Welcome to the O'Neill Lab
I have been most fortunate to join the laboratory of Dr. C. Ronald Kahn during my endocrinology fellowship and beyond. My work thus far has investigated two interesting components of skeletal muscle physiology. In the projects which I developed under the tutelage of Dr. Kahn, I have investigated the impact of combined loss of insulin receptor (IR) and IGF-1 receptor (IGFR) signaling in skeletal muscle on glucose metabolism and protein turnover. Using mouse models, we show that loss of IR/IGFR in muscle does not lead to diabetes or changes in whole body glucose homeostasis, primarily due to increased basal glucose uptake when IR and IGFR are deleted. However, loss of IR/IGFR does markedly affect muscle mass by dysregulated protein turnover and autophagy, which is regulated chiefly by FoxO transcription factors. These findings are clinically relevant because skeletal muscle insulin resistance is a cardinal feature of type 2 diabetes and metabolic syndrome, and loss of muscle strength is accelerated in older individuals with uncontrolled type 2 diabetes, putting these patients at higher risk for injury and disability. In addition, I am testing the effects of genetic loss of IR/IGFR signaling, as well as diet-induced obesity and streptozotocin-induced diabetes, on muscle transcriptomics by RNA-seq techniques, and metabolite profiles using an unbiased large-scale metabolomics approach. Along with my expertise in mitochondrial studies, I plan to interrogate these data sets to discover metabolic pathways that are perturbed in states of insulin deficiency and insulin resistance. We hope these results will provide better insight into the metabolic complications and dysregulation of muscle physiology that occur in obesity and diabetes, and potentially identify novel therapeutic targets for treatment of these diseases. Ultimately, I plan to build a career studying the impact of diabetes and insulin resistance on protein turnover and mitochondrial metabolism.
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.
Softic S, Gupta MK, Wang GX, Fujisaka S, O'Neill BT, Rao TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR.
J Clin Invest. 2017 Oct 3. pii: 94585. doi: 10.1172/JCI94585.
Glucose transporter 4 (GLUT4) deficient hearts develop maladaptive hypertrophy in response to physiologic or pathologic stresses.
Wende AR, Kim J, Holland W, Wayment BE, O'Neill BT, Tuinei J, Brahma MK, Pepin ME, McCrory MA, Luptak I, Halade GV, Litwin SE, Abel ED.
Am J Physiol Heart Circ Physiol. 2017 Aug 19:ajpheart.00101.2017. doi: 10.1152/ajpheart.00101.2017.
Insulin Regulation of Proteostasis and Clinical Implications.
James HA, O'Neill BT, Nair KS.
Cell Metab. 2017 Aug 1;26(2):310-323. doi: 10.1016/j.cmet.2017.06.010. Epub 2017 Jul 14. Review.
Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression.
Cai W, Sakaguchi M, Kleinridders A, Gonzalez-Del Pino G, Dreyfuss JM, O'Neill BT, Ramirez AK, Pan H, Winnay JN, Boucher J, Eck MJ, Kahn CR.
Nat Commun. 2017 Mar 27;8:14892. doi: 10.1038/ncomms14892.
Adipocyte Dynamics and Reversible Metabolic Syndrome in Mice with an Inducible Adipocyte-Specific Deletion of the Insulin Receptor.
Sakaguchi M, Fujisaka S, Cai W, Winnay JN, Konishi M, O'Neill BT, Li M, García-Martín R, Takahashi H, Hu J, Kulkarni RN, Kahn CR.
Cell Metab. 2017 Feb 7;25(2):448-462. doi: 10.1016/j.cmet.2016.12.008. Epub 2017 Jan 5.
Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.
Butler CR, Ogilvie K, Martinez-Alsina L, Barreiro G, Beck EM, Nolan CE, Atchison K, Benvenuti E, Buzon L, Doran S, Gonzales C, Helal CJ, Hou X, Hsu MH, Johnson EF, Lapham K, Lanyon L, Parris K, O'Neill BT, Riddell D, Robshaw A, Vajdos F, Brodney MA.
J Med Chem. 2017 Jan 12;60(1):386-402. doi: 10.1021/acs.jmedchem.6b01451. Epub 2016 Dec 20.
Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors.
Zuhl AM, Nolan CE, Brodney MA, Niessen S, Atchison K, Houle C, Karanian DA, Ambroise C, Brulet JW, Beck EM, Doran SD, O'Neill BT, Am Ende CW, Chang C, Geoghegan KF, West GM, Judkins JC, Hou X, Riddell DR, Johnson DS.
Nat Commun. 2016 Oct 11;7:13042. doi: 10.1038/ncomms13042.
Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells.
Wang X, Lockhart SM, Rathjen T, Albadawi H, Sørensen D, O'Neill BT, Dwivedi N, Preil SR, Beck HC, Dunwoodie SL, Watkins MT, Rasmussen LM, Rask-Madsen C.
Diabetes. 2016 Dec;65(12):3680-3690. Epub 2016 Aug 25.
Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis.
O'Neill BT, Lee KY, Klaus K, Softic S, Krumpoch MT, Fentz J, Stanford KI, Robinson MM, Cai W, Kleinridders A, Pereira RO, Hirshman MF, Abel ED, Accili D, Goodyear LJ, Nair KS, Kahn CR.
J Clin Invest. 2016 Sep 1;126(9):3433-46. doi: 10.1172/JCI86522. Epub 2016 Aug 15.