Validation of Novel Small Molecule Inhibitor to Improve Outcomes in Obesity, Insulin Resistance and Osteoarthritis

Project title Validation of novel small molecule inhibitor to improve outcomes in obesity, insulin resistance and osteoarthritis Abstract Osteoarthritis and Type 2 Diabetes Mellitus are two prevalent and intertwined chronic diseases in the United States, with knee osteoarthritis affecting 14% of adults aged 25 years and older and 34% of those above the age of 65. Concurrence of osteoarthritis and type 2 diabetes is frequent and is a source of greater disability and economic burden. Osteoarthritis and type 2 diabetes share a common risk factor in obesity, yet the molecular basis for the high prevalence of osteoarthritis in those with type 2 diabetes is not entirely clear. A growing body of evidence further indicates that there may be shared molecular mechanisms underlying the pathogenesis of osteoarthritis and type 2 diabetes and that the two conditions likely exacerbate each other. Skeletal muscle provides mechanical support of the knee as well as ~80% of insulin-stimulated glucose disposal, underscoring its fundamental role in knee osteoarthritis and insulin resistance. Our published and pilot data in osteoarthritis underscores a pro-inflammatory and fibrotic knee extensor muscle phenotype, which is a shared pathology in muscle from patients with type 2 diabetes. The enzyme nicotinamide N- methyltransferase (NNMT) is increased by inflammatory signaling and its genetic knockdown improves insulin sensitivity in diet-induced obesity. We have previously identified NNMT as a therapeutic target to improve aged skeletal muscle function and recovery after injury. Additionally, our pilot data show NNMT inhibition rescues mitochondrial respiration deficits and reduces intramyocellular lipids in skeletal muscle, both of which are hallmarks of osteoarthritis and type 2 diabetes. We hypothesize that NNMT-driven metabolic dysfunction in skeletal muscle is a key molecular link between weakness, fibrosis, inflammation, insulin resistance and osteoarthritis. We have identified a novel mechanism that potently decreases systemic inflammation and muscle fibrogenesis and rescues aberrant lipid metabolism as well as osteoarthritis severity. We have developed a mouse knee-injury model that recapitulates human osteoarthritis pathophysiology, and we are well positioned to mechanistically validate our novel NNMT inhibitor to improve metabolic health and knee osteoarthritis outcomes in two specific aims. 1) We will define NNMT-derived adaptations in inflammation, quadriceps fibrosis and weakness and osteoarthritis severity. 2) We will determine NNMT-derived adaptations to body composition, quadriceps mitochondrial function and lipid metabolism. Our proposed experiments will provide fundamental information regarding potential molecular links between osteoarthritis and insulin resistance/type 2 diabetes and obesity. Our research team has the requisite expertise, and all rodent models and compounds in place. The proposed experiments are needed to collect compelling pilot data for successful extramural federal grant opportunities (R01-level), and we are responsive to the UK Center of Research in Obesity and Cardiovascular Disease (COCVD) call for pilots in the research area of the relationship between obesity and type 2 diabetes.