Lysosomal Metabolomics: A Novel Approach to mTOR Activation and Metabolic Diseases
Abstract
The obesity epidemic is by far the most prevalent cause of metabolic disease worldwide and is a major burden on the Department of Defense Military Health System (MHS) in particular. Given that 70% of MHS beneficiaries and 72% of Veterans are overweight or obese, it is not surprising that the MHS now spends billions of dollars each year on expenses related to obesity and its medical consequences, including type 2 diabetes, fatty liver disease, high blood pressure, and cardiovascular disease resulting from excess cholesterol and lipids in the bloodstream. Recent research has revealed that many of these detrimental effects, known collectively as metabolic syndrome, are caused by excess activation of a protein complex called mTORC1 in various body tissues under conditions of chronic overfeeding. Within each cell, the mTORC1 complex is activated in response to the presence of nutrients, including glucose and amino acids, through a mechanism known to involve the lysosome, a specialized compartment responsible for recycling and storage of cellular materials. However, it is not known which nutrient or nutrient-derived molecules actually trigger mTORC1 activation, what proteins are involved in directly "sensing" nutrient presence inside the lysosome, or how these processes may become deregulated in metabolic disease. Obtaining this information is a critical step toward developing new ways to block mTORC1 overactivation as a strategy to treat metabolic syndrome. In our proposed research, we will develop a new method to identify and measure the nutrients and other small molecules found inside the lysosome. Using this method, we will determine how the levels of those molecules change when mTORC1 is activated in both cultured cells and animal tissues -- currently unavailable information that is crucial to a full understanding of nutrient sensing. We will also identify proteins that are directly involved in nutrient sensing and that, when inhibited in experimental animals, can block the metabolic consequences of mTORC1 overactivation in response to a "Western" (high-fat and high-cholesterol) diet. These studies will introduce a novel paradigm in nutrient sensing research, as well as a potential new approach to the treatment of metabolic syndrome in humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510337
Entities
People
- Elizaveta Freinkman
Organizations
- United States Army
- Whitehead Institute