Abstract
Adipose tissue development begins in utero and is a key target of developmental programming. Here the influence of nutritionally-mediated prenatal growth-restriction on perirenal adipose tissue (PAT) gene expression and adipocyte phenotype in late fetal life was investigated in both sexes in an ovine model. Likewise circulating leptin concentrations and non-esterified fatty acid (NEFA) and glycerol responses to glucose challenge were determined in relation to offspring adiposity at key stages from birth to mid-adult life. In both studies' singleton-bearing adolescent sheep were fed control or high nutrient intakes to induce normal or growth-restricted pregnancies, respectively. Fetal growth-restriction at day 130 of gestation (32% lighter) was characterised by greater body-weight-specific PAT mass and higher PAT expression of peroxisome proliferator-activated receptor gamma (PPARɤ), glycerol-3-phosphate dehydrogenase, hormone sensitive lipase (HSL), insulin-like growth factor 1 receptor, and uncoupling protein 1. Independent of prenatal growth, females had a greater body-weight-specific PAT mass, more multilocular adipocytes, higher leptin and lower insulin-like growth factor 1 mRNA than males. Growth-restricted offspring of both sexes (42% lighter at birth) were characterised by higher plasma NEFA concentrations across the life-course (post-fasting and after glucose challenge at 7, 32, 60, 85 and 106 weeks of age) consistent with reduced adipose tissue insulin sensitivity. Circulating plasma leptin correlated with body fat percentage (females>males) and restricted compared with normal females had more body fat and increased abundance of PPARɤ, HSL, leptin and adiponectin mRNA in PAT at necropsy (109 weeks). Therefore, prenatal nutrient supply and sex both influence adipose tissue development with consequences for lipid metabolism and body composition persisting throughout the life-course.
Highlights
Appropriate prenatal adipose tissue development to facilitate non-shivering thermogenesis at birth is fundamental to the immediate survival of precocial mammals [1,2]
Irrespective of maternal nutrition or growth category, male fetuses were slightly heavier than females (P = 0.015), and by design growth-restricted fetuses of both sexes were lighter than the corresponding sex of normally-growing control and non-restricted fetuses (32 to 38% lower, P
Summary non-esterified fatty acid (NEFA) and glycerol concentrations in the fasted state and following glucose challenge at 7, 32, 60, 85 and 106 weeks of age in relation to prenatal growth status and sex are presented in Table 6, and the latter acted as a proxy measure of insulin-induced adipose tissue lipid metabolism
Summary
Establishment of pregnancy and nutritional managementAll procedures were licensed under the UK Animals (Scientific Procedures) Act of 1986 and approved by the Rowett Institute’s Ethical Review Committee. On Day 0 at 16:00h, donor ewes underwent insemination directly into the uterine cavity under direct laparoscopic visualisation, as previously described [31] In both studies this involved fresh semen, collected by artificial vagina from the same sire of proven fertility, and diluted 1:3 with phosphate-buffered saline. Multiple embryos were recovered from donor ewes at laparotomy using a standard surgical technique of retrograde flushing of each oviduct This was achieved by advancing a fine glass cannula into the fimbria, injecting ovum culture media (ICN Biomedicals, Ohio, USA) warmed to 37 ̊C into the lumen of the ipsilateral uterine horn ~ 5cm from the utero-tubal junction and milking the media out through the cannula into a sterile glass embryo dish. The embryo transferred into the tip of the uterine horn ipsilateral to the ovary with the greater number of corpora lutea
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