Jacob E. Friedman, Ph.D.
Professor

Department/Division:
Department of Pediatrics, Biochemistry & Molecular Genetics

Contact information:
Office Location: Research Complex 1 - 7th Floor South
          Room L18-7127
Phone number: (303) 724-3983 (office)
                          (303) 724-3979 (lab)
email: Jed.Friedman@uchsc.edu

Area of Research:
Main Field
Insulin signaling, hepatic gene regulation, and energy metabolism in obesity and diabetes.


Current Research Interests
Regulation of C/EBP gene expression and gluconeogenesis; insulin receptor signaling and mechanisms of insulin resistance in human and mouse models of diabetes; fetal origins of adult obesity and diabetes.

Educational/Professional Background:

1989-1991      Post-Doc Fellow, Dept of Biochemistry & Endocrinology,
                       East Carolina Univ. SOM, Greenville,NC

1991-1992      Post-Doc Fellow, Dept of Biochemistry, Case Western
                       Reserve University SOM, Cleveland, OH.

1993-1999      Assistant Professor, Dept of Nutrition, Case Western
                       Reserve Univ School of Medicine, Cleveland, OH.

1999               Associate Professor of Nutrition (with Tenure), Case
                       Western Reserve Univ SOM, Cleveland, OH.

7/00-04          Associate Professor of Pediatrics, University of Colorado
                      Health Sciences Center, Denver, CO.

7/00-04          Associate Professor of Biochemistry & Molecular Genetics,
                      Univ of Colorado, HSC, Denver, CO

7/00-pres       Director, Molecular Biology Core Lab for UCD NIH Training
                      Program in Perinatal Medicine

7/00-pres       Director, Molecular Biology Core Lab for UCD NIH Perinatal
                      Emphasis Research Center.

7/02-pres       Director, Metabolism Core Lab for UCD NIH Center for
                      Human Nutrition Research.

1995-pres      Editorial Board, American Journal of Physiology:
                      Endocrinology & Metabolism.

1995              NIH-NIDDK Review Panel Program Project, Genes of
                      Glucose Homeostasis and Diabetes.

1999              NIH-NIDDK Review Panel Program Project, Central
                      and Peripheral Interactions in Energy Balance,

1999              NIH-NIDDK Review Panel, Center Grants for Nutrition
                      Research Units, Molecular Biology Cores.

1999-2000     NIH-NINDS, Special Emphasis Review Panel,
                      Neurological Complications of Diabetes.

2000              NIH-NIA, Special Emphasis Review Panel, Claude
                      Pepper Center Grants for Research on Aging.

2000-2001     NIH-Ad Hoc Study Section Member, Respiratory and
                      Applied Physiology Study Section.

2001              NIH-NIDDK Special Emphasis Review Panel, Phenotyping
                      Centers for Mouse Models of Diabetes.

2001              NIH-NIDDK, Special Emphasis Review Panel, Small
                      Business Grants in Nutrition and Metabolism.

2002              NIH-NIDDK, Ad Hoc Study Section Member, Skeletal
                      Muscle Biology.

2002              NIH-NIDDK, Study Section Review Panel, Diabetes
                      Research and Training Center Grants.

2002              NIH-NIDDK, Ad Hoc Study Section Member, Metabolism
                      study section.

2002              NIH-NIDDK, Ad Hoc Committee -Advancing Collaborative
                      Research in Obesity/Nutrition Centers

2003, 2004   NIH-NIDDK, Ad Hoc Study Section Member, Endocrinology
                     Study Section.

2003            External Review Panel, USDA Pediatric Research Center at Baylor.

2003            Grant Review Panel, American Diabetes Association, RFA on
                    Diabetes in Pregnancy.

2004            NIH-NIDDK, Ad Hoc Study Section, PPG’s –Central and
                    Peripheral Interactions on Energy Balance-Harvard Med School,
                    and Hypothalamic Control of food intake and Body Weight
                    -Univ.of Washington.

2005           Professor of Pediatrics, Biochemistry & Molecular Genetics
                   Univ of Colorado HSC, Aurora, CO

2005-pres   Editorial Board, Archives of Physiology and Biochemistry

2006-2009  Editorial Board, The Journal of Biological Chemistry

2005           NIH Review Panel, Integrative Clinical Endocrinology and Reproduction
                   (ICER)  study section

2005           NIH Panelist:The Intrauterine Environment: Consequences for Obesity &
                   Metabolic Disease.

2006-pres  External Advisory Board, The European Society for the Study of Diabetes
                  and Pregnancy

2006          NIH Review Panel, Integrated Physiology of Obesity and Diabetes (IPOD) study
                  section.

2007         Program Committee, American Diabetes Association Council on Diabetes
                 & Pregnancy.

2007-2008 Summary of Active and Pending Research Grants:

NIH-NIDDK RO1 DK062155 4/01/03-3/31/07
(Friedman ) Mechanisms of Insulin Resistance in GDM
The major goal of this research is to elucidate the underlying molecular signaling mechanisms that provoke skeletal muscle insulin resistance in women with GDM using muscle fiber strips and primary human myocytes.

NIH/NIDDK, R01-DK56261 9/1/06-8/30/11
(Friedman) Regulation of Glucose Homeostasis by C/EBP b
The major goal of this application is to create mice bearing a liver and brain-specific deletion for the transcription factor C/EBP b to determine its effect on food intake, hepatic lipid deposition and insulin sensitivity. A secondary goal will be to examine the expression pattern of C/EBP b in archival liver biopsies from obese children with and without steatosis and non alcoholic steatohepatitis (NASH)

NIH-NIDDK 60685 9/1/04 –12/31/07
Seeding Collaborative Research in Obesity (SCRO) Award“Tissue Specific Mechanisms of Imprinting Fetal insulin Resistance in Rhesus Macaques”Jacob E. Friedman, Co-Investigator.
The major goal of these studies is to collaborate with the Oregon National Primate Research Center to develop a model of maternal high fat feeding during gestation to study the ontogeny of neural feeding circuits and mechanisms for insulin resistance in fetal brain, liver, and skeletal muscle.

NIH-NIDDK 7/01/05-12/30/10
P30-DK48520Clinical Nutrition Research Unit (CNRU) - PI –Metabolic Core
A major goal of the CNRU is to promote and enhance clinical and basic nutrition research at the University of Colorado. The Metabolic Core performs assays of hormones, metabolites, and cell signaling.

NIH-NIDDK 4/01/02 -3/30/06
R01-DK52138 WW Hay Jr., PI Fetal Glucose and Amino Acid DeprivationJ.E.F. Co-I. The major goals are to identify the developmental patterns of expression of insulin signaling proteins responsible for glucose uptake and protein synthesis in skeletal muscle using an ovine model of intrauterine growth restriction.

PENDING:

NIH- NIDDK-RO1-076648 (Friedman, Co-PI)7/2007-6/2012
Exploring the Fuel-Mediated Programming of Neonatal Growth
The goal of these studies is to 1. To determine the consequences of exposure to GDM and maternal obesity during pregnancy in >1900 women on infant body size, body fat and estimated insulin resistance at birth. 2. To explore the mechanisms by which maternal gestational diabetes and maternal obesity during pregnancy may affect infant body fat accretion at birth using biomarkers for insulin resistance.

NIH-NIDDK- RO1-077630 (Friedman, PI) 7/2007- 6/2012
Regulation of Maternal Fuel Supply and Neonatal Adiposity
The major goal of these studies is to determine the independent effect(s) of obesity and GDM on unexplained hyperglycemia and lipid availability during early and late pregnancy and the relationship to fetal adiposity and markers of insulin resistance in the fetus. A second goal is to examine the mechanisms underlying the molecular events for the transition from lipogenesis to lipolysis in adipose tissue biopsies taken early and in late gestation in lean, obese, and women who develop GDM.

NIH- R01DK-077627 (Friedman, PI) 7/1/2007- 06/2012
Mechanisms for Fetal Hepatic Programming in the Non-Human Primate
The major goal of these studies is to determine the effect of maternal high fat feeding on the mechanisms for inflammation, steatosis, and excess gluconeogenesis in the fetal liver. A second goal is to examine insulin sensitivity in the offspring from these mothers after weaning. Lastly, we will examine the effect of return to normal chow diet in obese mothers on the development of these disorders .

Selected Peer-reviewed Publications (From a total of 70 original articles):

1. Friedman, J.E., Dudek, R.W., Whitehead, D., Downes, D., Frisell, W., Caro, J.F., and G.L. Dohm (1991). Immunolocalization of glucose transporter GLUT4 in human skeletal muscle. Diabetes 40 (1):150-154.
2. Friedman, J.E., Dohm, G.L., Elton, C.W., Rovira, A., Chen, J.J., Leggett, N., Atkinson, S.M., Thomas, F.T., and J.F. Caro (1991). Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors. Amer. J. Physiol., 261:E87-E94, 1991.
3. Friedman, J.E., Caro, J.F., Azevedo, J.E., W.J. Pories and G.L. Dohm (1994). Glucose metabolism in incubated human muscle: effect of obesity and non-insulin dependent diabetes mellitus. Metabolism, 43:1-9.
4. Friedman, J.E., Ishizuka, T., Liu, S., Farrell, C.J., Bedol, D., Kaung, H.L., Koletsky, R.J. and P. Ernsberger. (1997). Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. Amer. J. Physiol., 273:E1023-E1023.
5. Friedman, J.E., Sun,Y., Ishizuka,T., Farrell, C.J., McCormack. S.E., Herron, L.M., Hakimi, P., Lechner, P and Yun, J.S. (1997). Phosphoenolpyruvate Carboxykinase (GTP) gene transcription and hyperglycemia are regulated by glucocorticoids in genetically obese db/db transgenic mice. J. Biol. Chem., 272:31475-31481.
6. Highman, T., Friedman, J.E., Huston, L., Wong, W., and P. Catalano. (1998). Longitudinal changes in maternal serum leptin concentrations, body composition and resting metabolic rate in pregnancy. Amer. J. Obstet. Gyn., 178:1010-1015.
7. Liu, S., Croniger, C. Arizmendi, C. A., Hirada-Shiba, M., Ren, J.M., Poli, V., Hanson, R.W., and Friedman, J.E. (1999). Hypoglycemia and impaired hepatic glucose production in mice with a deletion in the gene for CCAAT/Enhancer-binding Protein b. J. Clin. Invest., 103: 207-213.
8. Arizmendi, C. A., Liu, S., Croniger, C., Poli, V., and Friedman, J.E. (1999). The transcription factor CCAAT/Enhancer-binding Protein b regulates Phosphoenolpyruvate Carboxykinase (GTP) gene expression and gluconeogenesis during diabetes. J. Biol. Chem., 274:13033-13040.
9. Ishizuka, T, Klepcyk, P., Liu, S., Panko, L., Liu, S., Gibbs, E.M., and Friedman, J.E. (1999). Effects of over-expression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/JLeprdb/+ mice. Diabetes, 48:1061-1069.
10. Friedman, J.E., Ishizuka, T., Huston, L., Liu, S., Highman, T., Jianhua, S., and P. Catalano. (1999). Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with Gestational Diabetes Mellitus. Diabetes, 48:1807-1814.
11. Wang, L, Shao, J., Muhlenkamp, P., Ren, J-M., and Friedman, J.E.. (2000). Increased insulin receptor substrate-1 and enhanced insulin sensitivity in mice lacking transcription factor CCAAT/Enhancer-binding Protein b J. Biol. Chem., 275:14173-14181.
12. Shao, J., Catalano, P.M., Yamashita, H., Smith, S., Ruyter, I., Youngren, J.F.,and Friedman, J.E. (2000). Decreased insulin receptor tyrosine kinase activity and PC-1 over-expression in skeletal muscle from obese women with Gestational Diabetes Mellitus: Evidence for increased serine/threonine phosphorylation. Diabetes, 49: 603-610.
13. Draznin, B, Miles, P.D.G., Kruszynska, Y., Olefsky, J.M., Friedman, J.E., Goalstone, M.L., Golovchenko, I., Stjernholm, R., and K. Wall. (2000). Effects of insulin on prenylation as a mechanism of potentially detrimental influence of hyperinsulinemia. Endocrinology, 141:1310-1316.
14. Yamashita, H., Jianhua, S., and Friedman, J.E. (2000). Physiologic and molecular alterations in carbohydrate metabolism during pregnancy and gestational diabetes mellitus. J. Clin. Obst. Gyn. 43:87-98.
15. Shao, J., Yamashita, H., and Friedman, J.E. (2000). Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. J. Endo., 167:109-117.
16. Shao, J., Catalano, P.M., Ishizuka, T., and Friedman, J.E. (2000). Vanadate enhances, but does not normalize, glucose transport and insulin receptor phosphorylation in skeletal muscle from women with gestational diabetes. Amer. J. Obstet. Gyn., 183:1263-1270.
17. Croniger, C., Millward, C., Kawai, Y., Arinze, A., Liu, S., Harada-Shiba, Friedman, J.E., Poli, V., and R.W. Hanson. (2001). Mice with a deletion in the gene for CCAAT/Enhancer-binding Protein?b have an attenuated response to cAMP and impaired carbohydrate metabolism. J. Biol. Chem., 276(1): 629-638.
18. Yamashita, H. Shao, J., Ishizuka, T., Klepcyk, P.J., Qiao, L, Hoggard, N. and Friedman, J.E. (2001). Leptin administration prevents spontaneous gestational diabetes in heterozygous C57BLKS/J Leprdb/+ mice: Effects on placental leptin and fetal growth. Endocrinology 142: 2888-2897.
19. Shao, J., Yamashita, H., Qiao, Draznin, B.,and Friedman, J.E.(2002). Phosphatidylinositol 3-Kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes. Diabetes, 51:19-29.
20. Catalano, P, Nizielski, S., Shao, J., Liu, S., and Friedman, J.E. (2002). Down-regulated IRS-1 and PPARg expression in obese women with gestational diabetes: Relationship to free fatty acids during pregnancy. Amer J. Physiol., 282:E113-124.
21. Barbour L, Shao, J., Qiao, L., Bartke, A., Draznin, B., and Friedman, J.E.(2002). Over-expression of human placental growth hormone causes severe insulin resistance in transgenic mice. Amer J. Obstet. Gyn, 186:512-517.
22. Sun, Y., Liu, S., Ferguson, S., Liu, S., Wang, L., Klepcyck, P., Yun, J.S., and Friedman, J.E. (2002). Phosphoenolpyruvate Carboxykinase over-expression selectively attenuates insulin signaling and impairs hepatic insulin sensitivity. J. Biol. Chem, 277: 23301-23307.
23. Kirwan, J.P., Haugel-De Mouzon, S., Lepercq, J., Challier J-C, Huston-Presley, L., Kalhan, S.C., Friedman, J.E., and P.M. Catalano (2002). TNF-a is a predictor of insulin resistance in human pregnancy. Diabetes 51, 51(7):2207-13.
24. Yamashita, H., Shao, J., Qiao, L., Pagliassotti, M., and J.E. Friedman (2003). Effects of caloric restriction on fetal and post-natal hepatic insulin resistance in offspring from spontaneous   gestational diabetic Lepr ^db/+ mice. Ped. Res. 53:411-418.25.
25. Shao, J., Qiao, L., and J.E. Friedman (2004). Prolactin, progesterone and dexamethasone regulate glucokinase activity and cAMP/PDE cascades in MIN6 b cells. American Journal of Physiology:Endocrinology &Metab. 286(2):E304-10.
26. Barbour L.A., Shao, J., Qiao, L., Leitner, W., Anderson, M., Bartke, A., J.E. Friedman and B. Draznin (2004). Human Placental Growth Hormone increases expression of the p85 regulatory subunit of PI 3-kinase and triggers insulin resistance in skeletal muscle, Endocrinology, 145(3):1144-50.2004
27. Qiao, L., MacLean P., Schaack, J., Orlicky, D.J, Dairymont, C., Pagliassotti, M, Friedman J.E., and J. Shao (2005). C/EBP a Regulates Human Adiponectin Gene Transcription through an Intronic Enhancer. Diabetes, 54(6):1744-54.
28. Barbour, L., Rahman, SM, Gurevich, I, Fisher, S, Roper, M., Knotts, T., McCurdy, C., Yakar, S, LeRoith, D., Kahn, CR, Cantley, L., Friedman, J.E.*, and Draznin, B. (2005). Increased p85 a is a potent negative regulator of skeletal muscle insulin signaling and induces insulin resistance in response to excess growth hormone. Journal of Biological Chemistry 280(45):37489-94. *Corresponding Author
29. Barry, JS, Davidsen ML, Limesand SW, Galan HL, Friedman JE, Regnault TR, and W. Hay, (2006).Developmental changes in ovine myocardial glucose transporters and insulin signaling during hyper-thermia induced intrauterine fetal growth restriction . Exp Biol Med , 231(5):566-75 .
30. McCurdy, C., and JE Friedman (2006). Early foetal programming of hepatic gluconeogenesis: Glucocorticoids strike back. Diabetologia;49(6):1138-41.
31. Shroeder-Gloeckler JM, Rahman SM, and JE Friedman. Hepatic CCAAT/Enhancer Binding Protein b : (C/EBP b ): engineer of diabetes, obesity, and inflammatory disease processes. Advances in Molecular and Cellular Endocrinology, Elsevier Science NL Publishers, Amsterdam, 2006.
32. del Rincon JP, Iida K, Gaylin BD, Kopchick JJ, Leitner JW, Barbour LA, McCurdy, C., Friedman JE, Draznin B, and Thorner, M (2007). Growth hormone regulation of p85 a Expression and PI 3-Kinase Activity in Adipose Tissue: Mechanism for GH Mediated Insulin Resistance. Diabetes (In Revision).
33. Friedman, J.E. Volume Editor: New Transcription Factors and their role in Diabetes and its Treatment, Advances in Molecular and Cellular Endocrinology, Elsevier Science NL Publishers, Amsterdam, 2006.
34. Rahman, SM, Schroeder-Gloecker, J, Janssen, RC, Qadri, I, Maclean, KN, and J.E. Friedman. CCAAT/enhancer binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology 45(5):1108-1117, 2007.
35. Barbour, LA, McCurdy, CE, Knotts, TA., Shao, J, Kirwan, J, Catalano, P., and J.E. Friedman.  Cellular Mechanisms for Insulin Resistance in Pregnancy and Gestational Diabetes, Diabetes Care,Suppl 2:S112-9, 2007.
36. Friedman, JE, Kirwan JP, Jing M, Presley L, and P. Catalano.  Increased skeletal muscle TNFα and impaired insulin signaling persist in obese women with GDM 1 year post-partum. Diabetes. 57(3):606-13, 2007.
37. Rozance, PJ, Limesand SW, Barry JS, Brown LD, LoTurco D, Regnault TRH, Friedman J.E., Hay WW. Chronic late gestation hypoglycemia up-regulates hepatic PEPCK by activating PGC1α and pCREB in Fetal Sheep. American Journal of Physioliology Endocrinol & Metabolism. 294(2):E365-70, 2007.
38. Fox K, Colton LA, Erickson PF, Friedman JE, Cha HC, Keller P, MacDougald OA, and Klemm DJ.  Regulation of cyclin D1 and Wnt10b gene expression by CREB during early adipogenesis involves differential promoter methylation.  Journal of Biological Chemistry, 283(50):35096-105, 2008.
39. Brown LB, Rozance PJ, Barry JS, Friedman JE, and Hay WW. Insulin is required for amino acid stimulation  of the dual pathways for protein translation in skeletal muscle in the late gestation ovine fetus. American Journal of Physiology Regulatory,Integrative & Comparative. 296(1):E56-63, 2009.  
40. Bishop J*, McCurdy* CE, Williams SM, Smith S, Friedman + JE , and Grove + , KL. Maternal high fat diet triggers lipotoxicity in the fetal liver of the non-human primate. Journal of Clinical Investigation, 119(2):323-35, 2009.  + Co-Senior Authors .
41. Thorn S, Regnault T, Roper M, Keng J, Rozance P, Brown L., Hay WW, and Friedman JE. Intrauterinegrowth restriction increases hepatic gluconeogenic capacity, reduces mRNA translation initiation, and impairsnutrient sensing in fetal liver and skeletal muscle.  Endocrinology, 2009 Apr 2. [Epub ahead of print].
42. Rahman, SM, Qadri I, Janssen RC, and Friedman JE.  Fenofibrate and PBA restore fatty acid-induced loss of adiponectin receptor R2 and AMP Kinase in human hepatoma cells and in Hepatitis C-virus induced fatty liver.  Journal of Lipid Research, 2009. Jun 5. [Epub ahead of print].

Selected Book Chapters and Reviews

1. Catalano, P., Ishizuka, T., and J.E. Friedman. Glucose Metabolism in Pregnancy. In: Principles of Perinatal-Neonatal Metabolism, Second Edition, edited by R.M. Cowett, Springer-Verlag, New York, NY, pp. 183-206, 1998.
2. Jianhua, S., Yamashita, H., Ishizuka, T., and J.E. Friedman. Physiologic and Molecular Alterations in Carbohydrate Metabolism During Pregnancy. In: Clinical Obstetrics and Gynecology-Diabetes in Pregnancy. edited by P. Catalano, Lippincott Press, Philadelphia, Pa, 43: No. 1, 1322-1333, 2000.
3. Friedman, J.E. Yeast-Worm-Animal similarities in Insulin-like receptors and signal transduction: The Aging Pathway Goes through Insulin Signaling. In: Pediatric Research News 49:(8), 691, 2001.
4. J.Shao and J.E. Friedman. Spontaneous Gestational Diabetes in heterozygous C57BLKS/JLepr^db/+ mice: A Unique Model for Studying Maternal Diabetes and its impact on the Fetus: In: Frontiers in Animal Diabetes Research, edited by B.F. Hansen and E. Shafrir, Harwood Academic Press, Amsterdam, The Netherlands, 2002.
5. J.E. Friedman, Editor, New Transcription Factors and their role in Diabetes and its Treatment, Advances in Molecular and Cellular Endocrinology, Elsevier Science NL Publishers, Amsterdam, in production, 2004.