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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

 

Our Research Vision:  The old model of adult degenerative disease was based on the interaction between genes and an adverse environment in adult life. The new model that is developing will include programming by the environment in fetal and infant life.” The University of Colorado is recognized as a world leader in investigating mechanisms for how pregnancy and obesity (affecting up to 50% of pregnancies) and Gestational Diabetes (affecting 5-15% of women) increase the risk for childhood obesity and its co-morbidities in the next generation.  This rapid rise in pediatric obesity and its’s co-morbidities including cardiovascular disease, Type II diabetes, and Non-Alcoholic Fatty Liver Disease (NAFLD) may have its origins during pregnancy.  With outstanding faculty, and funds from NIH, American Diabetes Association, Bill & Melinda Gates Foundation, and the Colorado Children’s Hospital, over the past 10 years we have developed a powerful collaborative programed termed: “The Colorado Program for Nutrition and Healthy Development”.  The goal of this program is to utilize cutting edge new technologies (microbiome, stem cells, epigenetics) together with in-depth maternal-infant phenotyping (infant MRI, placental function, ultrasound, etc), to develop new therapies aimed at stopping the transmission of the obesity epidemic from mother to infant.

The program encourages 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 a basic science approach to a huge epidemic of obesity.    From human pregnancy intervention, to Non-Human Primates, to mouse models, and stem cells, we have a number of possible interventions in the pipeline in various stages of development.  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).  Emboldened by our insights, we are highly motivated to develop a basic science approach that can be translated to humans using a life-course approach to understanding what nutritional factors can be safely altered to slow down the obesity epidemic in the first 1000 days of life.   In so doing, 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 the 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. 

Along with my clinical-translational colleague, Dr. Lynn Barbour, M.D. the Program in Nutrition and Healthy Development includes PhD and MD basic scientists (human geneticists, biochemists, neonatologists, GI physiologists, informatics experts) and clinical-translational researchers in human pregnancy.  My main research interests are: 1. Role of maternal diet in metabolic programming of obesity and liver NAFLD in the infant. 2. Using human umbilical-derived mesenchymal stem cells (MSC’s) to investigate mechanisms for epigenetic regulation and mitochondrial dysfunction. 2.  Determine the role of maternal nutrition on evolution of the microbiome and “programming” in immune cells derived from infants, primates, and transgenic mice. My 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. My lab was the first to report the role of maternal obesity on fetal pre-natal fatty liver in Non-Human Primates (JCI, 2009), followed by an MRI/MRS study in humans demonstrating steatosis in 2 wk old neonates from obese GDM mothers (Pediatrics, 2013).  I have trained more than 31 Post-Docs, MD fellows, and graduate students (5RO1’s, 8 K’s, 5-F32’s), the majority of whom are Assistant Professor or above in academic institutions, including 9 currently on the faculty at the University of Colorado. I also direct the NIH Nutrition Obesity Research Center (NORC) Metabolic Core Lab, as well as the NIH-supported Training program in Perinatal Biology and Medicine. 


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