Steven Smith, M.D.
Steven Smith's Research Focus
Obesity and diabetes are epidemic in Western societies and account for at least 1/10th of health care expenditures nationwide. The reasons for this are complex; however, it is clear that there is wide variation in individual susceptibility to our obesogenic environment. Our fundamental hypothesis is that the regulation of metabolism in peripheral tissues, specifically skeletal muscle, determines susceptibility to our rich environment and ultimately the common chronic diseases diabetes and cardiovascular disease. In the clinic, we aim to understand the control of fatty acid metabolism but also test novel therapeutic interventions to reduce body weight and treat diabetes. Our more "basic" research focuses on the control of substrate switching between fat and carbohydrate with a particular emphasis on the regulation of fatty acid oxidation in skeletal muscle and the adipose tissue dysfunction that occurs in obesity.
Insulin resistance in skeletal muscle is a key feature of the pre-diabetic state and a precursor to type 2 diabetes and cardiovascular diseases. Our laboratory developed several techniques to study substrate switching in primary human muscle cells and we use these techniques to better understand how insulin resistance develops. We also use these tools to develop and test new strategies to activate fat oxidation as a means to improve insulin action and reduce body weight. Myoblasts grown in culture retain the metabolic characteristics of the donor. This provides us with a tool to explore the origins of the reduced capacity for fat oxidation; a key feature of patients with type 2 diabetes and their offspring. Current efforts are directed toward identifying epigenetic "marks" that may account for these intrinsic differences in the capacity for fat oxidation. Using these same tools, new data from the lab suggests that insulin resistance is due in part to dysregulation of the breakdown of lipid within the muscle; we coined the term intramyocellular lipotoxicity to describe the insulin resistance that occurs due to an imbalance in these lipases. These data suggest that intramyocellular DAGs lead to insulin resistance in humans, and the dysregulation of the key lipolytic enzymes ATGL and HSL lie upstream of insulin resistance in skeletal muscle. Lastly, we are aggressively pursuing the regulation of the NAD+ producing enzyme NAMPT in skeletal muscle which lies upstream of the SIRTs as a potential therapeutic pathway in diabetes.
The second area of interest is in adipose tissue dysfunction. Hypertrophic adipocytes fail to regulate lipid metabolism and attract macrophages and other inflammatory cells via secretion of chemokines. The origin of this inflammatory milieu has been the subject of much speculation. We recently identified adipose tissue hypoxia and reduced capillary density (rarefaction) in obese humans; these changes are associated with an increase in the number of inflammatory cells and the chemokine MCP-1 suggesting that hypoxia is driving chemotaxis in obesity. These results indicate that the origins of adipose tissue dysfunction may lie in a failure of the capillary bed to expand as new fat cells develop and hypertrophy. Importantly, this study reinforces an emerging concept that the vasculature is critical for the development of obesity and its metabolic complications such as diabetes and cardiovascular diseases.
Steven Smith's Bio
Steven Smith, M.D., has over 15 years of post-graduate academic leadership and scientific accomplishments in the areas of translational science in metabolism, obesity and type 2 diabetes. Steven joined Sanford-Burnham in August 2009 from the Pennington Biomedical Research Center in Louisiana where he was Professor and Assistant Executive Director of Clinical Research. Dr. Smith received him M.D. from the University of Texas Health Science Center, San Antonio, Texas in 1988, completed a residency in Internal Medicine from Baylor University Medical Center, Dallas and went on to complete a fellowship in Endocrinology and Metabolism at the Ochsner Clinic in New Orleans. From New Orleans, he moved to Pennington Biomedical Research Center in Baton Rouge where he developed a translational research program in a multi-disciplinary research environment.