Maternal Bitter Melon Supplementation Reduces the Risk for Metabolic Defects Later in Life: Effects on Lipid Handling, Oxidative Stress and Inflammation in Offspring Born to Dams Fed a High Fructose Diet

This dissertation, "Maternal Bitter Melon Supplementation Reduces the Risk for Metabolic Defects Later in Life: Effects on Lipid Handling, Oxidative Stress and Inflammation in Offspring Born to Dams Fed a High Fructose Diet" by Hiu-ha, Ching, 程曉霞, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: The relationship between fructose consumption and metabolic diseases has drawn substantial attention in recent years. Dietary fructose consumption has climbed dramatically in the past 40 years, and this trend coincides with the prevalence of obesity and diabetes worldwide. In rodents, maternal obesogenic diets are associated with higher risks of metabolic derangement later in life whereas bitter melon (BM) supplementation has been shown to improve blood glucose and lipid profiles. The overall objective of this thesis was to test the hypothesis that through developmental programming metabolic derangement in offspring born to rat dams fed a high-fructose (F) diet could be offset by the addition of BM to the maternal diet. Virgin female rats received a control (C), F (60%) or BM-supplemented F (FBM,1%) diet 8 weeks before conception and throughout gestation and lactation. Weaned male offspring consumed C diet (C/C, F/C, FBM/C) for 11 weeks. The concentrations of serum insulin, triglyceride, free fatty acid (FFA), and hepatic lipids in FBM/C offspring matched that in C/C offspring and were significantly lower than F/C offspring. These phenotypic changes were accompanied with suppressed hepatic lipogenic gene expression but enhanced expression of lipid oxidation-related genes. In the second experiment, we extended the earlier findings by examining whether adding BM to F-fed dams would still benefit offspring if they continued to consume the F diet postweaning. This simulates the scenario in affluent societies where fructose overconsumption may occur in two consecutive generations. The dose-response effect of BM at doses of 0.85% (FBM1) and 1% (FBM2) was also examined. Male offspring born to dams fed the C, F, FBM1 or FBM2 diet were weaned to C or F diet (C/C, C/F, F/F, FBM1/F, FBM2/F) for 20 weeks. BM normalized the serum FFA elevation observed in F/F offspring, although hyperinsulinemia remained in FBM1/F and FBM2/F offspring. The altered liver lipid profile and its molecular changes observed in F/F offspring were ameliorated by maternal BM supplementation. Lower adipose expression of mesoderm-specific transcript, hormone sensitive lipase, sterol regulatory element-binding transcription factor 1, and peroxisome proliferator-activated receptor-gamma (PPARγ) and PPARγ-target genes in FBM1/F and FBM2/F offspring indicated that BM could reduce adipocyte size as well as lower lipolysis and lipogenesis. Since FFA stimulates reactive oxygen species generation that enhances cellular stress, oxidative stress and inflammation in offspring of two-generation F exposure with or without maternal BM supplementation were examined. FBM1/F and FBM2/F offspring showed reduced lipid peroxidation but enhanced antioxidant capacity in the liver. BM suppressed the expression of proinflammatory genes and phosphorylation of c-Jun amino terminal kinase1, as well as promoted insulin receptor substrate 1 protein expression. These BM-mediated antioxidant and anti-inflammatory effec