Abstract:
Background: The incidence of obesity and related metabolic disorders has become a major global health issue. A growing body of evidence suggests that early life nutritional adversity plays an important role in the development of long-term metabolic disorders. However, to date, the mechanisms underpinning the phenomenon is poorly understood. In addition, there is a growing interest in the field to explore potential intervention strategies to reverse the detrimental effects associated with a poor early life environment. Aim: The primary aim of the work detailed in this thesis was to identify potential mechanisms in established rodent models of developmental programming of obesity and metabolic dysfunction and evaluate the effectiveness of targeted pharmacologic and nutrition intervention strategies. Methods: The work described in this thesis investigated three animal models of altered maternal nutrition with corresponding interventions: 1) a maternal high fructose diet with taurine supplementation, whereby pregnant dams exposed to either chow or high fructose intake during pregnancy and lactation were supplemented either with or without taurine, 2) a maternal high fat:high fructose diet with taurine supplementation, whereby dams exposed to either chow or high fat:high fructose diet during pregnancy and lactation, and supplemented with or without taurine, and 3) maternal global caloric restriction with pre-weaning growth hormone (GH) treatment, in which dams were exposed to 50% caloric intake compared to control dams during pregnancy and offspring received GH treatment (2.5μg/g/day) daily during the pre-weaning period. The rational for taurine was based on limited evidence that taurine can ameliorate fructose and high fat diet induced insulin resistance in the non-pregnant state and has been shown to have protective effects on pancreatic development in rodent models of reduced maternal protein intake. However, taurine had yet to be examined as an intervention agent in the setting of a maternal obesogenic environment. GH was chosen due to known changes in the GH-insulin like growth factor axis in offspring born following a suboptimal early life nutritional environment but, as with taurine, had not been investigated in the setting of poor early life nutrition. The window of GH treatment was based on a key period of developmental plasticity where our group had shown previous efficacy of other interventions during this period such as leptin. In all studies body weight and food intakes were recorded regularly in both mothers and offspring. Blood samples and tissue of interest for each independent experiment were collected at the different key developmental time points. Importantly, both male and female offspring were examined to determine possible sexual-dimorphism in the offspring responsiveness to both the altered maternal dietary environment and the intervention. Results: Excessive fructose intake during pregnancy and lactation induced impaired maternal insulin sensitivity, hepatic steatosis and low-grade inflammation, increased offspring susceptibility to impaired glucose metabolism and induced early onset of puberty in female offspring. Taurine supplementation reversed most of the metabolic dysfunction in mothers arising from a high fructose intake and showed beneficial effects on offspring health outcomes in a sex-specific manner. A maternal high fat:high fructose diet led to profound maternal metabolic dysfunction and induced a number of adverse programming effects in offspring including an enhanced neonatal hepatic pro-inflammatory profile, impaired glucose metabolism and obesity in adulthood, altered food preference and early onset puberty. Taurine supplementation result in a number of protective effects in offspring in a sex-specific manner. Interestingly, despite showing some systemic beneficial effects taurine supplementation further impaired maternal hepatic lipid metabolism and inflammatory profile, which suggests a possible maternal trade-off to protect the offspring. Maternal global undernutrition resulted in a typical metabolic syndrome phenotype in offspring with increased adiposity, low-grade inflammation, impaired insulin sensitivity, increased blood pressure and endothelial dysfunction. Manipulating GH-IGF axis in the preweaning period normalised offspring postnatal growth and adiposity, and protected adult male offspring against cardio-metabolic dysfunction. Conclusions: Our findings further support the DOHaD hypothesis with evidence of adverse maternal and offspring health outcomes across a range of altered maternal nutritional environments. Both taurine and GH treatment during critical developmental windows showed great effectiveness in reducing long term adverse developmental programming effects in each respective cohort. Given that the directionality of effects was dependent upon prior maternal nutritional status and that sexually dimorphic responses to both altered maternal diet and intervention were observed, therapeutic approaches may need to be targeted to maximise potential efficacy. Our studies from a DOHaD perspective suggest promising strategies in combating the current global obesity and metabolic syndrome epidemic.