Brian O'Neill, MD, PhD
Associate Professor of Internal Medicine-Endocrinology and Metabolism
Primary Office
3314 Pappajohn Biomedical Discovery Building
Current Positions
- Associate Professor of Internal Medicine-Endocrinology and Metabolism
- Director, Endocrinology, Diabetes, and Metabolism Fellowship Program
Education
- MD/PhD, Biochemistry, University of Utah, Salt Lake City, Utah
- Resident, Internal Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Fellow, Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Graduate Program Affiliations
Center, Program and Institute Affiliations
Research Interests
- 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.
Licenses & Certifications
- Certification, American Board of Internal Medicine, Endocrinology, Diabetes, and Metabolism
- Certification, American Board of Internal Medicine
Selected Publications
- Bhardwaj G, Penniman CM, Klaus K, Weatherford ET, Pan H, Dreyfuss JM, Nair KS, Kahn CR, O'Neill BT. Transcriptomic Regulation of Muscle Mitochondria and Calcium Signaling by Insulin/IGF-1 Receptors Depends on FoxO Transcription Factors. Front Physiol. 2022 Feb 4;12:779121. PMID: 35185597
- Daneshgar N, Liang PI, Lan RS, Horstmann MM, Pack L, Bhardwaj G, Penniman CM, O'Neill BT, Dai DF. Elamipretide treatment during pregnancy ameliorates the progression of polycystic kidney disease in maternal and neonatal mice with PKD1 mutations. Kidney Int. 2021 Dec 22;S0085-2538(21)01164-9. PMID: 34953771
- Tadinada SM, Weatherford ET, Collins GV, Bhardwaj G, Cochran J, Kutschke W, Zimmerman K, Bosko A, O'Neill BT, Weiss RM, Abel ED. Functional resilience of c57bl/6j mouse heart to dietary fat overload. Am J Physiol Heart Circ Physiol. 2021 Sep 3. Online ahead of print. PMID: 34477461
- Homan EP, Brasil Brandao B, Softic S, El Ouaamari A, O'Neill BT, Kulkarni RN, Kim JK, Kahn CR. Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue. J Clin Invest. 2021 Aug 24:143328. Online ahead of print. PMID: 34428182
- Bhardwaj G, Penniman CM, Jena J, Suarez Beltran PA, Foster C, Poro K, Junck TL, Hinton AO Jr, Souvenir R, Fuqua JD, Morales PE, Bravo-Sagua R, Sivitz WI, Lira VA, Abel ED, O'Neill BT. Insulin and IGF-1 receptors regulate complex I-dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle. J Clin Invest. 2021 Sep 15;131(18):146415. PMID: 34343133
- Dougherty SM, Schommer J, Salinas JL, Zilles B, Belding-Schmitt M, Rogers WK, Shibli-Rahhal A, O'Neill BT. Immediate preoperative hyperglycemia correlates with complications in non-cardiac surgical cases. J Clin Anesth. 2021 Jun 16;74:110375 Online ahead of print. PMID: 34147016
- Cai W, Zhang X, Batista TM, García-Martín R, Softic S, Wang G, Ramirez AK, Konishi M, O'Neill BT, Kim JH, Kim JK, Kahn CR. Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens. Diabetes. 2021 May 24: Online ahead of print. PMID: 34031123
- Mishra A, Liu S, Promes J, Harata M, Sivitz W, Fink B, Bhardwaj G, O'Neill BT, Kang C, Sah R, Strack S, Stephens S, King T, Jackson L, Greenberg AS, Anokye-Danso F, Ahima RS, Ankrum J, Imai Y. Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria. JCI Insight. 2021 May 10;6(9):e144341. PMID: 33784258
- Skurski J, Penniman CM, Geesala R, Dixit G, Pulipati P, Bhardwaj G, Meyerholz DK, Issuree PD, O'Neill BT*, Maretzky T.* Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation. Metabolism. 2020 May;106:154194. PMID: 32135161 *-equal contribution
- Penniman CM, Suarez Beltran PA, Bhardwaj G, Junck TL, Jena J, Poro K, Hirshman MF, Goodyear LJ, O'Neill BT. Loss of FoxOs in muscle reveals sex-based differences in insulin sensitivity but mitigates diet-induced obesity. Mol Metab. 2019 Dec;30:203-220. PMID: 31767172