Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
The origins of susceptibility for cardiometabolic diseases in adult could be traced back to early life, a theory referred to as developmental origins of adult health and disease. It is now recognized that maternal diet impacts significantly the susceptibility to metabolic syndrome in adult offspring; however, how the maternal nutritional insults alter organogenesis and physiological adaptations resulting in the manifestation of cardiometabolic diseases and organ-specific programming in adulthood are largely unknown. Employing a rodent model of developmental programming of metabolic syndrome in response to maternal high fructose diet (HFD), this synopsis summarizes our recent work in the identification of mitochondrial dysfunction and tissue oxidative stress at the brain in the programming of metabolic syndrome in adult offspring. Maternal exposure to HFD (60%) during gestation and lactation induces metabolic traits of hyperinsulinemia, hypertriglyceridemia, insulin resistance, and the increase in blood pressure in young offspring at the age of 12 weeks old. This maternal HFD-programmed cardiometabolic disorder is associated with an increase in the reactive oxygen species production, a reduction in nitric oxide (NO) generation, as well as the decreases in mitochondrial DNA (mtDNA) copy number and the expressions of peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α), the nuclear DNA-encoded transcription factors for mitochondrial biogenesis, in the brain stem. Our next-generation RNA sequencing (NGS) findings further indicate that maternal HFD induces long-term transcriptional changes in the brain stem of adult offspring, promoting neural programming. Oral treatment with resveratrol or metformin to the HFD-fed mother significantly preserves mitochondrial biogenesis and bioenergetics. The same treatments also attenuate the enhanced redox-sensitive signaling, leading to protection against tissue oxidative stress, preservation of NO signaling in the brain, and delay in the programming of metabolic syndrome and the development of programmed hypertension in adult offspring. Together, our data suggest pivotal roles of brain mitochondrial dysfunction and tissue oxidative stress in the programming of adult cardiometabolic disorder, and that these signals could be targets for the development of therapeutic interventions to de-program adult metabolic syndrome of developmental origin.
