The Molecular Endocrinology Lab, under the direction of Dr. Steven R. Smith, M.D. focuses on the regulation of energy and substrate metabolism in adipose tissue and skeletal muscle. Using a variety of experimental approaches, the lab studies the physiological, cellular and molecular connections between diets, particularly those high in fat, and the development of insulin resistance, a precursor to type 2 diabetes.  

Specifically, we are interested in how people differ in their ability to burn fat and the cellular systems that controls fuel selection in muscle (i.e. what nutrient cells prefer to burn).   For example, we recently discovered that after taking muscle cells out of the body and growing them in a Petri dish, they retain the characteristics of their donors. In other words, cells that burn fat in the Petri dish come from lean, insulin sensitive people and cells that come from obese insulin resistant people that are unable to oxidize fat effectively in the clinic.   This tells us that a large portion of the inter-individual variability in risk for developing obesity and diabetes is attributable to fundamental differences in fuel metabolism in muscle cells.

Along these same lines, we recently discovered that diets high in fat change the pattern of genes turned on and off in muscle.   Genes required for glucose metabolism are turned off by high fat diets and, quite unexpectedly, genes required for mitochondrial biogenesis and energy metabolism were downregulated. This observation was recapitulated in a mouse model of diabetes and suggests a model for how dietary fat causes defects in energy metabolism that are increasingly recognized as a precursor of diabetes.

Recent studies in cultured human muscle cells have focused on unraveling the links between mitochondrial biogenesis and lipid oxidation. Former Post-doctoral fellow Barbara Ukropcova developed a cocktail to activate mitochondrial biogenesis in these cells. This cocktail, in addition to turning on mitochondrial biogenesis and the capacity for fat oxidation, increases insulin sensitivity. This highlights the inter-relationships between lipid metabolism and insulin sensitivity and provides a unique tool to dissect the transcriptional and signaling events that link exercise to improved insulin sensitivity.

Additional studies in the lab are focused on the regulation of lipolysis in muscle and the proteins that coat intramyocellular lipid droplets to regulate the lipolytic process and subcellular localization and organization. These studies use physiological and metabolic measures in the clinic, human tissue, cell derived from patients with and without T2DM and transgenic animals to unravel the mechanisms controlling lipid metabolism and insulin action in muscle.

These studies are complemented by our earlier studies of fat cells [although the lab has shifted almost exclusively its focus to muscle].   The ability of adipocytes to store and oxidize fats is a critical event in the development of diabetes.   If fat cells cannot store fat effectively, fat 'spills over' into the liver and the muscle producing deleterious effects such as insulin resistance.   Recent progress in the area came from our clinical studies examining the role of drugs used to treat diabetes.   We found that the TZD drugs increase the number of mitochondria in adipose tissue in vivo and increase the expression of genes involved in fat oxidation.

Ongoing clinical studies are testing the hypothesis that these same changes in mitochondrial mass occur in the muscle of type 2 diabetics. To test the mitochondrial hypotheses, we are collaborating with Dr. Kevin Conley to measure mitochondrial function in vivo in humans using a combination of 3T NMR and optical spectroscopy. NMR allows us to measure both resting and maximal ATP synthesis; when combined we can measure mitochondrial coupling with high precision. This is a unique capability and allows us to explore muscle mitochondrial functioning in vivo non-invasively.

Lastly, our lab is interested in the emerging field of microarrays and the bioinformatics analysis of these large datasets.   Microarrays are small 'chips' that allow us to measure the expression of thousands of genes at one time.   This mass of information presents great opportunities, and challenges to the researcher.   Harnessing this horsepower is a challenge and in collaboration with statisticians and bioinformaticians, we are using these tools to better diagnose subtypes of obesity and diabetes.   Our hope is that these tools will allow us to personalize treatment and improve patient care.

To view information on some of Dr. Smith's latest lab research, click on the following pdf file:

Measuring fatty acid oxidation in cultured human skeletal muscle cells

To find out about Dr. Smith's obesity related clinical studies, click on the following pdf file:

Obesity related studies

To view Dr. Smith's unpublished data on tBHQ, click on the link below.

tBHQ and adipocyte differentiation

To view Dr. Smith's 2005 Work In Progress presentation, entitled "Fat oxidation and obesity / insulin resistance: bench-to-bedside and back in the ADAPT studies", click on the following pdf file:

WIP 2005

To view Dr. Smith's talk presented at the Sixteenth European Meeting on Hypertension, click on the pdf file listed below. It is entitled "Novel concepts in obesity associated insulin resistance".

SMITH STEVEN Madrid ESH 2006

To view the pdf file of Dr. Smith's lecture, presented at the Physical Activity + Obesity Satellite Conference (ICO 2006), click on the link below. It is entitled "The Exercise Induced Increase In Sleeping Energy Expenditure Is Dependent On Dietary Fat Content".

Smith SR Brisbane 2006 final

To view Dr. Smith's most recent biosketch, click on the following pdf file:

smith biosketch 10-2007

To view Dr. Smith's talk presented at the American College of Cardiology Annual Scientific Sessions (ACC 2007), click on the link below. It is entitled "Adipose Tissue - The New Endocrine Organ".

ACC 2007 final

To view Dr. Smith's talk presented at the 2007 Human Ecology Nutrition Course, click on the link below. It is entitled " Regulation of Substrate Utilization, Triglyceride Synthesis, Fatty Acid Oxidation, and Expression of Associated Genes".

Nutrition course - fat oxidation updated

To view Dr. Smith's talk presented at the 2007 CARDIOMETABOLIC Health Congress, click on the link below. It is entitled "Peripheral Neuro-hormones as a Strategy to Treat Obesity".

SMITH SR CMC Boston 2007 v 1 2

To view Dr. Smith's talk presented at his visit to the NHRI in Taiwan, click on the link below.

Taiwan NHRI Feb 2008 presented v 2003 for pdf Compatibility Mode

To view Dr. Smith's presentation on mitochondrial dysfunction in type 2 diabetes mellitus, click on the link below.

HaPE Tutorial on Measuring Mitochondrial Biogenesis In Vivo