Skip to main content
Sign In
 

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

 

Our Research Vision:  The University of Colorado is recognized as a world leader in investigating how maternal obesity and GDM can be transmitted to the next generation to influence infants and child obesity and co-morbidities, including cardiovascular disease and its metabolic consequences.  We have the key personnel and with precious funds from NIH, supplemented by the Dean, CORI, and Children’s Hospital Funding we have moved from human epidemiological science to novel animal and cellular models and back over the past 10 years to establish a powerful collaborative base in nutrition and healthy development.  This has allowed our “team science” to expand into new technologies (microbiome, stem cells, epigenetics) and in-depth maternal-infant phenotyping (infant MRI, placental function, etc), along with recruiting new trainees that have earned new grants and career development opportunities, and found that interdisciplinary science in primordial prevention is a great opportunity to learn clinical medicine along with basic science approach to a huge epidemic of obesity.  The next step and breakthroughs in this field will come from studies that can show successful prevention/interventions in maternal and newborn and childhood precursors of disease.  We have a number of possible interventions in the pipeline in various stages of development from animals to humans, including clinical models and human therapies.  Our basic science is aimed at understanding the mechanisms that will potentially help us test and design new targets in addition to novel therapies, such as antioxidants, anti-inflammatory agents, and pro-biotics in fighting the obesity epidemic.

 

For example, we recently developed a maternal diet, termed the CHOICE™ diet (based on AHA healthy guidelines) delivered for 8 wks in obese women with GDM that showed success in pilot studies to reduce insulin resistance and infant adiposity (Diabetes Care, 2014 In press).  Emboldened by our insights, we were highly motivated to develop a  program that solidified our common goal to understand these results, build and sustain a program, and allow synergy necessary for multiple team science grants from animals to humans that use a life-course approach to understanding what nutritional factors can be safely altered to slow down the obesity epidemic  beginning during pregnancy and in the pre-adolescent.   In so doing, we seek to maximize and merge basic developmental biology research with state of the art maternal-infant clinical investigators to understand how the metabolic environment of the obese mother increases the risk for early development of obesity in infants, and what potentially can be done prenatally and postnatally to  attenuate this devastating trend.  With funds from the AHA, Gates Foundation, NIH, and the American Diabetes Association, we will be able to take even greater advantage of longitudinal studies and our own planned interventions to train fellows and the next generation of scientists that will begin to address how interventions in pregnancy and post-natally result in prevention of obesity possibly beginning in the womb.  We expect to change the course of clinical medical treatment of obese women and her infant to slow the impact of the current obesigenic environment during critical developmental windows that will have a long-lasting effect on a population level to reduce obesity and its metabolic consequences. 

 

Dr. Jed Friedman, along with Dr. Lynn Barbour, M.D. directs a Program in Nutrition and Healthy Development that includes PhD and MD basic scientists (human geneticists, biochemists, neonatologists, GI physiologists) and clinical-translational researchers in human pregnancy.  He also directs the Metabolic Core Lab for the NIH Nutrition and Obesity Research Center (NORC) and is the Director of the NIH-supported Molecular Biology Training program in perinatal medicine. He has successfully mentored >31 MD and PhD fellows into academic careers, 9 of whom have been retained to join the faculty with tenure track positions in the medical school.  His research portfolio includes innovative animal models of maternal obesity (non-human primates, transgenic mice), as well as invasive clinical studies of human tissues and cells (adipose, skeletal muscle, placental derived stem cells) from pregnant women.  Along with Dr. Barbour and Dr. Krebs his lab is collaborating on investigations of how nutritional intervention in obese women alters infant adiposity and epigenetic programming of stem cell DNA from these infants.  His portfolio also includes translational studies of nutrition intervention and metabolic pathways in underweight infants in 3rd  world countries with high probability of future metabolic syndrome, funded by the Bill and Melinda Gates Foundation. The trainees have explored basic metabolic pathways of insulin signaling in GDM (animals and humans), the role of mitochondrial dysfunction and inflammation on gene expression and nutritional programming of the microbiome, and the impact of nutritional therapies on genes that control inflammation and Non Alcoholic Fatty Liver Disease (NAFLD) and its consequences in juvenile non-human primates, human infants, and mouse models of obesity.


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. 


Dr. Friedman's Home Page

 


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, 96(5):1431-41,

2011. PMID:21289241,

 

Grant WF, Gillingham MB, Batra A, Fewkes NM, Comstock SM, Takahashi D, Laserev M, Grove KL,

Friedman JE, and Marks DL. Maternal high fat diet is associated with decreased plasma n–3 fatty acids

and fetal hepatic apoptosis in nonhuman primates. Plos-One. 6(2):e17261. 2011. PMID:21364873.

 

Hernandez TL, Friedman JE, Van Pelt RE, and Barbour LM. Patterns of glycemia in normal pregnancy:

should the current therapeutic targets be challenged? Diabetes Care 34(7):1660-8, 2011. PMID:21709299.

 

 Attia RR, Sharma P, Song S, Jannsen RC, Friedman JE, Lee JS, Elam MB, Cook GA, and EA Park. 

 Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by CCAAT/Enhancer Binding Protein β (C/EBPb).            Journal of Biological Chemistry, 286(27):23799-807, 2011. PMID:21586575.

 

 Brown LP, Rozance PJ, Thorn SR, Friedman JE, and Hay WW, Acute supplementation of amino acids

 increases net fetal protein accretion in the IUGR fetus. American Journal of Physiology, 303(3):E352-64,

2012. PMID: 22649066.

 

McCurdy CE, Schenk S, Holliday MJ, Philip A, Houck J, Patsouris D, MacClean P, Olefsky J,  Majka SM,

Klemm DJ, and Friedman JE. Attenuated PIK3r1 expression prevents insulin resistance and adipose

 tissue macrophage accumulation in diet-Induced obese mice. Diabetes 61(10):2495-505, 2012. PMID: 22698915.

 

 Rahman M, Janssen RC,  Choudhury M, Aiken, R. Baquero K, , De LaHoussaye B, Klemm D, and

Friedman JE. CCAAT/Enhancer Binding Protein-β (C/EBPb) regulates dietary-induced inflammation in

macrophages and adipose tissue in mice. Journal of Biological Chemistry, 287(41):34349-60, 2012.

PMID: 22902781.

 

Suter MA, Chen A, Burdine MS, Harris RA, Lane R, Grove KL, Tackett A, Choudhury M, Friedman JE,

Aagaard KM.  A maternal high fat diet modulates fetal SIRT1 histone and protein deacetylase activity

in a non-human primate model.  FASEB J, (12):5106-14, 2012.  PMID: 22982377

 

Qadri I, Choudhury M,  Knotts T, Iwahashi M, Puljak L, Simon FR, Kilic G, Fitz JG, and Friedman JE.

 Increased PEPCK gene expression and steatosis during Hepatitis C virus (HCV) subgenomic replication:

role of NS5A and C/EBPb. Journal of Biological Chemistry 287(44):37340-51, 2012 PMID: 22955269.

 

DuBois BN, O’Tierney P, Friedman JE, Thornburg K, and Cherala C. Maternal pre-gravid body mass index

alters feto-placental Cytochrome P4501A1 activity. Placenta, 33(12):1045-51, 2012 PMID: 23046808.

 

Grant W, Nico L, Grove K, Thorn SR, Friedman JE, and Marks D. Perinatal exposure to a high fat

diet is associated with reduced hepatic sympathetic innervation in 1 year old male Japanese Macaques.  Plos One  7(10):48119-27, 2012. PMID: 23118937.

 

Thorn SR, Brown LP, Rozance PJ, Hay WW, and Friedman JE. Increased hepatic glucose production

 in fetal sheep with intrauterine growth restriction is not suppressed by insulin. Diabetes, 62(1):65-73,

 2013. PMID: 22933111

 

Rahman SM, Choudhury M, Janssen RC, Bacquero KC, Miyazaki M, and Friedman JE. CCAAT/ Enhancer

Binding Protein-β deletion increases mitochondrial function and protects mice from LXR induced hepatic

steatosis. Biochemical Biophysics Research Communication, 430(1):336-9, 2013. PMID: 23159614.

 

Brumbaugh DE, Tearse P, Cree-Green M, Fenton LZ, Brown M, Scherzinger A, Reynolds R, Alston M, Pan Z,

Hoffman C, Friedman JE+, Barbour LA+.  Intrahepatic fat is increased in the neonatal offspring of obese women with gestational diabetes. Journal of Pediatrics 162(5):930-936, 2013.PMID:23260099.+Co-senior authors.

 

Heerwagen M, Stewart M, De La Houssaye B, Aikens R, Janssen R, and Friedman JE. Transgenic increase

in N-3/N-6 fatty acid ratio reduces maternal obesity-associated inflammation and limits adverse developmental

programming in mice. Plos One, Jun 25;8(6):6779, 2013. PMID:23825686.

 

Boyle KM, Newsom S, Barbour LA, Hernandez T, Lappas M, and Friedman JE. Skeletal muscle MnSOD,

mitochondrial complex II, and SIRT3 enzyme activities are decreased in maternal obesity during human

pregnancy and gestational diabetes mellitus. Journal of Clinical Endocrinology and Metabolism, 98(10):

E1601-9, 2013. PMID: 23956348.

 

Martin-Murphy BV, You Q, Wang H, De La Houssay B, Friedman JE, Ju C. Mice lacking Natural Killer T

cells are more susceptible to metabolic alterations following high fat diet feeding. Plos-One, 2014 (In Press).

 

Hernandez TL, Van Pelt RE, Anderson MA, Daniels LJ, West NA, Donahoo WT, Friedman JE, and Barbour

LA. A Higher Complex Carbohydrate Diet in Gestational Diabetes Achieves Glucose Targets and Lowers

Postprandial Lipids: A Randomized Crossover Study, Diabetes Care, 2014 (In Press).

 

Cardel M, Lemas DJ, Friedman JE, and Fernandez JR. Reported polyunsaturated fatty acid consumption is

associated with increased lean mass and decreased total and visceral adiposity in a racially diverse sample

of children. American Journal of Clinical Nutrition, 2014 (In Press).

 

Roberts V*, Pound L*, Thorn S, Gillingham M, Thornburg K, Friedman JE, Frias A#, Grove K#. Beneficial

and cautionary fetal outcomes of maternal resveratrol supplementation during pregnancy in the nonhuman       primate. *These authors contributed equally. #Co-senior authors. FASEB J, 2014 (In Press).

 

Hambidge MK, Krebs NF, Westcott JE, Garces A, Goudar S, Kodkany B, Pasha O, Tshefu A, Bose C, Figueroa

L, Goldenberg R, Derman R, Friedman JE, Frank D, McClure E, Stolka K, Das A, Koso-Thomas M, Signore

 C, Sundberg S. Preconception maternal nutrition: A multi-site randomized controlled trial. BMC Pediatrics,

2014 (In Press).


Reviews:

 

Boyle KE and Friedman JE. Maternal obesity and oxidative stress in the fetus: Mechanisms underlying

early-life shifts in skeletal muscle metabolism.  Fetal and Maternal Medicine Reviews, 22:3, 219-246, 2011.

 

Choudhury M, and Friedman JE. Childhood Obesity: Methylate now, pay later? Nature Reviews- Endocrinology

21;7(8):439-40, 2011. PMID: 21691305.

 

 Choudhury M, and Friedman JE. Epigenetics and microRNAs in Preeclampsia. Clinical and Experimental

Hypertension 34(5):334-41, 2012. PMID: 22468840.

 

Barbour LA, Van Pelt RE, Brumbaugh DE, Hernandez TL, Friedman JE. Comment on: Rowan et al. Metformin in Gestational diabetes: The Offspring Follow-Up (MiG TOFU): body composition at 2 years of age. Diabetes Care 2011;34:2279-2284. Diabetes Care. 2012 35(3): PMID: 22355031.

 

Brumbaugh D and Friedman JE. The Developmental Origins of Non-Alcoholic Fatty Liver Disease. Pediatric Research, 10: 1038-49, 2013. PMID: 24192698.


 Hernandez TL, Anderson MA, Chartier-Logan C, Friedman JE, and Barbour LA. Strategies in the Nutritional Management of Gestational Diabetes. In: Clinical Obstetrics and Gynecology-Diabetes in Pregnancy. Edited by M. Langdon, Lippincott Press, Philadelphia, Pa, 56(4):803-15, 2013. PMID: 24047934.


 Stewart MS, Heerwagen JR, and Friedman JE. Developmental Programming of Pediatric Non-Alcoholic Fatty Liver Disease: Redefining the ‘First-Hit’ Clinical Obstetrics & Gynecology, 56(3):577-90, 2013 PMID:23835912.



 
Latest Publications in PubMed