Leveraging adaptive hepatic glucose fasting responses against cardiometabolic disease

Brian DeBosch, M.D., Ph.D.

Project Summary 

One in every four deaths in the United States is due to cardiovascular disease. The long-term goal of our laboratory is to define new therapies against cardiac disease and its underlying causes, such as diabetes, obesity, and non-alcoholic fatty liver disease. We intend to achieve this by studying the detailed pathways that hurt or protect the heart, then design drugs that modulate these pathways to extend healthspan and lifespan.

Recent data indicate that intermittent fasting and caloric restriction can prevent the abnormal heart remodeling and dysfunction that occurs after cardiac insults, such as ischemia (“i.e., heart attack”) or pressure overload (“i.e., high blood pressure”). Because sustaining a calorie-restricted or intermittent fasting diet is often difficult in real-world clinical settings, we seek to identify drugs that mimic the body’s fasting responses. We discovered a naturally-occurring sugar, trehalose, which prevents other sugars from accessing the liver, ultimately mimicking the liver’s natural glucose fasting-response. Astonishingly, we found that treating mice with trehalose prevented them from developing heart failure in response to pressure overload, just as if they had been subjected to fasting. Based on these observations, the objective of this project is to answer two critical questions:

  1. How does the liver communicate the glucose fasting response to the heart to protect it from heart failure during pressure overload?
  2. Are there other heart disease contexts in which the liver’s fasting response can protect from heart failure and abnormal heart growth, such as ischemic (“heart attack”) or chronic stress-hormone exposure?