Vanderbilt University School of Medicine

Stafford, John Michael , M.D., Ph.D.
Assistant Professor of Medicine
Assistant Professor of Molecular Physiology and Biophysics

Lab Url:

Phone Number: 615-936-6113


Stafford, John's picture

Office Address   Mailing Address

7445 MRBIV

7445 MRBIV 37232-6303

Research Keywords
obesity, triglycerides, liver, adipose, gut, cardiovascular disease, glucose, lipid, menopause, metabolic syndrome, exercise,Cardiac function,Diabetes,Endocrinology

Research Specialty
Cardiovascular risk associated with diabetes and obesity. Lipid Metabolism and HDL, Sex-differences in metabolism, Exercise and HDL function

Research Description
Objective: The long-term goal of our lab is to define and target the pathways by which obesity and diabetes increase risk of cardiovascular disease.

Overview of research topic: Death and disease from obesity are largely due to the development of insulin resistance. Insulin resistance leads to diabetes and a dyslipidemia characterized by high triglycerides and low HDL. Our lab aims to understand how obesity alters control points in lipid metabolism. We focus on the mechanisms by which metabolism of glucose and triglyceride 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. We also study sex-difference in cardiovascular risk, which may related to the ability of estrogen to coordinate glucose and triglyceride metabolism.

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 (CETP) 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 hormones in protecting from abnormalities in liver metabolism with obesity. We have found that ovarian hormones have a protective role against HDL changes associated with high-fat feeding. 2) HDL composition and function: High density lipoprotein (HDL) protects from coronary heart disease (CHD). HDL prevents inflammation, and accepts cholesterol from tissues by reverse cholesterol transport (RCT). In obesity, HDL may lose its ability to limit inflammation and participate in RCT. In humans, impaired HDL function correlated with the development of obesity, insulin resistance, and fatty liver. Our lab studies how changes in glucose and triglyceride metabolism with obesity contribute to alterations in HDL composition and function. We use both targeted and shotgun proteomics to define HDL composition changes in our obesity models, and relate this to HDL function assays. 3) Coordination of liver glucose and triglyceride metabolism: In the liver metabolism of glucose and triglyceride are exquisitely coordinated to meet changing metabolic needs, including those day-to-day events such as fasting and feeding. This coordination occurs through a convergence of physiologic, signaling, and transcriptional steps in the liver. The implication of this intricate regulation is that subtle defects in the metabolism of one macronutrient influence the other. For instance, liver fat accumulation leads to defects in glucose oxidation. Reciprocally high-carbohydrate diets increase lipogenesis in insulin resistant individuals. Our lab uses both genetic models and metabolic clamp techniques to define how abnormalities in glucose metabolism give rise to defects in triglyceride metabolism. Reciprocally we are interested in defining how defects in hepatic lipid metabolism give rise to defects in liver glucose handling. 4) Importance of exercise in HDL function: HDL is considered protective from cardiovascular disease. With obesity, however HDL loses its anti-inflammatory and atheroprotective properties. We propose that improved muscle fatty acid oxidation capacity with exercise will improve HDL function with regard to its anti-inflammatory and atheroprotective roles

Clinical Interests
Diabetes, Endocrinology, lipid metabolism

Cappel, DA, Lantier, L, Palmisano, BT, Wasserman, DH, Stafford, JM. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity. PLoS One, 10(8), e0136915, 2015.

Otero, YF, Stafford, JM, McGuinness, OP. Pathway-selective insulin resistance and metabolic disease: the importance of nutrient flux. J Biol Chem, 289(30), 20462-9, 2014.

Zhu, L, Martinez, MN, Emfinger, CH, Palmisano, BT, Stafford, JM. Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. Am J Physiol Endocrinol Metab, 306(10), E1188-97, 2014.

Cappel, DA, Palmisano, BT, Emfinger, CH, Martinez, MN, McGuinness, OP, Stafford, JM. Cholesteryl ester transfer protein protects against insulin resistance in obese female mice. Mol Metab, 2(4), 457-67, 2013.

Luo, P, Dematteo, A, Wang, Z, Zhu, L, Wang, A, Kim, HS, Pozzi, A, Stafford, JM, Luther, JM. Aldosterone deficiency prevents high-fat-feeding-induced hyperglycaemia and adipocyte dysfunction in mice. Diabetologia, 56(4), 901-10, 2013.

Zhu, L, Brown, WC, Cai, Q, Krust, A, Chambon, P, McGuinness, OP, Stafford, JM. Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes, 62(2), 424-34, 2013.

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.

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.

Wu, K., D. Cappel, M. Martinez, and J.M. Stafford. Impaired-inactivation of FoxO1 contributes to glucose-mediated increases in serum VLDL. . Endocrinology, 151(8), 3566-3576, 2010.

Stafford, JM, Yu, F, Printz, R, Hasty, AH, Swift, LL, Niswender, KD. Central nervous system neuropeptide Y signaling modulates VLDL triglyceride secretion. Diabetes, 57, 1-9, 2008.

Stafford, JM, Elasy, T. Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes. Vasc Health Risk Manag, 3(4), 503-10, 2007. PMCID:2291335

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.

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.

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.

Wang, JC, Stafford, JM, Scott, DK, Sutherland, C, Granner, DK. The molecular physiology of hepatic nuclear factor 3 in the regulation of gluconeogenesis. J Biol Chem, 275(19), 14717-21, 2000.

Pierreux, CE, Stafford, J, Demonte, D, Scott, DK, Vandenhaute, J, O''Brien, RM, Granner, DK, Rousseau, GG, Lemaigre, FP. Antiglucocorticoid activity of hepatocyte nuclear factor-6. Proc Natl Acad Sci U S A, 96(16), 8961-6, 1999. PMCID:17715

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.

Wang, JC, Stafford, JM, Granner, DK. SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4. J Biol Chem, 273(47), 30847-50, 1998.

Postdoctoral Position Available

Postdoctoral Position Details
We are interested in recruiting an experienced animal physiologist and molecular biologists. Our studies involve exposure to techniques ranging from molecular biology to animal physiology. Experience with animal surgical techniques is not required but preferred. A research background in diabetes or lipid biology is required. Molecular biology experience is required, though training will be provided for specific techniques. Common techniques include: lipoprotein chromatography and lipid assays, western blots for protein, RT-PCR, cell culture, adenovirus purification. Ideal applicants will be: bright, enthusiastic, focused on work activities during working-hours, meticulous to detail and record keeping. A high level of independence, autonomy and intellectual collaboration is encouraged.
Applicants must be NIH training grant eligible (US citizen or US permanent resident).

For more information, please contact:
John M. Stafford MD, PhD

Updated Date

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