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Abstract:

Gravidas with obesity and diabetes may transmit this syndrome to their children through genetic and non-genetic mechanisms. The aim of this thesis was to examine the effect of an obese and/or GDM intrauterine or early-life environment on the development of adipose tissue and on glucose and insulin metabolism in postnatal life, using existing and newly developed rodent models for obesity and/or GDM. In the first study, we bred and examined Leprdb/+ mice to investigate in a comprehensive manner the relative magnitude conferred by the db/+ early-life environment vs. the db/+ genotype, on adipose tissue development and glucose metabolism until or at a postpubertal age (8 weeks). +/+ Mice exposed to an early-life db/+ environment exhibited accelerated weight gain and adipose tissue accumulation, compared to mice exposed to an early-life +/+ environment. In addition, the former mice showed relative adipocyte hypertrophy, and their adipose tissue leptin and apelin gene expression was upregulated. But the effects conferred by the db/+ genotype on adipose tissue characteristics and glucose metabolism (in particular, on insulin sensitivity) were definitely more prominent than those conferred by the early-life db/+ environment. In addition, the influence of early-life db/+ environment on adipose tissue characteristics was not amplified in mice fed a high-fat diet during postnatal life, as indeed it was in db/+ offspring. We concluded that there was a discernible effect of the early-life db/+ environment on adipose tissue phenotype, but that it was notably smaller than the impact of the db/+ genotype or a high-fat diet. In the second study, we examined adipose tissue characteristics and glucose tolerance in a longitudinal manner in the offspring of dietary-obese rats which had received a highly palatable carbohydrate-rich diet from early adulthood until day 2 postpartum; such a diet was previously shown to induce glucose intolerance in late gestation. Their neonatal offspring (2-5 weeks old) displayed overweight, increased adiposity, adipocyte hypertrophy and upregulated TNF-α gene expression in sc adipose tissue. In addition, there was a slight impairment in glucose tolerance. But these effects were no longer discernible at a postpubertal (8 weeks) or adult (14 weeks) age; at these ages, sex-specific differences prevailed. We concluded that an exogenous obesity intra-uterine environment engendered early hyperadiposity, but that this effect waned with age. In the third study, we infused recombinant mouse TNF-α or saline into gravid C57BL6/J mice (sc, from d11.5 to d18.5), to examine the effect of TNF-α on maternal glucose tolerance and adipose tissue and lipid metabolism, as well as its effect on growth and adipose tissue accumulation in the offspring. We documented a dose-specific response on maternal glucose tolerance, with 2µg but not 4µg TNF-α resulting in a higher peak glucose value on d18.5; in addition, the 2µg dose led to an increase in fetal weight. However, TNF-α (2µg dose) had no effect on maternal adipose tissue and lipid parameters. Female but not male offspring of TNF-α-infused mothers (2µg dose) demonstrated accelerated weight gain, hyperadiposity, a consistent increase in adipose tissue leptin gene expression, and higher fasting glucose levels. We concluded that TNF-α resulted in a mild GDM-like syndrome with fetal overweight, and postnatal overweight and hyperadiposity in a sex-specific manner. The data suggest that TNF-α is a mediator of intra-uterine programming in GDM pregnancies. Although the effect of the genetic constitution (including sex) and the postnatal environment are likely more prominent for the pathogenesis of obesity than the intrauterine or early-life environment, our experimental studies have further established the existence of perinatal programming of hyperadiposity beyond reasonable doubt. Our data have implications for women and their children, in whom weight control and – if applicable – tight glycemic control are of prime importance.