Our genes haven’t changed that much in thousands of years, but we have seen a rapid change in the environment, and that has interacted with our genetic propensity toward obesity.
Dr. Smith’s research focuses on the control of metabolic substrate switching between fat and carbohydrate.
Dr. Smith received him MD from the University of Texas Health Science Center, San Antonio, ΑΩΑ in 1988.
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Influence of gender, obesity, and muscle lipase activity on intramyocellular lipids in sedentary individuals.
Moro C, Galgani JE, Luu L, Pasarica M, Mairal A, Bajpeyi S, Schmitz G, Langin D, Liebisch G, Smith SR
J Clin Endocrinol Metab. 2009 Sep;94(9):3440-7
Subtyping obesity with microarrays: implications for the diagnosis and treatment of obesity.
Wang S, Sparks LM, Xie H, Greenway FL, de Jonge L, Smith SR
Int J Obes (Lond). 2009 Apr;33(4):481-9
Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response.
Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR
Diabetes. 2009 Mar;58(3):718-25
Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study.
Smith SR, Blundell JE, Burns C, Ellero C, Schroeder BE, Kesty NC, Chen KS, Halseth AE, Lush CW, Weyer C
Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E620-7
Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle.
Ukropcova B, Sereda O, de Jonge L, Bogacka I, Nguyen T, Xie H, Bray GA, Smith SR
Diabetes. 2007 Mar;56(3):720-7
Unsupervised clustering of gene expression data points at hypoxia as possible trigger for metabolic syndrome.
Ptitsyn A, Hulver M, Cefalu W, York D, Smith SR
BMC Genomics. 2006;7:318
High-fat/low-carbohydrate diets regulate glucose metabolism via a long-term transcriptional loop.
Sparks LM, Xie H, Koza RA, Mynatt R, Bray GA, Smith SR
Metabolism. 2006 Nov;55(11):1457-63
Corticotropin-releasing hormone directly stimulates thermogenesis in skeletal muscle possibly through substrate cycling between de novo lipogenesis and lipid oxidation.
Solinas G, Summermatter S, Mainieri D, Gubler M, Montani JP, Seydoux J, Smith SR, Dulloo AG
Endocrinology. 2006 Jan;147(1):31-8
Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor.
Ukropcova B, McNeil M, Sereda O, de Jonge L, Xie H, Bray GA, Smith SR
J Clin Invest. 2005 Jul;115(7):1934-41
A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle.
Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR
Diabetes. 2005 Jul;54(7):1926-33
Steven Smith's Research Focus
Cardiovascular Diseases, Atherosclerosis, Heart Disease, Metabolic Diseases, Metabolic Syndrome, Obesity, Type 2 Diabetes
Watch Dr. Smith describe his research
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 towards 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.
About Steven Smith
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 MD from the University of Texas Health Science Center, San Antonio, ΑΩΑ 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.