Ph.D., University of Illinois, 1982
NIH Postdoctoral Fellow, The Johns Hopkins School of Medicine, 1985
The Bernlohr laboratory is focused on understanding the molecular alterations that arise due to obesity, from the expanded adipose tissue to its associated pathologies, including type 2 diabetes, inflammation and cancer (Bernlohr). Within that goal, projects within the lab can be grouped into three major themes:
Adipose Biology and Obesity Linked Insulin Resistance: Role of FABPs, UCP2, and Inflammation
A major research area in the laboratory focuses on the metabolic relationships between obesity and insulin action. Many studies have shown a strong connection of obesity to chronic, low-grade inflammatory state in adipose tissue. Using a combination of biochemical, biophysical and molecular methodologies, the laboratory studies adipocytes, as well as the accumulation of inflammatory macrophages and other immune cells in adipose tissue. Specifically we examine fatty acid binding proteins and their role(s) in mediating fatty acid metabolism in adipocytes and macrophages. The adipocyte fatty acid binding protein (FABP4) binds a long chain fatty acid, providing solubility and proper cellular trafficking of fatty acids. Using FABP4 null animal models, we (and others) have shown a major protection from obesity-dependent diseases. Recently, we have discovered an inverse relationship in the expression of FABP4 and uncoupling protein 2 (UCP2) in adipose macrophages, and furthermore that UCP2 underlies many of the protective affects of reduced FABP4 expression. These experiments demonstrate the importance of the metabolic flexibility in macrophages, ie altered fatty acid fates, as contributors to health and disease. Such studies provide a framework for the analysis of obesity-linked insulin resistance.
Josephrajan, A., Hertzel, A.V., Bohm, E.K., McBurney, M.W., Imai, S.-I., Mashek, D., Kim, D.H. and Bernlohr, D.A. (2019) Unconventional Protein Secretion of FABP4 Is Mediated By Autophagy In A SIRT1 Dependent Manner. Diabetes 68; 1767-1777 doi: 10.2337/db18-1367
Najt, C.P., Khan, S.A., Heden, T.D., Witthuhn, B.A., Perez, M., Mead, L.E., Franklin, M.P., Karanja, K.K., Mashek, M.T., Bernlohr, D.A., Parker, L., Chow, L. and Mashek, D.G. (2019) Lipid droplet-derived monounsaturated fatty acids traffic via PLIN5 to allosterically activate SIRT1. Molecular Cell 77(4):810-824.e8. doi: 10.1016/j.molcel.2019.12.003.
Hertzel, A.V., Xu, H., Downey, M., Kvalheim, N. and Bernlohr, D.A. (2018) Fatty Acid Binding Protein 4/aP2-Dependent BLT1R Expression and Signaling. J. Lipid Res. 59 (3):416-428. doi: 10.1194/jlr.M077487.
Ge, X.N., Bastan, I., Dileepan, M., Greenberg, Y., Ha, S.G., Steen, K.A., Bernlohr, D.A., Rao, S.P. and Sriramarao, P (2018) FABP4 regulates eosinophil recruitment and activation in allergic airway inflammation. American Journal of Physiology-Lung Cellular and Molecular Physiology. 315:L227-L240. doi: 10.1152/ajplung.00429.2017.
Hertzel A.V., Xu H., Downey M., Kvalheim N., Bernlohr D.A. (2017) Fatty Acid Binding Protein 4/aP2-Dependent BLT1R Expression and Signaling. Journal of Lipid Research. May 25. pii: jlr.M074542. doi: 10.1194/jlr.M074542.
Duffy, C. M., Xu, H., Nixon, J. P., Bernlohr, D. A., and Butterick, T. A. (2017) Identification of a fatty acid binding protein4-UCP2 axis regulating microglial mediated neuroinflammation. Molecular and Cellular Neuroscience. 80, 52–57.
Zhang, Y., Rao, E., Zeng, J., Hao, J., Sun, Y., Liu, S., Sauter, E. R., Bernlohr, D. A., Cleary, M. P., Suttles, J., and Li, B. (2017) Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-Induced Macrophage Cell Death through Enhancing Ceramide Production. Journal of Immunology. 198(2):798-807
Xu, H., Hertzel, A. V., Steen, K. A., and Bernlohr, D. A. (2016) Loss of Fatty Acid Binding Protein 4/aP2 Reduces Macrophage Inflammation Through Activation of SIRT3. Molecular Endocrinology 30, 325–334.
Steen, K. A., Xu, H., and Bernlohr, D. A. (2016) FABP4/aP2 regulates macrophage redox signaling and inflammasome activation via control of UCP2. Molecular and Cellular Biology. 10.1128/MCB.00282-16
Xu, H., Hertzel, A. V., Steen, K. A., Wang, Q., Suttles, J., and Bernlohr, D. A. (2015) Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. Molecular and Cellular Biology. 35, 1055–1065
Hotamisligil, G. S., and Bernlohr, D. A. (2015) Metabolic functions of FABPs—mechanisms and therapeutic implications. Nature Reviews Endocrinology. 11, 592–605.
Ge, X. N., Greenberg, Y., Hosseinkhani, M. R., Long, E. K., Bahaie, N. S., Rao, A., Ha, S. G., Rao, S. P., Bernlohr, D. A., and Sriramarao, P. (2013) High-fat diet promotes lung fibrosis and attenuates airway eosinophilia after exposure to cockroach allergen in mice. Exp. Lung Res. 39, 365–378
Long, E. K. A., Hellberg, K., Foncea, R., Hertzel, A. V., Suttles, J., and Bernlohr, D. A. (2013) Fatty acids induce leukotriene C4 synthesis in macrophages in a fatty acid binding protein-dependent manner. Biochim. Biophys. Acta. 1831, 1199–1207
Mahadevan J, Parazzoli S, Oseid E, Hertzel AV, Bernlohr DA, Vallerie SN, Liu CQ, Lopez M, Harmon JS, Robertson RP. (2013) Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves β-cell mass and function in ZDF rats. Diabetes. 62(10):3582-8.
Adipose Oxidative Stress, Carbonylation and the Epigenome
Obesity leads to a loss of the antioxidant defense system in adipose tissue, resulting in increased oxidative stress. Under these conditions, membrane lipids can undergo chemical and enzymatic peroxidation leading to the generation of a,b-unsaturated aldehydes such as 4-hydroxynonenal. Such reactive lipids form chemical cross links with proteins and DNA and are implicated in oxidative diseases such as psoriasis, aging, macular degeneration and type 2 diabetes. Moreover, such protein modification, termed carbonylation, leads to system-wide changes in cellular function including mitochondrial respiration and signal transduction. More recently, we have discovered that adipose nuclear proteins are subject to carbonylation, with dramatic increases occurring with obesity or aging. Utilizing a mass spectrometry approach, we have identified endogenous sites of carbonylation on nuclear transcription factors, as well as on histones. Currently we are mapping the chromatin sites of these histone modifications and studying the effect of carbonylation on known epigenetic marks of histones. Such changes in histone modification may underlie many of the transcriptional events linked to insulin resistance and lead to new insight in age and nutrient-dependent diseases.
Hauck, A.K., Huang, Y., Hertzel, A.V. and Bernlohr, D.A. (2019) Oxidative Stress and Adipose Biology. J. Biol. Chem. 294: 1083-1088. doi:10.1074/jbc.R118.00321
Hauck, A.K., Zhou, T., Hahn, W.S., Petegrosso, R, Kuang, R., Chen, Y and Bernlohr, D.A. (2018) Obesity-Induced Protein Carbonylation In Murine Adipose Tissue Regulates The DNA Binding Domain Of Nuclear Zinc-Finger Proteins. J. Biol. Chem. 293:13464-13476. doi: 10.1074/jbc.RA118.003469.
Olson, D.H., Burrill, J.S., Kuzmicic, J., Hahn, W.S., Park, J-M. Kim, D-H. and Bernlohr, D. A. (2017) Down regulation of Peroxiredoxin 3 in 3T3-L1 adipocytes leads to oxidation of Rictor in the mammalian-target of rapamycin complex 2 (mTORC2) Biochem Biophys Res Commun. 2017 Nov 25;493(3):1311-1317.
Hauck, A. K., and Bernlohr, D. A. (2016) Oxidative stress and lipotoxicity. Journal of Lipid Research. 10.1194/jlr.R066597
Burrill, J. S., Long, E. K., Reilly, B., Deng, Y., Armitage, I. M., Scherer, P. E., and Bernlohr, D. A. (2015) Inflammation and ER stress regulate branched-chain amino acid uptake and metabolism in adipocytes. Mol. Endocrinol. 29, 411–420
Frohnert, B. I., and Bernlohr, D. A. (2014) Glutathionylated products of lipid peroxidation: A novel mechanism of adipocyte to macrophage signaling. Adipocyte. 3, 224–229
Hahn, W. S., Kuzmicic, J., Burrill, J. S., Donoghue, M. A., Foncea, R., Jensen, M. D., Lavandero, S., Arriaga, E. A., and Bernlohr, D. A. (2014) Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Am. J. Physiol. Endocrinology Metabolism. 306, E1033–45
Xu, Q., Hahn, W. S., and Bernlohr, D. A. (2014) Detecting protein carbonylation in adipose tissue and in cultured adipocytes. Meth. Enzymol. 538, 249–261
Bernlohr, D. A. (2014) Exercise and mitochondrial function in adipose biology: all roads lead to NO. Diabetes. 63, 2606–2608
Frohnert, B. I., Long, E. K., Hahn, W. S., and Bernlohr, D. A. (2014) Glutathionylated lipid aldehydes are products of adipocyte oxidative stress and activators of macrophage inflammation. Diabetes. 63, 89–100
Parra, V., Verdejo, H. E., Iglewski, M., Del Campo, A., Troncoso, R., Jones, D., Zhu, Y., Kuzmicic, J., Pennanen, C., Lopez-Crisosto, C., Jaña, F., Ferreira, J., Noguera, E., Chiong, M., Bernlohr, D. A., Klip, A., Hill, J. A., Rothermel, B. A., Abel, E. D., Zorzano, A., and Lavandero, S. (2014) Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 signaling pathway. Diabetes. 63, 75–88
Ruskovska, T., and Bernlohr, D. A. (2013) Oxidative stress and protein carbonylation in adipose tissue - implications for insulin resistance and diabetes mellitus. J Proteomics. 92, 323–334
Long E.K., Olson D.M., Bernlohr D.A. (2013) High-fat diet induces changes in adipose tissue trans-4-oxo-2-nonenal and trans-4-hydroxy-2-nonenal levels in a depot-specific manner. Free Radical Biology Medicine. 63:390-8.
Frohnert B.I., Bernlohr D.A. (2013) Protein carbonylation, mitochondrial dysfunction, and insulin resistance. Advances Nutrition. 4(2):157-63.
Curtis J.M., Hahn W.S., Stone M.D., Inda J.J., Droullard D.J., Kuzmicic J.P., Donoghue M.A., Long E.K., Armien A.G., Lavandero S., Arriaga E., Griffin T.J., Bernlohr D.A. (2012) Protein carbonylation and adipocyte mitochondrial function. Journal of Biological Chemistry. 287(39):32967-80.
Curtis J.M., Hahn W.S., Long E.K., Burrill J.S., Arriaga E.A., Bernlohr D.A. (2012)
Protein carbonylation and metabolic control systems. Trends Endocrinology Metabolism. 23(8):399-406.
Bariatric Surgery, Type 2 Diabetes and Cancer
In humans, obesity is associated with increased risk of the development of associated pathologies including type 2 diabetes, atherosclerosis, asthma and cancer. Bariatric surgeries, including Roux-en Y and Vertical Sleeve Gastrectomy, are the most effective treatments of obesity to allow weight loss and resolution of the associated pathologies.
In this collaborative project with bariatric surgeons here at the University of Minnesota, the laboratory examines the mechanism associated with improved insulin sensitivity that results from the surgery, prior to weight loss. We have data that shows a major change in adipose tissue lipid metabolism, including an increase in fat oxidation, resulting from a switch in expression of the peroxisome proliferator activated receptor (PPAR) g isoform, to the PPARd isoform. Accompanying this is a switch from FABP4 expression to FABP5 expression. Interestingly, this molecular mechanism occurs in multiple cell types within adipose tissue, including adipocytes and the stromal vascular cells, and is independent of a hypocaloric diet. Importantly, bariatric surgery also results in decreased levels of secreted FABP4. Secreted FABP4 may affect development of cancer cells and we are currently expanding our efforts to include detailed analysis of overall metabolic changes in patients, compared to the molecular changes in adipose tissue. Ultimately, the laboratory is interested in translating our basic science molecular mechanisms into alternative treatment options for patients.
Jahansouz, C, Xu, H., Kizy, S., Thomas, A.J., Josephrajan, A., Hertzel, A.V., Foncea, R., Billington, C.J., Jensen, M., Korner, J., Bernlohr, D.A. and Ikramuddin, S. (2018) Serum FABP4 Concentrations Decrease Following Roux-en-Y Gastric Bypass but not After Intensive Medical Management. Surgery. S0039-6060(18)30517-8. doi: 10.1016/j.surg.2018.08.007
Jahansouz C., Staley C., Bernlohr D.A., Sadowsky M.J., Khoruts A., Ikramuddin S. (2017) Sleeve Gastrectomy Drives Persistent Shifts in the Gut Microbiome.
Surgery for Obesity and Related Diseases. 2017 Jan 4. pii: S1550-7289(17)30003-5. doi: 10.1016/j.soard.2017.01.003
Jahansouz, C., Xu, H., Hertzel, A. V., Serrot, F. J., Kvalheim, N., Cole, A., Abraham, A., Luthra, G., Ewing, K., Leslie, D. B., Bernlohr, D. A., and Ikramuddin, S. (2015) Bile Acids Increase Independently From Hypocaloric Restriction After Bariatric Surgery. Annals of Surgery. 10.1097/SLA.0000000000001552
Jahansouz, C., Serrot, F. J., Frohnert, B. I., Foncea, R. E., Dorman, R. B., Slusarek, B., Leslie, D. B., Bernlohr, D. A., and Ikramuddin, S. (2015) Roux-en-Y Gastric Bypass Acutely Decreases Protein Carbonylation and Increases Expression of Mitochondrial Biogenesis Genes in Subcutaneous Adipose Tissue. Obesity Surgery. 25, 2376–2385