David A. Bernlohr
Office: 7-128 MCB
Laboratory: 7-178 MCB Telephone: (612) 624-9798
Adipose Biology and Obesity Linked Insulin Resistance
A major research study in the laboratory focuses on the metabolic relationships between obesity and insulin action. Our laboratory specifically examines cytoplasmic fatty acid binding proteins and their role(s) in mediating fatty acid metabolism in adipocytes and macrophages, particularly leukotriene synthesis.
Diagram showing the metabolic relationships between obesity and insulin action.
Using a combination of biochemical, biophysical and molecular methodologies, the laboratory studies the synthesis of inflammatory lipids in macrophages and other cells. Importantly, animal models either null or transgenic for fatty acid binding proteins reveal that intracellular lipid metabolism control the synthesis and secretion of adipose-derived cytokines (adipokines) linked to glucose and lipid metabolism in muscle and liver. Using a drug discovery approach, small molecule inhibitors of FABPs have been identified that exhibit anti-inflammatory properties in macrophages. Such studies provide a framework for the analysis of obesity-linked insulin resistance.
Li., B., J. M. Reynolds, R. D. Stout, D. A. Bernlohr and J. Suttles. (2009) Regulation of Th17 Differentiation by Epidermal Fatty Acid-Binding Protein. J. Immunol. 182:7625
Thompson, B.R., Mazurkiewicz-Munoz, A.M., Suttles, J., Carter-Su, C., and Bernlohr, D.A. (2009) Interaction of adipocyte fatty acid binding protein and Jak2; AFABP/aP2 as a regulator of Jak2 signaling. J. Biol. Chem., 284: 13473 - 13480
Hertzel, A.V., Hellberg, K., Reynolds, J.M., Kruse, A.C., Juhlmann, B.E., Smith, A.J., Sanders, M.A., Ohlendorf, D.H., Suttles, J. and Bernlohr, D.A. (2009) Identification and Characterization of a Small Molecule Inhibitor of Fatty Acid Binding Protein, J. Med Chem. 52, 6024–6031
Oxidative Stress and Mitochondrial Function
Plasma membrane lipids undergo chemical and enzymatic peroxidation leading to the generation of a,b-unsaturated aldehydes such as 4-hydorxynonenal.
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. In this project, the Bernlohr laboratory examines antioxidant defense systems operable in adipose tissue and their regulation by pro-inflammatory cytokines. Importantly, loss of antioxidant defenses in type 2 diabetes leads to increased protein carbonylation and decreased mitochondrial function. Such mitochondrial dysfunction may underlie many of the biochemical events linked to insulin resistance and lead to new insight in age and nutrient-dependent diseases.
Hellberg, K, Grimsrud, PA, Kruse, AC, Banaszak, LJ, Ohlendorf, DH, Bernlohr, DA. (2010) Adipocytes Fatty Acid Binding Protein (aP2) Modified with 4-Hydroxynonenal. Protein Science 19; 1480-1489.
Curtis JM, Grimsrud PA, Wright WS, Xu X, Foncea RE, Graham DW, Brestoff JR, Wiczer BM, Ilkayeva O, Cianflone K, Muoio DE, Arriaga EA, Bernlohr DA. (2010) Down Regulation of Adipose Glutathione S-Transferase Leads to Increased Protein Carbonylation, Oxidative Stress and Mitochondrial Dysfunction. Diabetes 59:1132-1142.
Frohnert, B.I., Sinaiko, A.R., Serrot, F., Foncea, R.E., Moran, A., Ikramuddin, S., Choundry, U., and Bernlohr, D.A. (2011) Increased adipose protein carbonylation in human obesity. Obesity In press
Adipokine Biology and Insulin Resistance
Fat cells and macrophages synthesize and secrete a number of signaling proteins involved in control of local and systemic energy metabolism.
In this project, the laboratory examines the role(s) of LCN2, a newly described adipokine and renin, the enzyme that is rate limiting for synthesis of angiotensin II, in adipose biology. LCN2 is a member of the Lipocalin supergene family of hydrophobic ligand binding proteins and binds retinoic acid. LCN2 is secreted by adipocytes and regulates gene expression by nuclear hormone receptors in the liver. LCN2 null mice develop insulin resistance and defects in control of whole body energy metabolism. The secretion of both renin and LCN2 secretion is increased in response to pro-inflammatory cytokines such as TNFa
Fowler, J.D., Krueth, S., Bernlohr, D.A., and Katz, S.A. (2009) Renin angiotensin system component dynamics in adipose tissue: adipose tissue control of local renin concentrations. Am J Physiol Endocrinol Metab 296:343-350
Fowler, J.D., Johnson, N.D., Haroldson, T.A., Brintnall, J. A., Herrera, J.E., Katz, S.A. and Bernlohr, D.A. (2009) Regulated renin release from 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 296; E1383-E1391
Guo, H., Jin, D., Zhang, Y., Wright, W., Brockman, D.D., Bernlohr, D.A., Chen, X. (2010) Lipocalin 2-deficiency impairs adaptive themogenesis and potentiates diet-induced insulin resistance in mice. Diabetes 59(6):1376-1385
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