Dr. Chung's primary research interest is in understanding how the energy and nutrient status affects cellular physiology and diseases associated with obesity and aging. Mitochondria, the main site of energy production, is an important link between the energy status and the diseases associated with obesity and aging. Using both cellular and animal models, Dr. Chung’s laboratory is seeking novel drugs to ameliorate the diseases associated with obesity and aging.
As an endocrinologist, Dr. Chung has been interested in the “obesity-aging” paradox: an average American gains approximately 30 lbs over 30 years in midlife, even though food intake decreases during this period. The weight gain, which occurs primarily in the abdominal/visceral depot, is an important driver of many chronic diseases of Western society: type 2 diabetes, cardiovascular diseases and even cancer and Alzheimer’s disease. One possible explanation for the paradox is that aging leads to loss of mitochondria, the organelle that burns fat and generates energy. In a recent Cell Metabolism paper, Dr. Chung’s group revealed the mechanism for the mitochondrial loss: increased activity of DNA-dependent protein kinase (DNA-PK) during aging suppresses the activity of AMP-activated protein kinase (AMPK), an important regulator of energy metabolism and mitochondrial function.
Dr. Chung’s group is also working to understand the key molecular mechanisms that underlie the beneficial effects of caloric restriction in order to develop therapeutic strategies that mimic these effects and protect against metabolic diseases. Resveratrol, perhaps best known as a component of red wine, has been shown to mimic certain beneficial aspects of caloric restriction, including mitochondrial biogenesis, autophagy and protection against obesity-related diseases such as type 2 diabetes. Dr. Chung and his colleagues are studying the signaling pathways activated by resveratrol to tease apart their modes of action and discover the pathways that contribute to the prevention of type 2 diabetes. Using various animal models, they have demonstrated that while resveratrol does not directly target SIRT1, as previously proposed, it can inhibit phosphodiesterases (PDEs), which results in increased levels of the signaling molecule cyclic AMP and activation of AMPK. They have been able to mimic the protective effects of resveratrol with a selective inhibitor of PDE4. This work was selected as a "best of 2012 Cell paper" by Cell.
Many common obesity and aging-related diseases are linked to mitochondrial production of oxygen radicals, which activate the inflammatory pathways. Indeed, signature hallmarks of obesity and aging are mitochondrial dysfunction and inflammation. Dr. Chung’s laboratory is employing an extensive range of in vitro and mouse models to understand the biochemical pathways that couple metabolic and mitochondrial dysfunction to vascular diseases, immune dysfunction (inflammation), type 2 diabetes, fatty liver and neurodegeneration.