MUSCLE FATTY ACID METABOLISM

MANIPULATING FATTY ACID METABOLISM TO PREVENT AND REVERSE DIABETES

Excessive fatty acid oxidation is a cornerstone in the development of insulin resistance, diabetes, and diabetic cardiomyopathy, yet the therapeutic potential of specifically targeting fatty acid oxidation to reverse insulin resistance and diabetes-related heart dysfunction remains unexplored. This problem is important because of the growing epidemic of diabetes and because the number one killer of diabetics is heart disease. Ellis Lab’s work is focused on determining the role of fatty acid oxidation in the development and the reversal of skeletal muscle and cardiac muscle insulin resistance. For these investigations, the lab is supported by NIH R01 funding to use several mouse models to determine how activating or inhibiting muscle fatty acid oxidation at specific points in this pathway can protect against or reverse high-fat diet-induced insulin resistance. The long-term goal of this work is to improve the lives and prevent health complications in the rapidly growing diabetic population. This work will provide mechanistic insight into the metabolic underpinnings of diabetes and will ultimately shape therapeutic strategies to reverse insulin resistance and prevent diabetes-related mortality.

DETERMINING THE ROLE OF FATTY ACID OXIDATION IN MUSCLE CELL HEALTH AND SURVIVAL

The heart and skeletal muscle have high bioenergetic demands relying primarily on fatty acid substrates. Fatty acid oxidation is so critical for these muscles that the loss of mitochondrial fatty acid oxidation causes severe heart dysfunction, rhabdomyolysis (death of skeletal muscle cells), and complete resistance to diet-induced obesity. Why muscles cannot meet their bioenergetic requirements through substrate flexibility remains unrealized. We are interested in determining the mechanistic underpinnings that regulate heart structure and function and that prevent obesity in the absence of fatty acid oxidation. Additionally, because inherited disorders of fatty acid oxidation are the most commonly inherited metabolic disorders we wish to identify alternative fuel substrates that improve muscle health in fatty acid oxidation-limited conditions. The Ellis lab is uniquely positioned to pursue these research questions due to novel mouse models and accessibility to methodology through collaborative efforts. The long-term goal of this work is to provide mechanistic understanding and preventative therapies that will inform and improve the health of patients suffering cardiac hypertrophy, obesity, and patients with inherited disorders of fatty acid oxidation.