Abstract

Metabolic syndrome encompasses a cluster of interrelated risk factors, including glucose intolerance, obesity, dyslipidemia, and hypertension, that significantly elevate the likelihood of developing diabetes. Approximately 25% of the US population is affected by this multifaceted syndrome, imposing a substantial healthcare burden. Consequently, there is a pressing need to explore innovative therapeutic avenues for mitigating metabolic syndrome and its downstream consequence, diabetes.
One intriguing avenue of inquiry has emerged from high-altitude studies, where individuals residing at elevated altitudes exhibit a lower prevalence of obesity, diabetes, hypertension, and hypercholesterolemia. Although epidemiological studies at high altitudes may be influenced by confounding variables, these trends have been largely replicated in rigorously controlled experiments using rodents and humans. For instance, preliminary data from experiments with wild-type mice exposed to varying degrees and durations of hypoxia have corroborated key findings such as reduced fasting plasma glucose, diminished food intake, decreased body weight, and lower circulating cholesterol and triglycerides.
However, the underlying molecular mechanisms responsible for these adaptations remain enigmatic. This research proposal aims to unravel the intricate mechanisms by which hypoxia adaptation confers protection against metabolic syndrome. Our central hypothesis posits that hypoxia orchestrates systemic changes in glucose, fatty acid, and redox metabolism that favorably impact metabolic syndrome. The elucidation of these mechanisms may have profound implications for patient care by revealing potential molecular targets that could pave the way for more practical therapeutic strategies targeting diabetes and metabolic syndrome.