Jacob E (Jed) Friedman, Ph.D. Professor Department of Pediatrics, Biochemistry & Molecular Genetics Director, NIH Center for Human Nutrition Research Metabolism Core Laboratory, UC-Denver. University of Colorado Denver Mail Stop 8106 Research Complex-1 South 12801 East 17th Ave Room 7127 Aurora, CO 80045 (303) 724-3983 (office) (303) 724-3920 (fax) jed.friedman@ucdenver.edu

Research Interests:

Molecular Mechanisms for Insulin Resistance in GDM: Our clinical studies are focused on the cellular and molecular mechanisms of insulin resistance in obese women with Gestational Diabetes Mellitus (GDM). GDM is an enormous public health concern, as children from these pregnancies have demonstrated a dramatic rise in obesity and type II DM in young adulthood. Despite the dramatic increase in the incidence of GDM, and the long-term effects on the fetus, there are very few mechanistic data in the field of insulin resistance of GDM. Working with clinical investigators in the department of Ob-Gyn and women’s health at UCD, we utilize a novel incubated human muscle fiber system suitable for the study of muscle metabolism and signal transduction in-vitro. We have demonstrated that obese women with GDM have a unique insulin receptor defect that may underlie future risk for the development of type II DM. We identified specific intracellular serine-threonine kinases as possible candidates for inhibitors of insulin signal transduction and a novel pathway for insulin resistance. We are currently using Mass-Spectroscopy Core laboratories to carry out 2D/Mass-spec phosphopeptide mapping of the insulin receptor and IRS-1 to identify proteins that affect insulin signaling in human muscle during and 6 wks post-partum in human skeletal muscle biopsies.

Role of C/EBPb in development of diabetes and non-alcoholic fatty liver disease (NASH). We are interested in the regulation of fatty liver disease and gluconeogenesis in the liver. We are currently investigating the role of the nuclear transcription factor CCAAT/Enhancer Binding Protein b (C/EBP b) in carbohydrate and lipid metabolism and its role in ER stress and the imflammatory pathways leading to NASH. Using a combination ofmetabolic tracer metabolism in vivo and isolated tissues in vitro, we have shown that deletion of C/EBPb protects mice from diabetes and obesity by regulating key lipogenic and gluconeogenic genes, and through the inflammatory pathway. The major goal of this work is to create mice bearing a liver and brain-specific deletion for C/EBPb to determine its effect on food intake, hepatic lipid deposition and susceptibility to NASH. A secondary goal will be to examine the expression pattern of C/EBPb in archival liver biopsies from obese children with and without fatty liver disease.

Exploring the Fuel-Mediated Programming of Neonatal Growth in Non-Human Primates Despite the dramatic rise in the incidence of pediatric obesity, and the predicted effects of impaired glucose tolerance during pregnancy on childhood obesity, there are very few mechanistic data documenting the specific metabolic consequences of abnormal maternal insulin/glucose, leptin, or fatty acids on insulin resistance in the fetus. To address this issue we have begun a long-term project using adult Japanese Macaques subjected to a high fat diet during repeated pregnancies. Elevated hepatic triglycerides and HNF4a expression suggest that babies born from overweight mothers chronically consuming a high fat diet are born with early signs of liver steatosis and possibly the metabolic syndrome. 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 observed in the fetal liver.

Selected Publications

1. Schroeder-Gloecker* J, Rahman*, SM, Janssen, R., Shao, J, Qiao, L, Roper M, Fisher, S, Lowe, E,  Orlicky, D, Mcmanaman, J, Palmer, C, Gitomer, WL, Huang, W, O’Dohrety, RM, Becker, TC, Klemm, DJ, Jensen, DR, Pulawa, L, Eckel, RH, and JE Friedman. CCAAT/Enhancer Binding Protein b (C/EBPb) deletion reduces adiposity, hepatic steatosis, and hyperglycemia in Leprdb/db mice.  Journal of Biological Chemistry, 282(21):15717-29, 2007.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.  

7. 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.

8. Thorn S, Regnault T, Roper M, Keng J, Rozance P, Brown L., Hay WW, and Friedman JE. Intrauterine growth restriction increases hepatic gluconeogenic capacity, reduces mRNA translation initiation, and impairs nutrient sensing in fetal liver and skeletal muscle.  Endocrinology, 2009 Apr 2. [Epub ahead of print].

9. 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].

Latest Publications in PubMed