Obesity and cardiovascular disease are among the leading causes of morbidity and mortality worldwide. Our research focuses on the interplay between intermediary metabolism and these disease processes. Derangements in the processing of carbohydrates, fats, and amino acids are central drivers of disease pathogenesis, but the roles of another metabolic fuel class, ketone bodies, are less well understood. We use novel genetic mouse models with engineered deficiencies in ketone body metabolism to study the metabolic shifts that occur in response to obesity, cardiovascular disease, and dynamic environmental challenges. From these models, we have developed new perspectives of how metabolism adapts in obesity, diabetes, nonalcoholic fatty liver disease (NAFLD/NASH), and cardiomyopathy; how these adaptations ultimately prove deleterious, and how innovative and personalized nutritional and pharmacological therapies may mitigate these adverse responses.
We leverage recent advances in stable isotope tracer based NMR and mass spectrometry-based untargeted metabolomics technologies to study metabolism on a systems level, and we also employ established techniques in molecular cell biology and biochemistry to reveal phenotypic shifts at the cellular level. Complex in vivo phenotyping methodologies are strategically aligned with these sophisticated chemical profiling platforms to generate high resolution phenotypic pictures. In addition to our mouse studies, we perform studies in humans to learn how alterations of ketone metabolism and related pathways may serve as diagnostic biomarkers and therapeutic targets for obesity, diabetes, NAFLD/NASH, heart failure/CHF, and metabolic maladaptations that can occur in any disease state.
1. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics.
Puchalska P, Crawford PA.
Cell Metab. 2017;25(2):262-284.
2. Circulating Acylcarnitine Profile in Human Heart Failure: A Surrogate of Fatty Acid Metabolic Dysregulation in Mitochondria and Beyond.
Ruiz M, Labarthe F, Fortier A, Bouchard B, Thompson Legault J, Bolduc V, Rigal O, Chen J, Ducharme A, Crawford PA, Tardif JC, Des Rosiers C.
Am J Physiol Heart Circ Physiol. 2017 PMID: 28710072
3. Comprehensive and Quantitative Analysis of Polyphosphoinositide Species by Shotgun Lipidomics Revealed Their Alterations in db/db Mouse Brain.
Wang C, Palavicini JP, Wang M, Chen L, Yang K, Crawford PA, Han X.
Anal Chem. 2016 Dec 20;88(24):12137-12144.
4. Lactate metabolism is associated with mammalian mitochondria.
Chen YJ, Mahieu NG, Huang X, Singh M, Crawford PA, Johnson SL, Gross RW, Schaefer J, Patti GJ.
Nat Chem Biol. 2016;12(11):937-943.
5. The Failing Heart Relies on Ketone Bodies as a Fuel.
Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Krüger M, Hoppel CL, Lewandowski ED, Crawford PA, Muoio DM, Kelly DP.
6. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease.
Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, Kang S, Horvath TL, Fahmy TM, Crawford PA, Biragyn A, Alnemri E, Dixit VD.
Nat Med. 2015;21(3):263-9.
7. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling.
Schugar RC, Moll AR, André d'Avignon D, Weinheimer CJ, Kovacs A, Crawford PA.
Mol Metab. 2014;3(7):754-69.
8. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia.
Cotter DG, Ercal B, Huang X, Leid JM, d'Avignon DA, Graham MJ, Dietzen DJ, Brunt EM, Patti GJ, Crawford PA.
J Clin Invest. 2014; 124(12):5175-90.