The Crowded Uterine Horn Mouse Model for Examining Postnatal Metabolic Consequences of Intrauterine Growth Restriction vs. Macrosomia in Siblings.

Differential placental blood flow and nutrient transport can lead to both intrauterine growth restriction (IUGR) and macrosomia. Both conditions can lead to adult obesity and other conditions clustered as metabolic syndrome. We previously showed that pregnant hemi-ovariectomized mice have a crowded uterine horn, resulting in siblings whose birth weights differ by over 100% due to differential blood flow based on uterine position. We used this crowded uterus model to compare IUGR and macrosomic male mice and also identified IUGR males with rapid (IUGR-R) and low (IUGR-L) postweaning weight gain. At week 12 IUGR-R males were heavier than IUGR-L males and did not differ from macrosomic males. Rapid growth in IUGR-R males led to glucose intolerance compared to IUGR-L males and down-regulation of adipocyte signaling pathways for fat digestion and absorption and type II diabetes. Macrosomia led to increased fat mass and altered adipocyte size distribution compared to IUGR males, and down-regulation of signaling pathways for carbohydrate and fat digestion and absorption relative to IUGR-R. Clustering analysis of gonadal fat transcriptomes indicated more similarities than differences between IUGR-R and macrosomic males compared to IUGR-L males. Our findings suggest two pathways to adult metabolic disease: macrosomia and IUGR with rapid postweaning growth rate.

The estrogenic endocrine disrupting chemical bisphenol A (BPA) and obesity.

There is increasing experimental and epidemiological evidence that fetal programming of genetic systems is a contributing factor in the recent increase in adult obesity and other components of metabolic syndrome. In particular, there is evidence that epigenetic changes associated with the use of manmade chemicals may interact with other factors that influence fetal and postnatal growth in contributing to the current obesity epidemic. The focus of this review is on the developmental effects of estrogenic endocrine disrupting chemicals (EDCs), and more specifically on effects of exposure to the estrogenic EDC bisphenol A (BPA), on adipocytes and their function, and the ultimate impact on adult obesity; BPA exposure also results in impaired reproductive capacity. We discuss the interaction of EDCs with other factors that impact growth during fetal and neonatal life, such as placental blood flow and nutrient transport to fetuses, and how these influence fetal growth and abnormalities in homeostatic control systems required to maintain normal body weight throughout life.

A new 'crowded uterine horn' mouse model for examining the relationship between foetal growth and adult obesity.

Obesity is an increasing health problem, not only in developed countries but also all over the world. In addition to the focus on food intake and energy expenditure, current studies suggest two other important influences on adult body weight: birth weight and postnatal rate of growth. A common procedure in laboratory animal studies to examine the relationship of low birth weight and adult obesity is maternal nutrient restriction, but maternal undernutrition is not the basis for the majority of obese individuals in developed countries. We have thus developed a new mouse model for human obesity referred to as 'the crowded uterine horn model'. By removing one ovary from a female CD-1 mouse, the female produces a litter of about 13 pups in one uterine horn, resulting in crowding and a 4-fold difference in placental blood flow among foetuses in a litter. Restricted placental blood flow results in intrauterine growth restriction (IUGR); these animals show a 2-fold increase in body weight during the week after weaning, while macrosomial foetuses that go through a very small amount of growth during the same postnatal period. Male mice categorized as IUGR or macrosomic at birth both are obese in adulthood. This pattern of changes in body weight throughout life in male mice mirrors findings from epidemiological studies of human foetuses with IUGR and macrosomia who become obese, and thus may provide a new model that reflects the condition of people in developed countries who become obese.