Our project aligns with Fiscal Year 2014 Peer Reviewed Medical Research Program Topic Areas metabolic disease (including obesity, obesity-associated metabolic disease, and type 2 diabetes) and osteoarthritis.

Obesity rates among Veterans and military beneficiaries exceeds 30%, putting these groups at unacceptable risks for serious chronic disease including obesity-associated metabolic disease, type 2 diabetes, and osteoarthritis. This is one of the most urgent health issues faced by the Department of Defense (DoD) healthcare system, since treating these and other obesity-linked chronic diseases accounts for a major part of the Department of Veterans Affairs budget. Efforts to prevent and reduce obesity through diet, exercise, surgery, and/or appetite suppression have largely failed.

We propose a radical rethinking of the obesity problem, where we move away from failed efforts to eat less and exercise more in the hope that body fat and excess weight will decrease. Instead, we propose to establish a new paradigm whereby novel drugs are used to stimulate the metabolism of fat cells, causing them to exhaust their food stores and shrink the body's excess fat. These fewer and smaller fat cells will then produce metabolism-related hormones at levels found in normal-weight individuals, thus helping to lower the body weight set point, increase resting energy levels, and sustain weight loss.

Our project will discover inhibitors to a novel high-value target responsible for fat tissue growth and associated weight gain, thus launching the above paradigm shift in treatments for obesity and obesity-related diseases. Our expert team is developing drugs that exploit recent observations that interfering with the enzyme nicotinamide N-methyltransferase (NNMT) can shrink white fat tissue and produce weight loss in animals, without any change in diet or exercise. We have applied our advanced computational, medicinal chemistry, and metabolism expertise to identify molecules that are predicted to inhibit NNMT. In this project, we will complete a series of biochemical and animal studies to determine which of our molecules are best able to inhibit NNMT and shrink white fat tissue, without causing harm to test animals.

The novel NNMT inhibitors identified in our innovative proof-of-concept project will ultimately be developed into radically new mechanism-of-action weight loss drugs that produce previously unimagined reductions in obesity and obesity-linked diseases, thus improving the health of Veterans and their dependencies while significantly reducing DoD healthcare expenditures.