- Other Endocrine
Research Faculty Profile
John Michael Stafford, M.D., Ph.D.Assistant Professor of Medicine
Assistant Professor of Molecular Physiology and Biophysics
Nashville, TN 37232-6303
EducationM.D., Vanderbilt University
Ph.D., Vanderbilt University
B.A., Vanderbilt University
Research Keywordsobesity, triglycerides, liver, adipose, gut, cardiovascular disease, glucose, lipid, menopause, metabolic syndrome
Research DescriptionObjective: Our lab aims to understand how obesity and diabetes contribute to cardiovascular risk, with a focus on how control points in lipid metabolism are altered.
Overview of research topic: While death from coronary heart disease (CHD) has declined in the general US population, for patients with obesity and diabetes, risk of death from CHD has doubled in recent decades. Our lab aims to understand how obesity and diabetes contribute to cardiovascular risk, with a focus on how control points in lipid metabolism are altered. We study sex-difference in cardiovascular risk, which may related to the ability of estrogen to coordinate glucose and triglyceride metabolism. We also study the molecular mechanisms by which metabolism of glucose and triglyceride metabolism are coordinated, the body???s two main energy sources. The corollary is that relatively subtle failure this coordinate regulation could lead to abnormalities in both glucose and lipid metabolism ???such as seen with obesity.
For humans, elevated serum triglycerides lead to elevated triglycerides in other lipoproteins. Triglyceride-enrichment of HDL promotes more rapid HDL clearance, and may impair HDL???s protective cardiovascular effects. Rodents do not mimic this biology well. Thus one research focus is to develop rodent models that are more similar to humans with regard to lipid metabolism. Mice transgenic for cholesteryl ester transfer protein have increased transfer of triglyceride into HDL. We have found that cholesteryl ester transfer protein expressing mice model certain HDL changes with obesity. Rodent models with biology more similar to humans may serve as a bridge between basic research and human disease, and help define how obesity and diabetes impact cardiovascular risk.
In addition to our experimental goals, a main focus is to train the next generation of scientist. We will create a research environment that is conductive to learning and testing new skills, as well as scientific ideas.
Research and Projects:
Innovative Techniques: The liver coordinates metabolism of the glucose and TG through the convergence of multiple metabolic signals, including hormonal signals such as insulin and glucagon, and substrate concentrations of glucose and fatty acids. The corollary is that relatively subtle failure this convergent signaling could lead to abnormalities in both glucose and lipid metabolism ???such as seen in obesity and diabetes. Traditional methods to study liver metabolism in vivo are confounded by counter-regulatory changes in glucose and insulin action. In our lab, our approach has been to use chronically-catheterized mice and rats. We then incorporate metabolic clamp techniques to control serum insulin, glucose, and glucagon levels, and thus avoid compensatory metabolic changes. This approach is the gold standard to define insulin sensitivity in vivo, but has not been widely applied to studying TG metabolism in rodents. On top of physiologic definition of insulin sensitivity and TG production, we use metabolic tracers to define the metabolic fate glucose and synthesis of TG. We overlay cutting-edge proteomics, metabolomics and transcriptomics techniques to relate lipid metabolism to insulin sensitivity.
Specific research projects include:
1) Sex-Differences in Cardiovascular risk: Compared to men, women have a delay in the onset of cardiovascular disease. In some studies, this is as much as 10 to 20 years. Some of this protection may be due to protection from the metabolic complications of obesity, including diabetes and a dyslipidemia characterized by increased VLDL, and low HDL. Our lab is interested in defining the molecular pathways that contribute to sex-differences in cardiovascular risk. We use genetic models with tissue-specific knock-out of estrogen receptor alpha. We also use a surgical model of ovariectomy, which mimics many aspects of menopause. Our lab has identified important roles of ovarian horm
Martinez, MN, Emfinger, CH, Overton, M, Hill, S, Ramaswamy, TS, Cappel, DA, Wu, K, Fazio, S, McDonald, WH, Hachey, DL, Tabb, DL, Stafford, JM. Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones. J Lipid Res, 53(3), 379-89, 2012
Zhu, L., W.C. Brown, Q. Cai, P. Chambon, O.P. McGuinness, J.M. Stafford. Estrogen Treatment After Ovariectomy Protects Against Fatty Liver and May Improve Pathway-Selective Insulin Resistance. Diabetes, 61, 2012
Rojas, JM, Stafford, JM, Saadat, S, Printz, RL, Beck-Sickinger, AG, Niswender, KD. Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats. Am J Physiol Endocrinol Metab, 303(12), E1479-88, 2012
Stafford, JM, Waltner-Law, M, Granner, DK. Role of accessory factors and steroid receptor coactivator 1 in the regulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. J Biol Chem, 276(6), 3811-9, 2001
Yoon, JC, Puigserver, P, Chen, G, Donovan, J, Wu, Z, Rhee, J, Adelmant, G, Stafford, J, Kahn, CR, Granner, DK, Newgard, CB, Spiegelman, BM. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature, 413(6852), 131-8, 2001
Stafford, JM, Wilkinson, JC, Beechem, JM, Granner, DK. Accessory factors facilitate the binding of glucocorticoid receptor to the phosphoenolpyruvate carboxykinase gene promoter. J Biol Chem, 276(43), 39885-91, 2001
Scott, DK, O''Doherty, RM, Stafford, JM, Newgard, CB, Granner, DK. The repression of hormone-activated PEPCK gene expression by glucose is insulin-independent but requires glucose metabolism. J Biol Chem, 273(37), 24145-51, 1998