and 5.3 ± 0.5%, respectively. At the initial FSIGT, glucose effectiveness and insulin sensitivity were reduced (P < 0.05) in offspring from OB compared with control ewes. During the feeding challenge, plasma concentrations of leptin were increased (P < 0.05) in offspring from OB compared with control ewes. Fasted plasma glucose before the feeding challenge tended to be greater (P = 0.06) in the OB offspring compared with the control offspring (83.3 ± 1.4 vs. 79.0 ± 1.6 mg/dL, respectively). At the end of the feeding challenge, fasted plasma glucose and insulin were increased (P < 0.05) in the OB offspring compared with the control offspring (84.0 ± 1.4 vs. 79.5 ± 1.5 mg/dL and 30.1 ± 2.1 vs. 23.4 ± 2.2 µIU/mL, respectively). During the feeding challenge, offspring from OB ewes consumed approximately 10% more feed (P < 0.05) and tended to have increased BW gain (approximately 14%; P = 0.08) compared with offspring from control ewes. At the final dual x-ray absorptiometry scan, percentage of body fat was greater (P < 0.05) for offspring from OB ewes than for offspring from control ewes (16.5 ± 1.2 vs. 10.8 ± 1.1%). At the final FSIGT, offspring from OB ewes had a decreased (P ≤ 0.05) acute insulin response to glucose, disposition index, and glucose effectiveness, and tended (P = 0.10) to have a decreased insulin sensitivity compared with offspring from control ewes. Maternal obesity induced before and during gestation leads to alterations in appetite, glucose and insulin regulation, and adiposity of mature offspring.

No abstract

Obesity of women at conception is increasing, a condition associated with offspring obesity. We hypothesized that maternal obesity increases placental fatty acid transporter (FATP) expression, enhancing delivery of fatty acids to their fetuses. Sheep are a commonly utilized biomedical model for pregnancy studies. Nonpregnant ewes were randomly assigned to a control group [100% of National Research Council (NRC) recommendations] or obese group (OB, 150% of NRC) from 60 days before conception to 75 or 135 days of gestation (dG; term = 150 dG), when placental cotyledonary tissue was collected for analysis. Fetuses of OB ewes were markedly heavier (P < 0.05) on 75 dG than fetuses from control ewes, but this difference disappeared by 135 dG. Maternal obesity markedly increased (P < 0.05) cholesterol and triglyceride concentrations of both maternal and fetal blood. There is no difference in lipoprotein lipase mRNA expression between control and OB group at either gestational age. On 75 dG, the mRNA expression of FATP1 (P < 0.05), FATP4 (P = 0.08), and fatty acid translocase CD (cluster of differentiation) 36 (P < 0.05) proteins were more enhanced in cotyledonary tissue from OB than control ewes; consistently, protein expression of FATP1 and FATP4 was increased (P < 0.05). Similarly, on 135 dG, the mRNA levels of FATP1, FATP4, and CD36 were all higher (P < 0.05), but only FATP4 protein content was enhanced (P < 0.05) in OB cotyledonary tissue. Peroxisome proliferator-activated receptor (PPAR)-γ regulates the expression of FATPs. Both the mRNA expression and protein content of PPARγ were increased in OB cotyledonary in the midgestation. In conclusion, maternal obesity enhances the mRNA expression and protein content of FATPs in cotyledonary in the midgestation, which is associated with higher PPARγ content in cotyledonary.

Non technical summary Leptin, an adipose tissue hormone, inhibits the brain's central drive to eat, enabling maintenance of normal body weight and composition. The leptin peak present in newborn rodents controls development of brain appetite regulatory areas, and alteration in its timing and amplitude predisposes to obesity in later life. However, unlike humans, rodents are born at an immature stage of development so to determine potential relevance to human development, we examined the leptin peak in newborn lambs, born at a more advanced level of maturity equivalent to humans. The normal peak was absent in lambs born to obese mothers who showed higher newborn levels of plasma cortisol. We conclude that similarities and differences exist in neonatal leptin in species born immature or mature. This information aids understanding of effects of the obesity epidemic in women on their offspring and will help promote diagnosis, prevention and therapy.Abstract A neonatal peak in rodent plasma leptin plays a central role in regulating development of the hypothalamic appetite control centres. Maternal obesity lengthens and amplifies the peak in altricial rodent species. The precise timing and characteristics of the neonatal leptin peak have not been established in offspring of either normal or obese mothers in any precocial species. We induced obesity by feeding female sheep for 60 days before conception, and throughout pregnancy and parturition with 150% of the diet consumed by control ewes fed to National Research Council recommendations. We have reported that mature offspring of obese sheep fed similarly exhibited increased appetite, weight gain and obesity in response to ad libitum feeding at 19 months of age. We observed a leptin peak in lambs of control ewes between days 6 and 9 of postnatal life, earlier than reported in rodents. This peak was not present in lambs born to obese ewes. The leptin peak in lambs born to control ewes was not clearly related to any changes in plasma cortisol, insulin, triiodothyronine, IGF-1 or glucose. However, there was a significant increase in cortisol at birth in lambs born to obese ewes related to an increase in leptin in the first day of life. We conclude that the increased cortisol seen in lambs of obese sheep plays a role in disrupting the normal peak of leptin in lambs born to obese ewes thereby predisposing them to increased appetite and weight gain in later life.

Fetal intrauterine growth restriction (IUGR) is known to negatively affect offspring health postnatally. This study evaluated the impacts of early gestational undernutrition followed by realimentation on bovine fetal and placental growth. Thirty multiparous beef cows bred to a single sire and gestating female fetuses were fed to meet NRC recommendations (control; n = 15) or fed below NRC recommendations (68.1% of NE(m) and 86.7% of MP recommendations; nutrient restricted, NR; n = 15) from d 30 to 125 of gestation. On d 125 of gestation, 10 control and 10 NR cows were necropsied. The remaining 5 NR cows were realimented to achieve similar BW and BCS with the remaining 5 control cows by d 190 of gestation; both groups were necropsied at d 245 of gestation. Fetal weight at d 125 of gestation was 948 +/- 14 g (n = 10) for control cows; however, fetal weights of NR cows fell into 2 distinct groups: NR non-IUGR cows had fetal weights similar to control cows (974 +/- 20 g, n = 6), whereas fetal weights of NR IUGR cows were reduced (773 +/- 23 g, n = 4; P < 0.01). Fetal brain weight as a percentage of fetal weight was increased (approximately 11%; P < 0.01) in the NR IUGR fetuses compared with fetuses from the other 2 groups, which were similar. Fetal heart weight as a percentage of fetal weight also tended to be increased (approximately 10%; P = 0.08) in NR IUGR fetuses compared with control fetuses. Nutrient-restricted IUGR cows exhibited reduced (P < 0.01) cotyledonary weights compared with NR non-IUGR and control cows, which were similar (192 +/- 27 vs. 309 +/- 22, and 337 +/- 17 g, respectively). Total placentome surface area also tended to be reduced (P = 0.07) in NR IUGR cows compared with NR non-IUGR and control cows, which again were similar (685.0 +/- 45.6 vs. 828.7 +/- 37.2 and 790.7 +/- 28.9 mm(2), respectively). On d 245 of gestation, fetal weights and caruncle weight were similar for NR and control cows; cotyledonary weights, however, were reduced in NR vs. control cows (1,430 +/- 133 vs. 2,137 +/- 133 g, P < 0.01). Decreased fetal growth in NR IUGR cows on d 125 of gestation was associated with decreased cotyledonary weights and reduced placentomal surface areas. The return of NR cows to a BW and BCS similar to that of control cows through realimentation beginning on d 126 resulted in similar fetal weights of NR and control cows by d 245 of gestation. Thus, a bout of fetal IUGR may go undetected if cows undernourished during early gestation receive feed supplementation in the second half of gestation to assure normal birth weight.