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.

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.

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.

The prevalence of maternal obesity is increasing rapidly in recent decades. We previously showed that maternal obesity affected skeletal muscle development during the fetal stage. The objective of this study was to evaluate the effects of maternal obesity on the skeletal muscle properties of offspring. Ewes were fed a control diet (100% energy requirement, Con) or an obesogenic diet (150% energy requirement, OB) from 2 mo before pregnancy to weaning. After weaning, the offspring lambs were fed a maintenance diet until 19 mo of age and then ad libitum for 12 wk to measure feed intake. At 22 mo old, the longissimus dorsi (LD) muscle was biopsied. The downstream insulin signaling was lower in OB than Con lambs as shown by reduction in the phosphorylation of protein kinase B, mammalian target of rapamycin, and 4-E binding protein 1. On the other hand, the phosphorylation of protein kinase C and insulin receptor substrate 1 was higher in OB compared to Con lambs. More intramuscular adipocytes were observed in OB compared to Con offspring muscle, and the expression of peroxisome proliferator-activated receptor gamma, an adipocyte marker, was also higher, which was consistent with the higher intramuscular triglyceride content. Both fatty acid transport protein 1 and cluster of differentiation 36 (also known as fatty acid translocase) were increased in the OB group. In addition, higher collagen content was also detected in OB compared to Con offspring. In conclusion, our data show that offspring from obese mothers had impaired insulin signaling in muscle compared with control lambs, which correlates with increased intramuscular triglycerides and higher expression of fatty acid transporters. These data clearly show that maternal obesity impairs the function of the skeletal muscle of offspring, supporting the fetal programming of adult metabolic diseases.

Angus x Hereford heifers (15 mo and artificially inseminated to a single sire) were used to evaluate the effect of prenatal nutritional restriction on postnatal growth and development. At d 32 of gestation, dams were stratified by BW and BCS and allotted to a low-nutrition [55% of NRC (1996) requirements, n = 10] or moderate-nutrition [100% of NRC (1996) requirements, n = 10] diet. After 83 d of feeding, dams were commingled and received a diet in excess of requirements. Dams were allowed to calve naturally, and birth weights and growth of calves were recorded. Bulls were castrated at birth. Steers (16 mo of age, 5 per treatment) received a high-concentrate diet ad libitum to a constant age (88 ± 1 wk). Steers were slaughtered and weights of the empty body and organs were recorded. Samples of organs, muscle (complexus), and perirenal and subcutaneous adipose tissue were stored at -80 degrees C, and then DNA and protein concentrations were quantified and expression of genes associated with fatty acid metabolism and glucose uptake were measured in adipose and muscle tissue. Dams had similar (P > 0.33) BW and BCS at the beginning of the experiment. At the end of restriction, dams on the low-nutrition diet weighed less (P ≤ 0.01) and had less BCS (P < 0.001) than those on the moderate-nutrition diet. Length of gestation was 274 ± 2 d for dams in the low-nutrition treatment and 278 ± 2 d (P = 0.05) for dams in the moderate-nutrition treatment. Nutrient restriction during gestation did not influence birth weight or postnatal growth of calves. Lungs and trachea of steers whose dams were fed the low-nutrition diet weighed less (P = 0.05) at slaughter than those of steers whose dams were fed the moderate-nutrition diet; weights of other organs were not influenced by treatment. Complexus muscle from steers whose dams were fed the low-nutrition diet had a greater (P = 0.04) concentration of DNA and larger muscle fiber area compared with steers whose dams were fed the moderate-nutrition diet. Abundance of mRNA for fatty acid binding protein 4, fatty acid translocase, and glucose transporter 4 was less in perirenal adipose tissue of steers whose dams were fed the low-nutrition diet compared with those whose dams were fed the moderate-nutrition diet. Nutritional restriction of dams during early gestation did not alter postnatal calf growth. However, concentrations of DNA in muscle tissue and muscle fiber area were greater in steers from dams exposed to restricted nutrient intake during early gestation.

Spring-calving Angus cows (n = 30) were used to evaluate changes in ruminal temperature (RuT) related to parturition and estrus. Cows were synchronized and artificially inseminated with semen from a single sire. Temperature boluses were placed in the rumen at 7.0 ± 0.2 mo of gestation. Boluses were programmed to transmit RuT every 15 min. Cows (BW = 623 ± 44 kg, BCS = 4.9 ± 0.4) calved during 3 wk, and estrus was synchronized at 77 ± 7 d after calving with PGF(2α). Cows were observed every 12 h to detect estrus. Daily average ambient temperatures ranged from 2 to 22 °C during parturition (February to March) and 17 to 25 °C during estrus (May to June). Ruminal temperature from 7 d before to 3 d after parturition and 2 d before to 2 d after visual detection of estrus was analyzed using the MIXED procedure. Ruminal temperatures <37.72 °C were attributed to water consumption and excluded from analyses. Day did not influence (P = 0.36) RuT from d -2 to -7 before parturition (38.94 ± 0.05 °C). Ruminal temperature decreased (P < 0.001) from d -2 to d -1 before parturition (38.88 ± 0.05 to 38.55 ± 0.05 °C, respectively). Ruminal temperature was not influenced (P = 0.23) by day from 1 d before to 3 d after parturition (38.49 ± 0.05 °C). Ruminal temperature at 0 to 8 h after detection of estrus (38.98 ± 0.09 °C) was greater (P < 0.001) compared with RuT at the same daily hour of the day before (38.37 ± 0.11 °C) or the day after estrus (38.30 ± 0.09 °C). Ambient temperature did not influence (P > 0.30) RuT at parturition or estrus. Ruminal temperature decreased the day before parturition and increased at estrus in spring-calving beef cows and has potential use as a predictor of parturition and estrus.