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

Benjamin L Coe,Julia A Taylor,Toshi Shioda,Frederick S Vom Saal

doi:10.3390/metabo12020102

Abstract

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.

Highlights

In the United States and many developed countries, the incidence of obesity and related diseases, collectively referred to as metabolic syndrome, are increasing at a rapid rate [1]
The total number of animals at birth consisted of 297 females and 308 males; the distribution of all male offspring body weights from birth until 12 weeks old is presented in Figure 2A; body weight at birth data were normally distributed
At six months of age, intrauterine growth-restriction (IUGR)-R males showed impaired response to a glucose challenge compared to IUGR-low postweaning growth rate (IUGR-L) males and altered expression of many genes in abdominal adipose tissue was revealed by microarray analysis

Summary

Introduction

In the United States and many developed countries, the incidence of obesity and related diseases, collectively referred to as metabolic syndrome, are increasing at a rapid rate [1]. When there is reduced fetal growth and body weight at birth, but the subsequent postnatal growth rate is markedly higher than the median, this results in body weight centile crossing, and significant metabolic abnormalities occur. This sequence of events is a central feature of the developmental basis of health and disease (DOHaD) hypothesis for metabolic diseases [3]. Regardless of the basis for their obesity, the outcome is that most obese individuals are at increased risk for developing other disorders associated with metabolic syndrome Among these co-morbidities are increased blood pressure, cardiovascular disease, insulin insensitivity, glucose intolerance, diabetes, fatty liver disease, and elevated triglycerides and cholesterol [1,2,7]

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