Christopher Newgard

Overview:

Over its 16 year history, our laboratory has investigated mechanisms of metabolic regulation and fuel homeostasis in mammalian systems. Major projects include: 1) Mechanisms involved in regulation of insulin secretion from pancreatic islet β-cells by glucose and other metabolic fuels; 2) Development of methods for protection of β-cells against immune-mediated damage; 3) Studies on spatial organization and regulation of systems controlling hepatic glucose balance; 4) Studies on the mechanisms involved in lipid-induced impairment of insulin secretion and action in diabetes.

Positions:

W. David and Sarah W. Stedman Distinguished Professor of Nutrition in the School of Medicine

Pharmacology & Cancer Biology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Director, Sarah W. Stedman Nutrition and Metabolism Center

Sarah Stedman Nutrition & Metabolism Center
School of Medicine

Professor of Biochemistry

Biochemistry
School of Medicine

Professor in Medicine

Medicine, Endocrinology, Metabolism, and Nutrition
School of Medicine

Affiliate, Duke Global Health Institute

Duke Global Health Institute
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1984

University of Texas at Dallas

Grants:

Iron homeostasis in mammalian muscle

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

G(alpha)Z signaling in insulin secretion and glucose tolerance

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

The Branched Chain Ketoacid Dehydrogenase Kinase-Phosphatase System as a New Regulatory Node in Myocardial Fuel Section

Administered By
Sarah Stedman Nutrition & Metabolism Center
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Post-Translational and Epigenetic Control of Branched-Chain Amino Acid Metabolism

Administered By
Sarah Stedman Nutrition & Metabolism Center
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

The Effects of a Novel Statin-Induced Protein Modification on Fatty Acid Synthase

Administered By
Sarah Stedman Nutrition & Metabolism Center
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

Publications:

Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions.

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic biomarkers that are associated with beneficial metabolic changes to weight loss and which distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N = 443), STRRIDE-PD (exercise intervention, N = 163), and CBD (surgical cohort, N = 125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%ΔHOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %ΔHOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p = 2.3e-5) and diacylglycerols (DAGs; p = 1.6e-4), with higher baseline TAG and DAG levels associated with a greater improvement in insulin resistance with weight loss. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.
Authors
Bihlmeyer, NA; Kwee, LC; Clish, CB; Deik, AA; Gerszten, RE; Pagidipati, NJ; Laferrère, B; Svetkey, LP; Newgard, CB; Kraus, WE; Shah, SH
MLA Citation
Bihlmeyer, Nathan A., et al. “Metabolomic profiling identifies complex lipid species and amino acid analogues associated with response to weight loss interventions.Plos One, vol. 16, no. 5, Jan. 2021, p. e0240764. Epmc, doi:10.1371/journal.pone.0240764.
URI
https://scholars.duke.edu/individual/pub1482896
PMID
34043632
Source
epmc
Published In
Plos One
Volume
16
Published Date
Start Page
e0240764
DOI
10.1371/journal.pone.0240764

Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.

BACKGROUND: A strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades. SCOPE OF REVIEW: More recently, human metabolomics and genetic studies have confirmed and expanded upon these observations, accompanied by a surge in preclinical studies that have identified mechanisms involved in the perturbation of amino acid homeostasis- how these events are connected to dysregulated glucose and lipid metabolism, and how elevations in branched-chain amino acids (BCAA) may participate in the development of insulin resistance, type 2 diabetes (T2D), and other cardiometabolic diseases and conditions. MAJOR CONCLUSIONS: In human cohorts, BCAA and related metabolites are now well established as among the strongest biomarkers of obesity, insulin resistance, T2D, and cardiovascular diseases. Lowering of BCAA and branched-chain ketoacid (BCKA) levels by feeding BCAA-restricted diet or by the activation of the rate-limiting enzyme in BCAA catabolism, branched-chain ketoacid dehydrogenase (BCKDH), in rodent models of obesity have clear salutary effects on glucose and lipid homeostasis, but BCAA restriction has more modest effects in short-term studies in human T2D subjects. Feeding of rats with diets enriched in sucrose or fructose result in the induction of the ChREBP transcription factor in the liver to increase expression of the BCKDH kinase (BDK) and suppress the expression of its phosphatase (PPM1K) resulting in the inactivation of BCKDH and activation of the key lipogenic enzyme ATP-citrate lyase (ACLY). These and other emergent links between BCAA, glucose, and lipid metabolism motivate ongoing studies of possible causal actions of BCAA and related metabolites in the development of cardiometabolic diseases.
Authors
White, PJ; McGarrah, RW; Herman, MA; Bain, JR; Shah, SH; Newgard, CB
MLA Citation
White, Phillip J., et al. “Insulin action, type 2 diabetes, and branched-chain amino acids: A two-way street.Mol Metab, vol. 52, Oct. 2021, p. 101261. Pubmed, doi:10.1016/j.molmet.2021.101261.
URI
https://scholars.duke.edu/individual/pub1482897
PMID
34044180
Source
pubmed
Published In
Molecular Metabolism
Volume
52
Published Date
Start Page
101261
DOI
10.1016/j.molmet.2021.101261

Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy.

BACKGROUND: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM. METHODS: Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed. RESULTS: A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p  =  2 × 10-7, and were differentially associated in participants with and without DM (beta 1.58, p  =  8  ×  10-8 vs. 0.67, p  =  9  ×  10-4, respectively; p value for interaction  =  0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p  =  0.24) than in those without DM (mean ∆ 0.16, p  =  0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p  =  2.74  ×  10-8), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p  =  3.21  ×  10-9 v. HR 0.90, p  =  0.104, p value for interaction  =  0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study. CONCLUSIONS: LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM. Trial Registration clinicaltrials.gov Identifier: NCT00047437.
Authors
Truby, LK; Regan, JA; Giamberardino, SN; Ilkayeva, O; Bain, J; Newgard, CB; O'Connor, CM; Felker, GM; Kraus, WE; McGarrah, RW; Shah, SH
MLA Citation
Truby, Lauren K., et al. “Circulating long chain acylcarnitines and outcomes in diabetic heart failure: an HF-ACTION clinical trial substudy.Cardiovasc Diabetol, vol. 20, no. 1, Aug. 2021, p. 161. Pubmed, doi:10.1186/s12933-021-01353-z.
URI
https://scholars.duke.edu/individual/pub1492751
PMID
34344360
Source
pubmed
Published In
Cardiovascular Diabetology
Volume
20
Published Date
Start Page
161
DOI
10.1186/s12933-021-01353-z

BCAA Supplementation in Mice with Diet-induced Obesity Alters the Metabolome Without Impairing Glucose Homeostasis.

Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is still ill-defined. Here we examined how high-fat high-sucrose (HFHS) or high-fat diet (HFD) feeding, with or without BCAA supplementation in water, alters the metabolome in serum/plasma and tissues in mice and whether raising circulating BCAA levels worsens insulin resistance and glucose intolerance. Neither HFHS nor HFD feeding raised circulating BCAA levels in insulin-resistant diet-induced obese mice. BCAA supplementation raised circulating BCAA and branched-chain α-keto acid levels and C5-OH/C3-DC acylcarnitines (AC) in muscle from mice fed an HFHS diet or HFD, but did not worsen insulin resistance. A set of short- and long-chain acyl CoAs were elevated by diet alone in muscle, liver, and white adipose tissue (WAT), but not increased further by BCAA supplementation. HFD feeding reduced valine and leucine oxidation in WAT but not in muscle. BCAA supplementation markedly increased valine oxidation in muscle from HFD-fed mice, while leucine oxidation was unaffected by diet or BCAA treatment. Here we establish an extensive metabolome database showing tissue-specific changes in mice on 2 different HFDs, with or without BCAA supplementation. We conclude that mildly elevating circulating BCAAs and a subset of ACs by BCAA supplementation does not worsen insulin resistance or glucose tolerance in mice. This work highlights major differences in the effects of BCAAs on glucose homeostasis in diet-induced obese mice versus data reported in obese rats and in humans.
Authors
Lee, J; Vijayakumar, A; White, PJ; Xu, Y; Ilkayeva, O; Lynch, CJ; Newgard, CB; Kahn, BB
MLA Citation
Lee, Jennifer, et al. “BCAA Supplementation in Mice with Diet-induced Obesity Alters the Metabolome Without Impairing Glucose Homeostasis.Endocrinology, vol. 162, no. 7, July 2021. Epmc, doi:10.1210/endocr/bqab062.
URI
https://scholars.duke.edu/individual/pub1477000
PMID
33765118
Source
epmc
Published In
Endocrinology
Volume
162
Published Date
DOI
10.1210/endocr/bqab062

Gut microbiome contributions to altered metabolism in a pig model of undernutrition.

The concept that gut microbiome-expressed functions regulate ponderal growth has important implications for infant and child health, as well as animal health. Using an intergenerational pig model of diet restriction (DR) that produces reduced weight gain, we developed a feature-selection algorithm to identify representative characteristics distinguishing DR fecal microbiomes from those of full-fed (FF) pigs as both groups consumed a common sequence of diets during their growth cycle. Gnotobiotic mice were then colonized with DR and FF microbiomes and subjected to controlled feeding with a pig diet. DR microbiomes have reduced representation of genes that degrade dominant components of late growth-phase diets, exhibit reduced production of butyrate, a key host-accessible energy source, and are causally linked to reduced hepatic fatty acid metabolism (β-oxidation) and the selection of alternative energy substrates. The approach described could aid in the development of guidelines for microbiome stewardship in diverse species, including farm animals, in order to support their healthy growth.
Authors
Chang, H-W; McNulty, NP; Hibberd, MC; O'Donnell, D; Cheng, J; Lombard, V; Henrissat, B; Ilkayeva, O; Muehlbauer, MJ; Newgard, CB; Barratt, MJ; Lin, X; Odle, J; Gordon, JI
MLA Citation
Chang, Hao-Wei, et al. “Gut microbiome contributions to altered metabolism in a pig model of undernutrition.Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 21, May 2021. Epmc, doi:10.1073/pnas.2024446118.
URI
https://scholars.duke.edu/individual/pub1483273
PMID
34001614
Source
epmc
Published In
Proceedings of the National Academy of Sciences of the United States of America
Volume
118
Published Date
DOI
10.1073/pnas.2024446118