Obesity is associated with buildup of fat within the cells of the liver, heart, and skeletal muscle. Intracellular fat accumulation leads to impairment in the ability of these cells to absorb glucose from the blood in response to insulin, called insulin resistance. However, the linkage between intracellular fat accumulation and insulin resistance is poorly understood. This invention has defined the upstream connection between fat accumulation in muscle cells and insulin resistance defining  a new candidate target strategy for the treatment of obesity-related metabolic disorders. 

Obesity is driving a dramatic increase in insulin resistance (type 2 diabetes), fatty liver disease, and cardiovascular disease. Obese individuals have intracellular lipid (fat) accumulation within the liver, heart, and skeletal muscle; organs which normally are responsible for absorbing glucose from the blood in response to insulin. Intracellular lipid accumulation in these tissues impairs the response to insulin, leading to insulin resistance and type 2 diabetes. The elusive connection between intracellular lipid accumulation and insulin resistance has been poorly understood, and thus, there are currently no therapeutics that target both the tissue toxicity downstream of lipid buildup and insulin resistance. This invention has identified a potential therapy.

Dr. Kelly and his colleagues developed a small molecule therapeutic that inhibits intracellular lipid accumulation in the liver and skeletal muscle while also reducing insulin resistance. This effect occurs by inhibiting the transcription factor MondoA.

Inhibition of MondoA has the potential reduce both the end-organ lipid toxicity and insulin resistance driven by obesity and type 2 diabetes. It could prevent intracellular lipid accumulation and enhance insulin signaling.

• Treatment of obesity-related dysfunction in the absence of diet/exercise
• Increases insulin sensitivity

• Treatment of obesity-related metabolic disorders
• Treatment for insulin resistance (type 2 diabetes)