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. 

Publications

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

Featured publications are shown below:

  1. EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance. Ghoshal K, Li X, Peng D, Falck JR, Anugu RR, Chiusa M, Stafford JM, Wasserman DH, Zent R, Luther JM, Pozzi A (2021) Diabetes
    › Primary publication · 34675004 (PubMed)
  2. Hepatocyte Small Heterodimer Partner Mediates Sex-Specific Effects on Triglyceride Metabolism via Androgen Receptor in Male Mice. Palmisano BT, Zhu L, Litts B, Burman A, Yu S, Neuman JC, Anozie U, Luu TN, Edington EM, Stafford JM (2021) Metabolites 11(5)
    › Primary publication · 34065318 (PubMed) · PMC8161262 (PubMed Central)
  3. Low-density lipoprotein receptor is required for cholesteryl ester transfer protein to regulate triglyceride metabolism in both male and female mice. Palmisano BT, Yu S, Neuman JC, Zhu L, Luu T, Stafford JM (2021) Physiol Rep 9(4): e14732
    › Primary publication · 33625789 (PubMed) · PMC7903989 (PubMed Central)
  4. Cholesteryl Ester Transfer Protein Impairs Triglyceride Clearance via Androgen Receptor in Male Mice. Palmisano BT, Anozie U, Yu S, Neuman JC, Zhu L, Edington EM, Luu T, Stafford JM (2021) Lipids 56(1): 17-29
    › Primary publication · 32783209 (PubMed) · PMC7818496 (PubMed Central)
  5. Response by Mueller et al to Letter Regarding Article, "Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases C-C Chemokine Receptor Type 7 (CCR7) Expression in Plaque Macrophages". Mueller PA, Zhu L, Tavori H, Huynh KT, Giunzioni I, Stafford JM, Linton MF, Fazio S (2019) Circulation 139(16): 1983-1984
    › Primary publication · 30986111 (PubMed) · PMC7447072 (PubMed Central)
  6. CETP Inhibition Improves HDL Function but Leads to Fatty Liver and Insulin Resistance in CETP-Expressing Transgenic Mice on a High-Fat Diet. Zhu L, Luu T, Emfinger CH, Parks BA, Shi J, Trefts E, Zeng F, Kuklenyik Z, Harris RC, Wasserman DH, Fazio S, Stafford JM (2018) Diabetes 67(12): 2494-2506
    › Primary publication · 30213825 (PubMed) · PMC6245220 (PubMed Central)
  7. Sex differences in lipid and lipoprotein metabolism. Palmisano BT, Zhu L, Eckel RH, Stafford JM (2018) Mol Metab : 45-55
    › Primary publication · 29858147 (PubMed) · PMC6066747 (PubMed Central)
  8. Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases C-C Chemokine Receptor Type 7 (CCR7) Expression in Plaque Macrophages. Mueller PA, Zhu L, Tavori H, Huynh K, Giunzioni I, Stafford JM, Linton MF, Fazio S (2018) Circulation 138(17): 1850-1863
    › Primary publication · 29794082 (PubMed) · PMC6343494 (PubMed Central)
  9. Hepatocyte estrogen receptor alpha mediates estrogen action to promote reverse cholesterol transport during Western-type diet feeding. Zhu L, Shi J, Luu TN, Neuman JC, Trefts E, Yu S, Palmisano BT, Wasserman DH, Linton MF, Stafford JM (2018) Mol Metab : 106-116
    › Primary publication · 29331506 (PubMed) · PMC5985047 (PubMed Central)
  10. Role of Estrogens in the Regulation of Liver Lipid Metabolism. Palmisano BT, Zhu L, Stafford JM (2017) Adv Exp Med Biol : 227-256
    › Primary publication · 29224098 (PubMed) · PMC5763482 (PubMed Central)
  11. High-Fat Feeding Does Not Disrupt Daily Rhythms in Female Mice because of Protection by Ovarian Hormones. Palmisano BT, Stafford JM, Pendergast JS (2017) Front Endocrinol (Lausanne) : 44
    › Primary publication · 28352249 (PubMed) · PMC5348546 (PubMed Central)
  12. Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition. Zhu L, Giunzioni I, Tavori H, Covarrubias R, Ding L, Zhang Y, Ormseth M, Major AS, Stafford JM, Linton MF, Fazio S (2016) Arterioscler Thromb Vasc Biol 36(8): 1483-95
    › Primary publication · 27365402 (PubMed) · PMC5346022 (PubMed Central)
  13. Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice. Palmisano BT, Le TD, Zhu L, Lee YK, Stafford JM (2016) J Lipid Res 57(8): 1541-51
    › Primary publication · 27354419 (PubMed) · PMC4959869 (PubMed Central)
  14. 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)
  15. 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)
  16. 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)
  17. 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)
  18. 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)
  19. Aldosterone deficiency prevents high-fat-feeding-induced hyperglycaemia and adipocyte dysfunction in mice. Luo P, Dematteo A, Wang Z, Zhu L, Wang A, Kim HS, Pozzi A, Stafford JM, Luther JM (2013) Diabetologia 56(4): 901-10
    › Primary publication · 23314847 (PubMed) · PMC3593801 (PubMed Central)
  20. Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats. Rojas JM, Stafford JM, Saadat S, Printz RL, Beck-Sickinger AG, Niswender KD (2012) Am J Physiol Endocrinol Metab 303(12): E1479-88
    › Primary publication · 23074243 (PubMed) · PMC3532466 (PubMed Central)
  21. 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)
  22. 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): 379-389
    › Primary publication · 22215797 (PubMed) · PMC3276461 (PubMed Central)
  23. 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)
  24. Central nervous system neuropeptide Y signaling modulates VLDL triglyceride secretion. Stafford JM, Yu F, Printz R, Hasty AH, Swift LL, Niswender KD (2008) Diabetes 57(6): 1482-90
    › Primary publication · 18332095 (PubMed) · PMC3968924 (PubMed Central)
  25. Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes. Stafford JM, Elasy T (2007) Vasc Health Risk Manag 3(4): 503-10
    › Primary publication · 17969380 (PubMed) · PMC2291335 (PubMed Central)
  26. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Nature 413(6852): 131-8
    › Primary publication · 11557972 (PubMed)
  27. Accessory factors facilitate the binding of glucocorticoid receptor to the phosphoenolpyruvate carboxykinase gene promoter. Stafford JM, Wilkinson JC, Beechem JM, Granner DK (2001) J Biol Chem 276(43): 39885-91
    › Primary publication · 11518712 (PubMed)
  28. Role of accessory factors and steroid receptor coactivator 1 in the regulation of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Stafford JM, Waltner-Law M, Granner DK (2001) J Biol Chem 276(6): 3811-9
    › Primary publication · 11069927 (PubMed)
  29. The molecular physiology of hepatic nuclear factor 3 in the regulation of gluconeogenesis. Wang JC, Stafford JM, Scott DK, Sutherland C, Granner DK (2000) J Biol Chem 275(19): 14717-21
    › Primary publication · 10799560 (PubMed)
  30. Antiglucocorticoid activity of hepatocyte nuclear factor-6. Pierreux CE, Stafford J, Demonte D, Scott DK, Vandenhaute J, O'Brien RM, Granner DK, Rousseau GG, Lemaigre FP (1999) Proc Natl Acad Sci U S A 96(16): 8961-6
    › Primary publication · 10430878 (PubMed) · PMC17715 (PubMed Central)
  31. SRC-1 and GRIP1 coactivate transcription with hepatocyte nuclear factor 4. Wang JC, Stafford JM, Granner DK (1998) J Biol Chem 273(47): 30847-30850
    › Primary publication · 9812974 (PubMed) · PMC3968904 (PubMed Central)
  32. The repression of hormone-activated PEPCK gene expression by glucose is insulin-independent but requires glucose metabolism. Scott DK, O'Doherty RM, Stafford JM, Newgard CB, Granner DK (1998) J Biol Chem 273(37): 24145-51
    › Primary publication · 9727036 (PubMed)