The effect of maternal obesity on subsequent offspring: modulation by postnatal high fat diet feeding and physical exercise

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Copyright: Rajia, Sultana
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Abstract
Obesity, a worldwide epidemic, is deeply rooted in both hereditary and environmental aspects that may originate in perinatal period. Obesity is no longer restricted to adults, from late 1980s childhood obesity has reached epidemic in some areas and on the rise in others. Obesity poses or exacerbates the likelihood of a cluster of disorders including impaired glucose tolerance, type 2 diabetes, dyslipidemia, and hypertension, increasing the risk of a metabolic syndrome like phenotype. Environmental influences in utero (e.g. level of maternal nutrition) or during the early postnatal period influence offspring body weight and alter energy homeostasis in adulthood. Maternal nutrition is a key determinant in programming fetal and newborn metabolism and has long term consequences for the development of hypothalamic neurones involved in energy homeostasis and the metabolic profile in offspring. Disturbed energy homeostasis results in obesity arising from a mismatch between energy expenditure and energy consumed. Food intake is regulated via a complex process comprising peripheral and central mechanisms. The circulating hormones insulin and leptin cause a reduction in hypothalamic arcuate nucleus (ARC) mRNA expression of anabolic peptides (e.g. neuropeptide Y (NPY)) and agouti related protein (AgRP) while anorexigenic pro-opiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART) are stimulated to inhibit food intake. Investigating the impact of maternal obesity in human population is difficult. Since physiological pathways including appetite regulation are highly conserved across mammalian species, thus information gained in the rodent should have relevance to humans. Studies in rodent can answer whether the degrees of maternal obesity differentially influences offspring outcome. This thesis contrasted effects of two degrees of maternal overnutrition, one induced by early postnatal overnutrition following litter size reduction, defined as mild maternal overnutrition, and another by high fat diet (HFD) consumption, to induce marked maternal obesity. Another goal was to examine the impact of offspring postweaning HFD consumption. HFD induced maternal obesity increased body weight in offspring as early as 4 days old. However, mild maternal overnutrition had modest effects on body weight. At weaning, various mediators involved in appetite regulation (signal transducer and activator of transcription-3 (STAT-3); suppressor of cytokine signalling-3 (SOCS-3) and anorexigenic POMC), and markers of fatty acid oxidation in liver were differentially altered by HFD induced maternal obesity. In adulthood, significant glucose intolerance was induced by both degrees of maternal overnutrition in HFD fed male offspring, but this difference was absent in the females. HFD induced maternal obesity increased leptin, insulin, and lipid profile, leading to insulin resistance in male offspring, which was exaggerated by postweaning HFD. A similar pattern was observed in the female offspring. Both degrees of maternal overnutrition differentially affected the expression of hypothalamic appetite regulators in the male offspring. Given the rise in maternal obesity and effects on offspring, there is an urgent need to develop interventions. Thus, the second project set out to investigate whether physical exercise can ameliorate the effects of HFD induced maternal obesity with offspring fed either low fat chow or HFD. Maternal obesity increased BW, adiposity and induced glucose intolerance; effects exaggerated by postweaning HFD, with a doubling of energy intake and increased insulin resistance. Exercise reduced adiposity, improved glucose homeostasis following maternal obesity regardless of postweaning diet. mRNA expression of hypothalamic POMC, adipose tumor necrosis factor-α (TNF-α) and 11β hydroxysteroid dehydrogenase type-1 (11βHSD-1), the enzyme that converts inactive cortisone to cortisol, were reduced by exercise in HFD fed offspring of obese mothers. As a result of exercise, values in chow fed offspring of HFD mothers were indistinguishable from healthy control sedentary chow fed offspring from chow mothers; however, after exercise these metabolic parameters in HFD fed offspring remained higher than the sedentary chow fed offspring from both lean and obese mothers. Taken together the findings in this thesis indicate that even mild overnutrition of the mother early in life, as induced by litter size reduction, led to affect on offspring adiposity, food intake and glucose homeostasis. A far greater impact of HFD induced marked maternal obesity was observed on offspring, who were at the highest risk of metabolic disorders. Thus, the different degrees of maternal overnutrition differentially affected offspring adiposity and appetite regulators. Given the rising incidence of obesity in women of childbearing age, maternal nutrition and body weight prior to pregnancy has important implications for the health of the next generation. The second project showed that while voluntary exercise almost completely reversed the metabolic effects of maternal obesity in chow fed offspring, it did not fully attenuate the effects in those offspring weaned onto HFD. We suggest that a combined exercise and healthy diet approach is needed to facilitate metabolic improvements in the offspring of obese mothers.
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Author(s)
Rajia, Sultana
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Morris, Margaret J.
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Publication Year
2012
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Thesis
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PhD Doctorate
UNSW Faculty
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