The Role of Maternal High Fat Diet in the Pathogenesis of Metabolic and Bone Disease in the Adult Offspring

Chronic diseases such as osteoporosis, type 2 diabetes, and cardiovascular disease are diseases of long duration, slow progression, and are by far the leading cause of death worldwide. A growing body of evidence links adverse exposures in early development with an increased risk of chronic diseases in adult life. The studies presented in this dissertation sought to exploit this phenomenon to determine the extent to which gestational and lactational exposure to a high fat diet predisposes the offspring to certain diseases in later life and if the eating habits of adult offspring would be able to mitigate or exacerbate these conditions.  In the study presented in Chapter III, dams fed an atherogenic high fat diet prior to conception and throughout gestation and lactation experienced excess hepatic lipid accumulation and poor birth outcome as characterized by smaller litter sizes and higher post-delivery mortality. In the offspring, gestational and lactational exposure to such a diet resulted in growth restriction and skeletal aberrations indicative of osteoporosis, despite being fed a standard rodent diet post-weaning. We propose that dietary-induced hyperlipidemia, along with pregnancy-associated factors, resulted in fatty liver and subsequently reduced litter sizes and increased early mortality, and that the skeletal aberrations seen in the mature offspring represent dietary-induced inhibition of osteogenesis in favor of adipogenesis. In the study presented in Chapter IV, early exposure to a high fat diet resulted in central obesity, elevated lipid levels, hyperglycemia, and additional markers used in the diagnosis of the metabolic syndrome. Altering the diets of the mature offspring demonstrated that the eating habits of adulthood have the potential to mitigate or exacerbate certain metabolic parameters established earlier in life. Mechanisms contributing to the observed metabolic aberrations could include developmental plasticity and mismatch, catch-up growth, and altered programming of the appetite regulatory network. Collectively, this research suggests that early exposure to a fat-rich diet can lead to metabolic and skeletal aberrations in the adult offspring and adds support to the developmental origins of health and disease hypothesis by finding that adverse nutritional exposures in early life can play a role in the chronic diseases of adulthood.