UAB Metabolomics Symposium December 12, 2012 Christopher B. Newgard, Ph.D. Sarah W. Stedman Nutrition and Metabolism Center Department of Pharmacology & Cancer Biology Duke University Medical Center “Metabolomics applied to chronic disease mechanisms”
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UAB Metabolomics Symposium December 12, 2012 Christopher B. Newgard, Ph.D. Sarah W. Stedman Nutrition and Metabolism Center Department of Pharmacology.
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UAB Metabolomics SymposiumDecember 12, 2012
Christopher B. Newgard, Ph.D.
Sarah W. Stedman Nutrition and Metabolism Center
Department of Pharmacology & Cancer Biology
Duke University Medical Center
“Metabolomics applied to chronic disease mechanisms”
Evolving Metabolic Profiling PlatformStedman Nutrition and Metabolism Center,
DukeDefinition: Development of Comprehensive Tools for Metabolic Analysis of Cultured Cells, Animal Models, and Clinical Samples,via…
“Targeted” MS Methods• GC/MS and MS/MS for “targeted” analysis. Current
Hypothesis: The BCAA/aromatic amino acid metabolicsignature provides a clue to the mechanism underlying the association of obesity with behavioral disorders (anxiety, depression)
Why are Aromatic Amino Acids Always Part of the BCAA-related
Metabolite Signature?
BrainTrp
Serotonin
Blood Brain BarrierLAT1
Trp TyrPhe
Leu
Iso
Val
ValVal
ValIso
IsoLeu
LeuLeu
Leu
Leu
LeuLeuValVal
IsoIsoLeu Leu
Tyr
Dopamine
Norepinephrine
ValIso
Leu
Leu
TRANSPORT OF LNAA THROUGH THE BLOOD BRAIN BARRIER
BCAA supplementation of energy-dense diets reduces Trp and Tyr Levels in frontal
cortex
Coppola, et al. Am. J. Physiol. in press, 2012
ANOVA, BCAA, p < 0.002
BCAA supplementation of energy-dense diets causes anxious behavior (elevated
maze test)
Anna Coppola
ANOVA, BCAA, p < 0.002
Fluoxetine (Prozac) Does Not Reverse BCAA-induced Anxious Behavior……
Anna Coppola
……but Tryptophan Does
Anna Coppola
Anna Coppola
Trp supplementation normalizes kynurenic acid levels in frontal cortex
Anna Coppola
Metabolomic Profiling in CATHGEN
– Study 1• Subjects with coronary artery disease (CAD) compared to
race- and sex-matched controls, index and validation cohorts.
– Study 2
• CAD cases who experienced CV events (MI, CV-related death within 2 yr. of follow up) and controls with no events; index and validation cohorts.
– Study 3
• Nested prospective study of 2023 consecutive subjects undergoing diagnostic cardiac catheterization, with CV events as outcome.
– Study 4
• Adverse outcomes in 478 subjects that underwent coronary artery bypass surgery (CABG).
Shah et al, Circulation Cardiovasc. Genetics 3: 207, 2010
Shah et al, Am. Heart Journal 163: 844, 2012
Shah, et al. J. Thoracic Cardiovasc. Surgery 143: 873, 2012
Shah, Kraus, Newgard, Circulation 126: 1110, 2012
Metabolites in DC-AC principal component clusters that predict CVD
Shah, Newgard, Hauser, Kraus, Newby et al., American Heart Journal 2012.
Study Population: N=3500 from CATHGEN biorepository, 70% with CAD, 29% with T2D
• All 3500 have targeted, quantitative metabolomic profling
•
• All have GWAS (Illumina Omni chip) genotyping completed
•
• All have peripheral blood gene expression profiling (Illumina microarray)
Allows analysis of genetic architecture underlying metabolic variability in this population
Ongoing Studies
Our laboratoryJie An Erin GlynnPhillip White Amanda LapworthDorothee Newbern Chinmeng KhooHelena Winfield Danhong LuSam Stephens Jeff TessemLisa Poppe Anna CoppolaMette Valentin Jensen Taylor Rosa Michelle Arlotto Paul AndersonTom Becker (Faculty) Heather HayesHans Hohmeier (Faculty) Jonathan HaldemanLarry Moss (Faculty) Jennifer Moss (Faculty)
CollaboratorsJames Bain (Faculty), Robert Stevens (Faculty), Brett Wenner, Olga Ilkayeva, Mike Muehlbauer, Stedman Center Core Laboratory; David Millington
Debbie Muoio, Tim Koves, Duke Stedman Center
Alan Attie, Mark Keller, University of Wisconsin
Bill Kraus, Svati Shah, E-Shyong Tai, Aslan Turer, Beth Hauser, Mihai Podgoreanu, Laura Svetkey, Lillian Lien, Andrea Haqq, Blandine LaFererre, Alfonso Torquati—Clinical Collaborators