Improving metabolic health via dietary and pharmacologic modulation of stress response pathways

Abstract

At the start of the 20th century, communicable diseases accounted for the majority of deaths in the United States. Advances in public health over the course of the century greatly reduced the impact of these diseases and increased lifespan. Now in the 21st century we are faced with a new epidemic of non-communicable disease including obesity and associated diseases such as diabetes and cardiovascular diseases which are currently among the leading causes of death in the United States. These diseases require new interventions if the public health successes of the 20th century are to be repeated. Calorie restriction has been shown to be extremely effective for the treatment and prevention of obesity and related diseases, but difficulties with adherence to caloric restriction make it an impractical strategy for many people. As such, the development of novel dietary and pharmacologic strategies to combat obesity and related diseases is of utmost importance. In the first two chapters of this dissertation I investigate the effects of dietary amino acid amount and source on metabolic health and take a deeper look at potential mechanisms using multiple omics methods. First, I show that there is surprisingly little difference in the amino acid composition of plant-based versus omnivorous dietary patterns based on dietary records of Americans. I also show that the amount of dietary protein has a much larger effect on metabolic health parameters than the source of dietary protein using mouse models. Second, I use multiple omics methods to investigate potential mechanisms of beneficial metabolic health effects on low protein diets. I found that changes in the fecal microbiome likely do not play a causal role in health benefits, but that rewiring of hepatic metabolism to support selective non-essential amino acid synthesis may play a role in the euglycemic effects of dietary protein restriction. In the second two chapters of this dissertation I profile the metabolic effects of a novel pharmacologic MetAP2 inhibitor which we considered a potential protein restriction-mimetic. This compound rapidly reversed diet-induced obesity in a mouse model and also reversed associated pathologies including insulin resistance and fatty liver. I then further investigated the physiologic and molecular mechanisms underlying these effects. I found that, although the overall metabolic improvements mirror dietary protein restriction, the mechanisms are distinct with the MetAP2 inhibitor causing metabolic improvement secondary to reduced food intake which required activation of P53 signaling. Collectively these studies demonstrate novel mechanisms of metabolic health improvement that can be achieved by dietary and pharmacologic interventions.