Research

Unraveling the complex connection between ketone bodies and insulin resistance
P. Puchalska, Acta Physiologica, 2023, e14077

Metabolic Messengers: ketone bodies
Nelson AB, Queathem ED, Puchalska P, Crawford PA. Nat Metab. 2023 Dec;5(12):2062-2074. 

Ketone bodies in right ventricular failure: A unique therapeutic opportunity
Blake M, Puchalska P, Kazmirczak F, Blake J, Moon R, Thenappan T, Crawford PA, Prins KW. Heliyon. 2023 Nov 15;9(11):e22227.

Ketone ester administration improves glycemia in obese mice
Tabatabaei Dakhili SA, Yang K, Locatelli CAA, Saed CT, Greenwell AA, Chan JSF, Chahade JJ, Scharff J, Al-Imarah S, Eaton F, Crawford PA, Gopal K, Mulvihill EE, Ussher JR. Am J Physiol Cell Physiol. 2023 Sep 1;325(3):C750-C757.

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation
Luda KM, Longo J, Kitchen-Goosen SM, Duimstra LR, Ma EH, Watson MJ, Oswald BM, Fu Z, Madaj Z, Kupai A, Dickson BM, DeCamp LM, Dahabieh MS, Compton SE, Teis R, Kaymak I, Lau KH, Kelly DP, Puchalska P, Williams KS, Krawczyk CM, Lévesque D, Boisvert FM, Sheldon RD, Rothbart SB, Crawford PA, Jones RG. Immunity. 2023 Sep 12;56(9):2021-2035.e8.

Transcriptional metabolic reprogramming implements meiotic fate decision in mouse testicular germ cells
Zhang X, Liu Y, Sosa F, Gunewardena S, Crawford PA, Zielen AC, Orwig KE, Wang N. Cell Rep. 2023 Jul 25;42(7):112749.

ATP- Gated Potassium Channels Contribute to Ketogenic Diet Mediated Analgesia in Mice
J. Enders, S. Thomas, P. Lynch, S. J. Jack, J. M. Ryals, P. Puchalska, P.A. Crawford, D. E. Wright, Neurobiol Pain, 2023, 3; 14: 100138.

Gender-based heterogeneity of FAHFAs in trained runner
Nelson AB, Chow LS, Dengel DR, Pan M, Hughey CC, Han X, Puchalska P, Crawford PA. bioRxiv. 2023 Jun 8:2023.06.07.543941.

Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner Nashif SK, Mahr RM, Jena S, Jo S, Nelson AB, Sadowski D, Crawford PA, Puchalska P, Alejandro EU, Gearhart MD, Wernimont SA. Front Cell Dev Biol. 2023 May 12;11:1167097. doi: 10.3389/fcell.2023.1167097. 

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation Mahr RM, Jena S, Nashif SK, Nelson AB, Rauckhorst AJ, Rome FI, Sheldon RD, Hughey CC, Puchalska P, Gearhart MD, Taylor EB, Crawford PA, Wernimont SA. Sci Rep. 2023 May 6;13(1):7387. 

Ketolysis is required for the proper development and function of the somatosensory nervous system
Enders J, Jack J, Thomas S, Lynch P, Lasnier S, Cao X, Swanson MT, Ryals JM, Thyfault JP, Puchalska P, Crawford PA, Wright DE. Exp Neurol. 2023 Jul;365:114428. 

Ketones and the Heart: Metabolic Principles and Therapeutic Implications
Matsuura TR, Puchalska P, Crawford PA, Kelly DP. Circ Res. 2023 Mar 31;132(7):882-898. 

Defective muscle ketone body oxidation disrupts BCAA catabolism by altering mitochondrial branched-chain aminotransferase
Mechchate H, Abdualkader AM, Bernacchi JB, Gopal K, Tabatabaei Dakhili SA, Yang K, Greenwell AA, Kong X, Crawford PA, Al Batran R. Am J Physiol Endocrinol Metab. 2023 May 1;324(5):E425-E436. 
 
Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice
Rome FI, Shobert GL, Voigt WC, Stagg DB, Puchalska P, Burgess SC, Crawford PA, Hughey CC. Am J Physiol Endocrinol Metab. 2023 Jan 1;324(1):E9-E23.

The Antipsychotic Dopamine 2 Receptor Antagonist Diphenylbutylpiperidines Improve Glycemia in Experimental Obesity by Inhibiting Succinyl-CoA:3-Ketoacid CoA Transferase
Tabatabaei Dakhili SA, Greenwell AA, Yang K, Abou Farraj R, Saed CT, Gopal K, Chan JSF, Chahade JJ, Eaton F, Lee C, Velázquez-Martínez CA, Crawford PA, Glover JNM, Al Batran R, Ussher JR. Diabetes. 2023 Jan 1;72(1):126-134.

Krebs takes a turn at cell differentiation
Deja, S., Crawford, P.A., Burgess, S.C., Cell Metab. 2022, 34, 5, 658-660

Artifactual fatty acid dimers mimic FAHFA signals in untargeted metabolomics pipelines
Nelson A.B., Chow L.S., Hughey C.C., Crawford P.A., Puchalska P. JLR. 2022.

Acute aerobic exercise reveals FAHFAs distinguish the metabolomes of overweight and normal weight runners
Nelson AB, Chow L.S., Stagg D.B., Gillingham J.R., Evans M.D., Pan M., Hughey C.C., Myers C.L., Han X., Crawford P.A., Puchalska P. JCI Insight. 2022. doi: 10.1172/jci.insight.158037

Ketone body oxidation increases cardiac endothelial cell proliferation
Weis E.M., Puchalska P., Nelson A.B., Taylor J., Moll I., Hasan S.S., Dewnter M., Hagenmueller M., Fleming T., Poschet G., Hotz-Wagenblatt A., Backs J., Crawford P.A., Fischer A. EMBO Mol Med (2022)e14753, doi: 10.15252/emmm.202114753

Metabolic and Signaling Roles of Ketone Bodies in Health and Disease
Puchalska P, Crawford PA; Annu. Rev. Nutr. 2021, October 11, 41, 49-77, doi.org/10.1146/annurev-nutr-111120-111518

Diminished ketone interconversion, hepatic TCA cycle flux, and glucose production in D-β-hydroxybutyrate dehydrogenase hepatocyte-deficient mice
Stagg DB, Gillingham JR, Nelson AB, Lengfeld JE, d’Avignon DA, Puchalska P, Crawford PA
Mol Metab. 2021 Jun 8;101269. doi: 10.1016/j.molmet.2021.101269

Determination of ketone bodies in biological samples via rapid UPLC-MS/MS
Puchalska P, Nelson AB, Stagg DB, Crawford PA
Talanta Volume 225, 1 April 2021; 122048. PMID: 33592770

Mitochondrial pyruvate carriers are required for myocardial stress adaptation
Zhang Y, Taufalele PV, Cochran JD, Robillard-Frayne I, Marx JM, Soto J, Rauckhorst AJ, Tayyari F, Pewa AD, Gray LR, Teesch LM, Puchalska P, Funari TR, McGlauflin R, Zimmerman K, Kutschke WJ, Cassier T, Hitchcock S, Lin K, Kato KM, Stueve JL, Haff L, Weiss RM, Cox JE, Rutter J, Taylor EB, Crawford PA, Lewandowski ED, Des Rosiers C, Abel ED.
Nat Metab. 2020 Oct 26. doi: 10.1038/s42255-020-00288-1. PMID: 33106689 0

Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation
Al Batran R, Gopal K, Capozzi ME, Chahade JJ, Saleme B, Tabatabaei-Dakhili SA, Greenwell AA, Niu J, Almutairi M, Byrne NJ, Masson G, Kim R, Eaton F, Mulvihill EE, Garneau L, Masters AR, Desta Z, Velázquez-Martínez CA, Aguer C, Crawford PA, Sutendra G, Campbell JE, Dyck JRB, Ussher JR.
Cell Metab. 2020 May 5;31(5):909-919.e8. doi: 10.1016/j.cmet.2020.03.017. Epub 2020 Apr 9. PMID: 32275862

Nonalcoholic Steatohepatitis: A Review
Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S.
JAMA. 2020 Mar 24;323(12):1175-1183. doi: 10.1001/jama.2020.2298. PMID: 32207804.

Ketogenic therapies for lymphedema?
Puchalska P, Crawford PA.
Nat Metab. 2019 Jul;1(7):656-657. doi: 10.1038/s42255-019-0090-3.PMID: 32694645.

Pyruvate Carboxylase Wields a Double-Edged Metabolic Sword
Hughey CC, Crawford PA.
Cell Metab. 2019 Jun 4;29(6):1236-1238. doi: 10.1016/j.cmet.2019.05.013.PMID: 31167118.

Application of Stable Isotope Labels for Metabolomics in Studies in Fatty Liver Disease
Puchalska P, Crawford PA.
Methods Mol Biol. 2019; 1996:259-272. doi: 10.1007/978-1-4939-9488-5_20.PMID: 31127561

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense
Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, Petucci C, Lewandowski ED, Crawford PA, Muoio DM, Recchia FA, Kelly DP
JCI Insight. 2019 Feb 21;4(4):e124079. doi: 10.1172/jci.insight.124079. eCollection 2019 Feb 21.PMID: 30668551.

Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis
Puchalska P, Martin SE, Huang X, Lengfeld JE, Daniel B, Graham MJ, Han X, Nagy L, Patti GJ, Crawford PA.
Cell Metab. 2019 Feb 5;29(2):383-398.e7. doi: 10.1016/j.cmet.2018.10.015. Epub 2018 Nov 15.PMID: 30449686.

Transport-exclusion pharmacology to localize lactate dehydrogenase activity within cells
Niu X, Chen YJ, Crawford PA, Patti GJ.
Cancer Metab. 2018 Dec 12;6:19. doi: 10.1186/s40170-018-0192-5. eCollection 2018.PMID: 30559963

Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure
Wang C, Liu F, Frisch-Daiello JL, Martin S, Patterson TA, Gu Q, Liu S, Paule MG, Hanig JP, Slikker W Jr, Crawford PA, Wang C, Han X.
Anal Chim Acta. 2018 Dec 11;1037:87-96. doi: 10.1016/j.aca.2017.11.052. Epub 2017 Nov 30.PMID: 30292318.

Isotope Tracing Untargeted Metabolomics Reveals Macrophage Polarization-State-Specific Metabolic Coordination across Intracellular Compartments
Puchalska P, Huang X, Martin SE, Han X, Patti GJ, Crawford PA.
iScience. 2018 Nov 30;9:298-313. doi: 10.1016/j.isci.2018.10.029. Epub 2018 Nov 2.PMID: 30448730.

Refueling the Failing Heart: A Case for Sodium-Glucose Cotransporter 2 Inhibition in Cardiac Energy Homeostasis
Crawford PA.
JACC Basic Transl Sci. 2018 Aug 26;3(5):588-590. doi: 10.1016/j.jacbts.2018.08.002. eCollection 2018 Oct.PMID: 30456330.

Ketone bodies as epigenetic modifiers
Ruan HB, Crawford PA.
Curr Opin Clin Nutr Metab Care. 2018 Jul;21(4):260-266. doi: 0.1097/MCO.0000000000000475.PMID: 29697540.

Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome
d'Avignon DA, Puchalska P, Ercal B, Chang Y, Martin SE, Graham MJ, Patti GJ, Han X, Crawford PA.
JCI Insight. 2018 Jun 21;3(12):e99762. doi: 10.1172/jci.insight.99762. eCollection 2018 Jun 21.PMID: 29925686.

Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin
Polidori D, Iijima H, Goda M, Maruyama N, Inagaki N, Crawford PA.
Diabetes Obes Metab. 2018 May;20(5):1321-1326. doi: 10.1111/dom.13224. Epub 2018 Feb 14.PMID: 29341404.

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 Oct 1;313(4):H768-H781. doi: 10.1152/ajpheart.00820.2016. Epub 2017 Jul 14.PMID: 28710072

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics
Puchalska P, Crawford PA.
Cell Metab. 2017 Feb 7;25(2):262-284. doi: 10.1016/j.cmet.2016.12.022.PMID: 28178565. 

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. doi: 10.1021/acs.analchem.6b02947. Epub 2016 Dec 1.PMID: 28193056

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 Nov;12(11):937-943. doi: 10.1038/nchembio.2172. Epub 2016 Sep 12.PMID: 27618187.

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.
Circulation. 2016 Feb 23;133(8):698-705. doi: 10.1161/CIRCULATIONAHA.115.017355. Epub 2016 Jan 27.PMID: 26819376.

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 Mar;21(3):263-9. doi: 10.1038/nm.3804. Epub 2015 Feb 16.PMID: 25686106.

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.
Clin Invest. 2014 Dec;124(12):5175-90. doi: 10.1172/JCI76388. Epub 2014 Oct 27.PMID: 25347470.

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 Aug 13;3(7):754-69. doi: 10.1016/j.molmet.2014.07.010. eCollection 2014 Oct.PMID: 25353003.

Impairments of hepatic gluconeogenesis and ketogenesis in PPARα-deficient neonatal mice
Cotter DG, Ercal B, d'Avignon DA, Dietzen DJ, Crawford PA.
Am J Physiol Endocrinol Metab. 2014 Jul 15;307(2):E176-85. doi: 10.1152/ajpendo.00087.2014. Epub 2014 May 27.PMID: 24865983.U

X13CMS: global tracking of isotopic labels in untargeted metabolomics
Huang X, Chen YJ, Cho K, Nikolskiy I, Crawford PA, Patti GJ.
Anal Chem. 2014 Feb 4;86(3):1632-9. doi: 10.1021/ac403384n. Epub 2014 Jan 24.PMID: 24397582.

Role of choline deficiency in the Fatty liver phenotype of mice fed a low protein, very low carbohydrate ketogenic diet
Schugar RC, Huang X, Moll AR, Brunt EM, Crawford PA.
PLoS One. 2013 Aug 29;8(8):e74806. doi: 10.1371/journal.pone.0074806. eCollection 2013.PMID: 24009777.

Impact of peripheral ketolytic deficiency on hepatic ketogenesis and gluconeogenesis during the transition to birth
Cotter DG, Ercal B, d'Avignon DA, Dietzen DJ, Crawford PA.
J Biol Chem. 2013 Jul 5;288(27):19739-49. doi: 10.1074/jbc.M113.454868. Epub 2013 May 20.PMID: 23689508.

PGC-1β and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner
Chambers KT, Chen Z, Lai L, Leone TC, Towle HC, Kralli A, Crawford PA, Finck BN.
Mol Metab. 2013 May 9;2(3):194-204. doi: 10.1016/j.molmet.2013.05.001. eCollection 2013.PMID: 24049734.

Ketone body metabolism and cardiovascular disease
Cotter DG, Schugar RC, Crawford PA.
Am J Physiol Heart Circ Physiol. 2013 Apr 15;304(8):H1060-76. doi: 10.1152/ajpheart.00646.2012. Epub 2013 Feb 8.PMID: 23396451.

Metabolic stress in the myocardium: adaptations of gene expression
Crawford PA, Schaffer JE.
J Mol Cell Cardiol. 2013 Feb;55:130-8. doi: 10.1016/j.yjmcc.2012.06.008. Epub 2012 Jun 21.PMID: 22728216.

Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation
Cotter DG, Schugar RC, Wentz AE, d'Avignon DA, Crawford PA.
Am J Physiol Endocrinol Metab. 2013 Feb 15;304(4):E363-74. doi: 10.1152/ajpendo.00547.2012. Epub 2012 Dec 11.PMID: 23233542.

Liver-specific PGC-1beta deficiency leads to impaired mitochondrial function and lipogenic response to fasting-refeeding
Chambers KT, Chen Z, Crawford PA, Fu X, Burgess SC, Lai L, Leone TC, Kelly DP, Finck BN.
PLoS One. 2012;7(12):e52645. doi: 10.1371/journal.pone.0052645. Epub 2012 Dec 28.PMID: 23285128.

Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease
Schugar RC, Crawford PA.
Curr Opin Clin Nutr Metab Care. 2012 Jul;15(4):374-80. doi: 10.1097/MCO.0b013e3283547157.PMID: 22617564.

Altered systemic ketone body metabolism in advanced heart failure
Janardhan A, Chen J, Crawford PA.
Tex Heart Inst J. 2011;38(5):533-8.PMID: 22163128.

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet
Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, Ezenwajiaku N, Cotter DG, Brunt EM, Crawford PA.
Am J Physiol Gastrointest Liver Physiol. 2011 Jun;300(6):G956-67. doi: 10.1152/ajpgi.00539.2010. Epub 2011 Mar 31.PMID: 21454445.

Obligate role for ketone body oxidation in neonatal metabolic homeostasis
Cotter DG, d'Avignon DA, Wentz AE, Weber ML, Crawford PA.
J Biol Chem. 2011 Mar 4;286(9):6902-10. doi: 10.1074/jbc.M110.192369. Epub 2011 Jan 5.PMID: 21209089.

Akt2 deficiency promotes cardiac induction of Rab4a and myocardial β-adrenergic hypersensitivity
Etzion S, Etzion Y, DeBosch B, Crawford PA, Muslin AJ.
J Mol Cell Cardiol. 2010 Dec;49(6):931-40. doi: 10.1016/j.yjmcc.2010.08.011. Epub 2010 Aug 20.PMID: 20728450.

Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment
Wentz AE, d'Avignon DA, Weber ML, Cotter DG, Doherty JM, Kerns R, Nagarajan R, Reddy N, Sambandam N, Crawford PA.
J Biol Chem. 2010 Aug 6;285(32):24447-56. doi: 10.1074/jbc.M110.100651. Epub 2010 Jun 7.PMID: 20529848.

Epitope mapping in cell surface proteins by site-directed masking: defining the structural elements of NTPDase3 inhibition by a monoclonal antibody
Ivanenkov VV, Crawford PA, Toyama A, Sévigny J, Kirley TL.
Protein Eng Des Sel. 2010 Jul;23(7):579-88. doi: 10.1093/protein/gzq027. Epub 2010 May 27.PMID: 20511214.

Coordinated regulation of the metabolome and lipidome at the host-microbial interface
Bäckhed F, Crawford PA.
Biochim Biophys Acta. 2010 Mar;1801(3):240-5. doi: 10.1016/j.bbalip.2009.09.009. Epub 2009 Sep 24.PMID: 19782151.

Regulation of myocardial ketone body metabolism by the gut microbiota during nutrient deprivation
Crawford PA, Crowley JR, Sambandam N, Muegge BD, Costello EK, Hamady M, Knight R, Gordon JI.
Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11276-81. doi: 10.1073/pnas.0902366106. Epub 2009 Jun 22.PMID: 19549860. 

Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis
Hughey C.C, Puchalska P., Crawford P., Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Aug, doi.org/10.1016/j.bbalip.2022.159209

Disrupted liver oxidative metabolism in glycine N-methyltransferase-deficient mice is mitigated by dietary methionine restriction
Rome F.I., Hughey C.C, Mol Metab, 2022, Feb 2; 101452, doi: 10.1016/j.molmet.2022.101452

Multitissue 2H/13C flux analysis reveals reciprocal upregulation of renal gluconeogenesis in hepatic PEPCK-C-knockout mice.
Mohsin Rahim, Clinton M Hasenour, Tomasz K Bednarski, Curtis C Hughey, David H Wasserman, Jamey D Young
JCI Insight. 2021 Jun 22;6(12):149278. doi: 10.1172/jci.insight.149278.

Rose Ankeriasniemi, Researcher, Crawford Lab and Puchalska Lab

Briana Clifton, Sarah Wernimont Lab

Kyle Fulghum, Postdoctoral Associate, Crawford and Puchalska Lab

Abdirahman Hayir, Researcher, Crawford and Puchalska lab

Sneha Jena, Researcher, Wernimont lab

Cassie Norbeck, Researcher, Wernimont Lab

Andres Ortega, Postdoctoral Associate, Hughey Lab

Lakshana Sadu Murari, Sarah Wernimont Lab

Kara Peak, Sarah Wernimont Lab

Ruth Pfeiffer, Curtis Hughey Lab

Eric Queathem, PhD thesis student, Biochemistry, Molecular Biology, and Biophysics Program, Crawford and Puchalska lab

Cha Mee Vang, Hughey Lab