About

Christopher Bang Newgard is the W. David and Sarah W. Stedman Distinguished Professor of Nutrition in the School of Medicine at Duke University. His research focuses on nutrition and its impact on health, as indicated by his title and position within the department. Further details about his specific research interests, background, or key contributions are not provided in the page text.

Research topics

• Medicine
• Internal medicine
• Biology
• Endocrinology
• Genetics
• Bioinformatics
• Biochemistry
• Physical medicine and rehabilitation
• Physical therapy
• Microbiology
• Computational biology
• Psychology

Selected publications

• Metabolic markers of kidney function and oxidative stress are associated with heart failure with preserved ejection fraction (HFpEF) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD)

  Metabolomics · 2026-04-28

  articleOpen access
  PublisherOA PDFDOI

• Dissecting the effect of mitochondrial BCAT inhibition in methylmalonic acidemia

  JCI Insight · 2025-09-08 · 3 citations

  articleOpen accessCorresponding

  Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic disorders. Metabolic flux analyses confirmed robust BCAT inhibition, with reduction of labeling of proximal and distal BCAA-derived metabolites in MMA hepatocytes. In vivo experiments verified the BCAT inhibition, but total levels of distal BCAA catabolite disease markers and clinical symptoms were not normalized, indicating contributions of substrates other than BCAA to these distal metabolite pools. Our study demonstrates the importance of understanding the underlying pathology of metabolic disorders for identification of therapeutic targets and the use of multiple, complementary models to evaluate them.

  PublisherOA PDFDOI

• 1727-P: Reduced Aromatic Amino Acid Suppression during Acute Hyperglycemia in Young Adults with Obesity

  Diabetes · 2025-06-13

  article

  Introduction and Objective: Hyperaminoacidemia due to impaired suppression of proteolysis is a hallmark of insulin resistance. We previously showed that healthy adults with obesity have lower brain glucose levels during hyperglycemia than lean controls, suggesting a blunted response to hyperglycemia in the central nervous system (CNS) paralleling that in the periphery. Here, we asked if peripheral amino acid changes during hyperglycemia are associated with brain glucose levels. Methods: We used targeted mass spectrometry-based metabolomic profiling to measure plasma amino acids, acylcarnitines, ceramides, and sphingomyelins in obesity and lean controls (n=8/group) who participated in a larger study using hyperglycemic clamp (target 180 mg/dL) coupled with 13C magnetic resonance spectroscopy to measure brain glucose. Results: There were no significant differences in HbA1c or insulin sensitivity between groups (obesity: age 27.3 ± 4.7 years; BMI 32.8 ± 2.6 kg/m2; A1c 5.4 ± 0.2%, HOMA-IR 3.4 ± 1.4 Matsuda index 4.1 ± 2.6; lean controls: age 27.3 ± 5.7 years; BMI 20.8 ± 1.8 kg/m2; A1c 5.4 ± 0.2%, HOMA-IR 2.4 ± 1.7, Matsuda index 5.6 ± 2.2). Acute hyperglycemia suppressed amino acids, but individuals with obesity had significantly less suppression of aromatic amino acids (AAAs, 6.4 ± 6.4% vs. 16.9 ± 7.8% reduction, p=0.01). There were no differences in branched chain amino acids. Higher aromatic amino acid levels were significantly correlated with lower brain glucose levels (ρ=-0.69, p<0.01). Conclusion: Obesity is associated with blunted central and peripheral responses to acute hyperglycemia. These changes may occur very early in the development of insulin resistance and prior to overt dysglycemia. Given that AAAs (phenylalanine, tryptophan, tyrosine) are precursors for key neurotransmitters, these findings suggest a potential mechanism for dysregulated post-prandial crosstalk between the CNS and periphery in obesity. Disclosure B.C. Matson: None. F. Gunawan: None. D.L. Rothman: None. G.F. Mason: Consultant; Merck & Co., Inc. Research Support; Pfizer Inc. Consultant; Leal Therapeutics. C.B. Newgard: Advisory Panel; Eli Lilly and Company, Novo Nordisk. Research Support; Boehringer-Ingelheim. J.J. Hwang: None. Funding National Institutes of Health (R01DK123227, P30DK124723)

  PublisherDOI

• Integration of metabolomic and transcriptomic analyses reveals regulatory functions of the ChREBP transcription factor in energy metabolism

  Cell Reports · 2025-02-01 · 10 citations

  articleOpen accessSenior author

  The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance.

  PublisherDOI

• Pathway Coessentiality Mapping Reveals Complex II is Required for <i>de novo</i> Purine Biosynthesis in Acute Myeloid Leukemia

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-02 · 2 citations

  preprintOpen access

  Abstract Understanding how cellular pathways interact is crucial for treating complex diseases like cancer, yet our ability to map these connections systematically remains limited. Individual gene-gene interaction studies have provided insights 1,2 , but they miss the emergent properties of pathways working together. To address this challenge, we developed a multi-gene approach to pathway mapping and applied it to CRISPR data from the Cancer Dependency Map 3 . Our analysis of the electron transport chain revealed certain blood cancers, including acute myeloid leukemia (AML), depend on an unexpected link between Complex II and purine metabolism. Through stable isotope metabolomic tracing, we found that Complex II directly supports de novo purine biosynthesis and exogenous purines rescue AML from Complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that Complex II must oxidize to sustain purine synthesis. This connection translated to a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML to Complex II inhibition. In mouse models, targeting Complex II triggered rapid disease regression and extended survival in aggressive AML. The clinical relevance of this pathway emerged in human studies, where higher Complex II gene expression correlates with both resistance to mitochondria-targeted therapies and worse survival outcomes specifically in AML patients. These findings establish Complex II as a central regulator of de novo purine biosynthesis and identify it as a promising therapeutic target in AML.

  PublisherOA PDFDOI

• Fiber Intervention Study in Prader-Willi Syndrome: Insights into Metabolic and Microbiota Shifts

  The Journal of Clinical Endocrinology & Metabolism · 2025-02-27 · 1 citations

  articleOpen access

  CONTEXT: While increased fiber intake may benefit appetite and metabolism in the general population, its effects in individuals with Prader-Willi syndrome (PWS), a condition characterized by hyperphagia, obesity, and metabolic dysregulation, remain to be explored. OBJECTIVE: This study assessed the effects of a fiber intervention on hyperphagia, metabolic health, and gut microbiota in individuals with PWS, and explored associations between changes in health markers and shifts in microbiota. METHODS: Participants received either a high-dose fiber intervention (35 g/day) or a control for 3 weeks. Following a washout period of 4 to 8 weeks, participants switched treatments for another 3 weeks. Fecal (bacterial 16S ribosomal RNA) and blood (immunometabolic markers, targeted metabolomics) samples were collected before and after each treatment. RESULTS: Fourteen participants (with a median age of 13.6 years, 8 [57.1%] were female) reported high tolerance to the fiber intervention. While it did not significantly alter hyperphagia or key metabolic markers, the fiber intervention led to shifts in gut microbiota diversity and increased the abundance of beneficial bacteria, such as Bifidobacterium longum and Faecalibacterium prausnitzii. Additionally, it altered fecal and serum metabolites, including a decrease in branched-chain fatty acids and an increase in serum C4-OH acylcarnitine. CONCLUSION: While this study did not observe significant changes in primary or secondary endpoints, it suggests that a short-term high-fiber intervention may induce beneficial shifts in gut microbiota and microbial metabolites in individuals with PWS. Further research is warranted to investigate the long-term effects and potential therapeutic applications of fiber interventions in PWS.

  PublisherOA PDFDOI

• Effects of the kinase inhibitor sorafenib on heart, muscle, liver and plasma metabolism in vivo using non‐targeted metabolomics analysis

  UNC Libraries · 2025-10-10 · 3 citations

  articleOpen access

  BACKGROUND AND PURPOSE: The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new kinase inhibitors developed to treat cancer, including sorafenib, also exhibit cardiotoxicity. We hypothesized that sorafenib cardiotoxicity is related to its deleterious effects on specific cardiac metabolic pathways given the critical roles of protein kinases in cardiac metabolism. EXPERIMENTAL APPROACH: FVB/N mice (10 per group) were challenged with sorafenib or vehicle control daily for 2&nbsp;weeks. Echocardiographic assessment of the heart identified systolic dysfunction consistent with cardiotoxicity in sorafenib-treated mice compared to vehicle-treated controls. Heart, skeletal muscle, liver and plasma were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. KEY RESULTS: Compared to vehicle-treated controls, sorafenib-treated hearts exhibited significant alterations in 11 metabolites, including markedly altered taurine/hypotaurine metabolism (25-fold enrichment), identified by pathway enrichment analysis. CONCLUSIONS AND IMPLICATIONS: These studies identified alterations in taurine/hypotaurine metabolism in the hearts and skeletal muscles of mice treated with sorafenib. Interventions that rescue or prevent these sorafenib-induced changes, such as taurine supplementation, may be helpful in attenuating sorafenib-induced cardiac injury.

  PublisherDOI

• Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia

  Nature Metabolism · 2025-12-05 · 2 citations

  articleOpen access

  Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.

  PublisherDOI

• 353-OR: Silencing of Mitochondrial Transaminase GPT2 in β-Cells Enhances Response to Antidiabetic Incretins

  Diabetes · 2025-06-13

  article

  Introduction and Objective: Despite promising incretin therapies for type 2 diabetes (T2D), many humans with T2D respond poorly to incretins, and the underlying mechanism is unclear. Methods: Human islets with GPT2 silencing and β-cell-specific Gpt2 knockout mice (Gpt2βKO) were used to study incretin response and β-cell survival. Results: We report that mitochondrial transaminase GPT2 was induced in glucolipotoxicity (GLT)-exposed non-diabetic (ND) islets and T2D islets (1.8 and 13.8-fold, respectively, P ≤0.01). Silencing GPT2 enhanced β-cell sensitivity to the GLP-1 receptor agonist Exendin4 (Ex4) (1.6 and 2.6-fold in ND and T2D islets, respectively, P≤0.01). Gpt2βKO mice had improved oral, but not intraperitoneal (IP), glucose tolerance and in vivo GSIS, highlighting improved incretin effect. Ex4 had a greater impact on IP GTT and GSIS in Gpt2βKO than Gpt2f/f mice (P≤0.05). Gpt2βKO islets showed enhanced response to Ex4 and GIP but not acetylcholine in static GSIS and in perifusion with 8 mM glucose and stepwise increase in [Ex-4] (EC50=169 nM vs 356 nM). Random blood glucose was lower in high-fat diet (HFD) fed Gpt2βKO mice (P≤0.01). HFD fed Gpt2βKO mice exhibited mildly improved IP GTT with no change in acute GSIS whereas OGTT and oral GSIS were markedly improved. After IP Ex4, HFD-fed Gpt2βKO mice exhibited lower glucose excursion than HFD-fed Gpt2f/f mice (-37%, P≤0.05). RNASeq revealed a reversal of metabolic stress-induced gene expression and upregulation of pro-survival genes in Gpt2βKO islets. β-cell silencing of human GPT2 reduced %TUNEL+ β-cells under GLT (1.3±0.2 vs 0.5±0.1, P ≤ 0.05) and T2D (1.2±0.2 vs 0.6±0.1, P≤0.05) conditions. Similarly, %TUNEL+ β-cells were reduced in GLT-exposed Gpt2βKO compared to Gpt2f/f islets (0.15±0.06 vs. 0.05±0.01, P ≤ 0.01) and Gpt2βKO mice showed improved β-cell mass (3.8±0.9 mg vs. 2.5±0.4 mg, P≤0.05) after HFD. Conclusion: GPT2 depletion enhances incretin sensitivity and supports β-cell survival, raising it as a therapeutic target to mitigate β-cell dysfunction in T2D Disclosure S. Sen: None. A.V. Rozo: None. M.W. Haemmerle: None. J. Roman: None. C. Juliana: None. S.A. Tersey: None. C.B. Newgard: Advisory Panel; Eli Lilly and Company, Novo Nordisk. Research Support; Boehringer-Ingelheim. D.A. Stoffers: Other Relationship; Amylyx. Funding National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK121175-03)

  PublisherDOI

• Branched chain amino acid metabolism and microbiome in adolescents with obesity during weight loss therapy

  medRxiv · 2025-02-04 · 2 citations

  preprintOpen access

  BACKGROUND: Obesity and weight loss in adults have been associated with distinct metabolome and gut microbiome features, but the extent to which those associations apply to adolescent stages remain unclear. METHODS: The Pediatric Obesity Microbiome and Metabolism Study (POMMS) enrolled 220 adolescents aged 10-18 with severe obesity (OB) and 67 healthy weight controls (HWC). Blood, stool, and clinical measures were collected at baseline and after a 6-month obesity intervention for the OB group. Metabolomic profiling in serum using targeted quantitative mass spectrometry and microbiome profiling in stool were performed, and those features were assessed for associations with BMI, insulin resistance, and inflammation. Fecal microbiome transplants were performed on germ-free mice using samples from both groups to assess effects on weight gain and metabolic pathways. RESULTS: Adolescents with OB exhibited higher serum branched-chain amino acid (BCAA) but lower ketoacid metabolite (BCKA) levels compared with HWC. This pattern was sex- and age-dependent, unlike adults with OB, who show elevated levels of both. Longitudinal analysis identified metabolic and microbial features correlated with changes in health measures during the intervention. The fecal microbiomes of adolescents with OB and HWC had similar diversity but differed in membership and functional potential. FMT from both OB and HWC donors had similar effects on mouse body weight, but specific taxa were linked to weight gain in FMT recipients. CONCLUSION: Adolescents with OB have unique metabolomic adaptations and microbiome signatures compared to their HWC counterparts and adults with OB. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03139877 (Observational Study) and NCT02959034 (Repository). FUNDING SOURCES: American Heart Association Grants: 17SFRN33670990, 20PRE35180195National Institute of Diabetes and Digestive and Kidney Diseases Grant: R24-DK110492.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R29DK040734

  NIH · $469k · 1993

• NIH Grant R37DK046492

  NIH · $3.5M · 2011

• Metabolomics Core

  NIH · $2.4M · 2020–2025

• Engineered Glucose Metabolism in Insulin Secreting Cells

  NIH · $8.8M · 1993–2026

• NIH Grant P01DK058398

  NIH · $45.3M · 2017

Frequent coauthors

• Olga Ilkayeva

  766 shared

• James R. Bain

  Duke University

  618 shared

• Michael J. Muehlbauer

  Duke Medical Center

  574 shared

• Robert D. Stevens

  407 shared

• Svati H. Shah

  Methodist Hospital

  189 shared

• Brett R. Wenner

  United States Air Force Research Laboratory

  183 shared

• Hans E. Hohmeier

  Duke University

  183 shared

• Thomas Becker

  University of Bonn

  139 shared

Labs

• Research by LabPI

Education

• PhD, Biochemistry

  The University of Texas Southwestern Medical Center Medical School