2010 Grant Award - Thomas A. White, Ph.D.

The Role of Small Molecule CD38 Inhibitors on the Development of Obesity and Obesity-related Metabolic Disturbances

Thomas A. White, Ph.D.
Department of Anesthesiology, Mayo Clinic

Obesity is one of the most serious health problems facing society today. Elucidating the signaling mechanisms by which high caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Investigators have previously described a novel and unique role for the enzyme CD38 as a necessary component of the biochemical pathway that leads to the development of obesity and some of its deleterious metabolic effects. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers, and has been implicated in the regulation of a wide variety of signaling pathways in numerous cell types. CD38 is also a NADase and we have previously demonstrated that CD38 plays a key role in the regulation of intracellular NAD levels and subsequently regulates NAD-dependent deacetylases such as sirtuins (also known as SIRT enzymes). SIRT enzymes have been implicated as regulators of energy metabolism and longevity. Recent studies have shown that activation of SIRT can protect laboratory animals from high fat diet-induced obesity and its deleterious effects. We propose that by decreasing intracellular levels of NAD, CD38 promotes inactivation of the SIRT enzymes. Decreased SIRT activity leads to inhibition of the peroxisome proliferator-activated receptor γ co-activator 1 (PGC1α) that is involved in the development of obesity. CD38 appears to be a nearly obligatory component of the cellular cascade that leads to high fat (caloric) diet (HFD)-induced obesity in mice. In fact, CD38-deficient mice are protected against HFD-induced obesity. We have recently identified small molecule CD38 inhibitors by a high throughput screening (HTS) assay. We hypothesize that small molecule CD38 inhibitors, such as apigenin, will prevent the development of obesity and its deleterious metabolic effects. Successful completion of these proposed studies will lead to a better understanding of obesity and may lead to new therapeutic approaches for this condition.