A Gut-Centric Model of Metabolic Homeostasis

Modern changes in diet and lifestyle have led to an explosion of insulin resistance and metabolic diseases around the globe which, if left unchecked, will become a principal driver of morbidity and mortality in the 21st century. The nature of the metabolic homeostatic shift within the body has therefore become a topic of considerable interest. While the gut has long been recognized as an acute nutrient sensor with signaling mechanisms to the other metabolic organs of the body, its role in regulating the body’s metabolic status over longer periods of time has been underappreciated. Recent insights from bariatric surgery and intestinal nutrient stimulation experiments provide a window into the adaptive role of the intestinal mucosa in a foregut/hindgut metabolic balance model that helps to define metabolic parameters within the body—informing the metabolic regulation of insulin resistance versus sensitivity, hunger versus satiety, energy utilization versus energy storage, and protection from hypoglycemia versus protection from hyperglycemia. This intestinal metabolic balance model provides an intellectual framework with which to understand the distinct roles of proximal and distal intestinal segments in metabolic regulation. The model may also aid in the development of novel disease-modifying therapies that can correct the dysregulated metabolic signals from the intestine and stem the tide of metabolic diseases in society.