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Jacob (Jed) E. Friedman, Professor

Ph.D.


Department of Pediatrics, Biochemistry & Molecular Genetics
Director, NIH Center for Human Nutrition Research Metabolism Core Laboratory, UC-Denver.

Campus Box 8106
RC1 S, L18-7127

Phone: 303-724-3983

Jed.Friedman@ucdenver.edu

 

Research Interests:

I am currently the director of the Colorado Program for Nutrition and Developmental Health.  

Goals of the Program

• To understand basic mechanisms underlying the role of nutrition and the environment on maternal-infant health in animal models that can be translated to humans.

• To develop safe nutritional/interventional strategies to achieve a healthier pregnancy and improve newborn health during the first 1000 days of life.  

• To facilitate collaborative research within Colorado and beyond.

• To provide education for trainees, medical professionals, and the lay public.

Exploring the Fuel-Mediated Programming of Neonatal Growth in Non-Human Primates.

Development of a Non-Human Primate Model of High-Fat/Calorie Diet-Effects on the Fetus: The prevalence of obesity has been increasing dramatically in the United States over the past decades and obesity is now present at increasingly younger ages, indicating that risk factors for this condition start operating very early in life. Fetal life is considered one of the critical (or sensitive) periods when an exposure may have lifelong effects on the structure and/or function of organs, tissues, and body systems through biological programming. The notion that abnormal maternal metabolism in obesity may trigger changes in the fetus that underlie susceptibility to juvenile obesity is increasingly gaining acceptance. However, the mechanisms involved in generating such responses are far from understood. We have a long-term collaborative project with the Oregon National Primate Research Center using adult Japanese macaques subjected to a high fat diet during repeated pregnancies. Despite no change in maternal weight gain or fetal birth weight we found elevated fetal hepatic triglycerides, inflammation, and increased oxidative stress in the liver during the early 3rd trimester (JCI, 2009; Plos One 2011). The offspring also demonstrate significant changes in the hypothalamus, skeletal muscle, and pancreas. Significance: These studies demonstrate (1) fetuses from overweight mothers chronically consuming a high fat diet show early signs of liver steatosis and possibly nonalcoholic fatty liver disease, (2) the fetus is highly vulnerable to excess lipids independent of changes in maternal glucose, and (3) accelerated obesity in the fetus may result in “epigenetic signatures” in key genes as a result of excessive nutrient transfer to the fetal/ placental unit. I and my colleagues are currently addressing the cellular mechanisms for these findings and closely following the behavior and metabolic profiles of the juvenile animals as they develop post-natally.  These results have profound public health implications.

  

Molecular Mechanisms for Insulin Resistance in Human Pregnancy: Impact on the Fetus: 


Our clinical studies are focused on the cellular/molecular mechanisms of insulin resistance in tissues(adipose and skeletal muscle) obtained from obese women with obesity and Gestational Diabetes Mellitus (GDM). Maternal obesity is an enormous public health concern, as children from these pregnancies have demonstrated a dramatic rise in obesity and T2DM in young adulthood, and mothers with GDM have an extremely high risk of progressing to T2DM after pregnancy. 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 the University of Colorado Denver, we are investigating how changes in dietary lipid and glucose metabolism, inflammation, and insulin resistance result in excess nutrient transfer to the fetus. In skeletal muscle from pregnant obese women we have found a pattern of reduced mitochondrial function that may underlie the failure to oxidize nutrients and insulin resistance that may underlie excess weight gain. In maternal adipose tissue, we find that maternal obesity is associated with infiltration of macrophages and inflammatory processes that contribute to excessive lipolysis and may result in excessive insulin resistance and excess nutrient transfer to the fetus. We are investigating Lipoprotein Lipase activity (a key gate keeper of lipid uptake by placenta) and infant adiposity at birth, and the role of maternal breast-feeding nutrient composition as potential points for intervention. Nutritional strategies that can lower maternal lipids, inflammation, or oxidative stress may hold promise for potentially preventing the obesity epidemic in children as pregnancy is considered a key time for adipogenesis, fat storage, and epigenetic programming in early signatures for weight gain. 

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Dr. Friedman's Home Page

 

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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.

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.  

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.

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].

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].

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, 150(7):3021-30, 2009.

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, 50(11):2193-202, 2009.

Moriarty, M, McCurdy CE, Janssen R, Shaw T, Leitner JW, Friedman JE, and B Draznin. In vivo knock-down of p85α with Anti-Sense Oligonucleotides improves insulin sensitivity in Lep(ob/ob) and diet-induced obese mice.Hormone & Metabolic Research, 41(10):757-61, 2009.

Payne VA, Au W-S, Lowe CE, Rahman SM, Friedman JE, O’Rahilly S, and JJ Rochford.C/EBP transcription factors regulate SREBP1c gene expression during adipogenesis.Biochemical Journal, 425(1):215-23. 2009.

>Heerwagen M, Miller M, Barbour LA, and Friedman JE. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. American Journal of Physiology: Regulatory and Integrative, 2010 Jul 14. [Epub ahead of print] PMID: 20631295

Majka S, Fox K, Psilas J, Helm K, Childs C, Acosta A, Janssen R, Friedman JE, Woessner B, Shade T, Varella-Garcia M, and Klemm D. De Novo generation of white adipocytes from the myeloid lineage via Mesenchymal Intermediates Is Age, Adipose Depot and Gender Specific. Proc Natl Acad Sci U S A. 2010 Aug 2. [Epub ahead of print] PMID: 20679227.

Kendrick A, Choudhury M, Rahman MR, McCurdy C, Watson PA, Birdsey N, Bao J, Gius D, Sack MN, +Friedman JE, and Jonscher KR. Fatty Liver is associated with reduced SIRT3 Activity and mitochondrial protein hyperacetylation. Biochemical Journal 2010 (In Press). +Corresponding author.<

Barbour LA, McCurdy CE, Draznin B, Hernandez TC, and Friedman JE. Chronically Increased S6K1 and IRS1 serine phosphorylation are associated with skeletal muscle insulin resistance in GDM women with impaired glucose tolerance postpartum. Journal of Clinical Endocrinology & Metabolism 2010 (In Press).

 
Latest Publications in PubMed​