Profile

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

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. Dai C, Kayton NS, Shostak A, Poffenberger G, Cyphert HA, Aramandla R, Thompson C, Papagiannis IG, Emfinger C, Shiota M, Stafford JM, Greiner DL, Herrera PL, Shultz LD, Stein R, Powers AC (2016) J Clin Invest 126(5): 1857-70
    › Primary publication · 27064285 (PubMed) · PMC4855919 (PubMed Central)
  2. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity. Cappel DA, Lantier L, Palmisano BT, Wasserman DH, Stafford JM (2015) PLoS One 10(8): e0136915
    › Primary publication · 26313355 (PubMed) · PMC4551677 (PubMed Central)
  3. Pathway-selective insulin resistance and metabolic disease: the importance of nutrient flux. Otero YF, Stafford JM, McGuinness OP (2014) J Biol Chem 289(30): 20462-9
    › Primary publication · 24907277 (PubMed) · PMC4110258 (PubMed Central)
  4. Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. Zhu L, Martinez MN, Emfinger CH, Palmisano BT, Stafford JM (2014) Am J Physiol Endocrinol Metab 306(10): E1188-97
    › Primary publication · 24691030 (PubMed) · PMC4116406 (PubMed Central)
  5. Cholesteryl ester transfer protein protects against insulin resistance in obese female mice. Cappel DA, Palmisano BT, Emfinger CH, Martinez MN, McGuinness OP, Stafford JM (2013) Mol Metab 2(4): 457-67
    › Primary publication · 24327961 (PubMed) · PMC3854988 (PubMed Central)
  6. Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Zhu L, Brown WC, Cai Q, Krust A, Chambon P, McGuinness OP, Stafford JM (2013) Diabetes 62(2): 424-34
    › Primary publication · 22966069 (PubMed) · PMC3554377 (PubMed Central)
  7. Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones. Martinez MN, Emfinger CH, Overton M, Hill S, Ramaswamy TS, Cappel DA, Wu K, Fazio S, McDonald WH, Hachey DL, Tabb DL, Stafford JM (2012) J Lipid Res 53(3): 379-89
    › Primary publication · 22215797 (PubMed) · PMC3276461 (PubMed Central)
  8. Impaired-inactivation of FoxO1 contributes to glucose-mediated increases in serum very low-density lipoprotein. Wu K, Cappel D, Martinez M, Stafford JM (2010) Endocrinology 151(8): 3566-76
    › Primary publication · 20501667 (PubMed) · PMC2940519 (PubMed Central)