Abstracts of Current Research:- Kinases linking fat tissue stress sensing to adipose tissue malfunction in obesity: Obesity has been proposed to impose a variety of "stresses", including inflammatory, metabolic, oxidative, and endoplasmic reticulum stress. These, through the activation of "stress-sensing pathways", result in functional alterations, which ultimately lead to the co-morbidities associated with obesity. Although obesity is a systemic condition, the extent and response to the environmental conditions it imposes can be generalized, but may also display organ and cell-type –specific features. Here we review the evidence supporting the development of various stresses in obesity specifically in adipocytes and/or adipose tissue, which frequently exhibits impaired metabolic and endocrine function. The evidence for activation of several stress-sensing pathways and their involvement in adipose tissue malfunction is reviewed.
- Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species: Multiple roles of Reactive Oxygen and Nitrogen Species (ROS and RNS, respectively) have been uncovered in recent years, placing them as major players in both normal physiological functions and in patho-physiological processes. ROS are formed as by-products of oxidative metabolism, but are also generated in a regulated manner in response to extracellular cues including insulin. Regulated ROS/RNS production balanced by diverse anti-oxidant systems ensures a physiological role of these species with minimal oxidative damage to cellular components. In contrast, when these processes are dys-regulated, oxidatively-modified lipids, DNA and/or proteins accumulate, potentially resulting in cellular and organellar dysfunction. This Review explores how ROS/RNS participate and modify insulin action. Intriguingly, evidence exists for a physiological role of ROS and RNS as second messengers in insulin signal transduction. Yet, emerging evidence suggests that conditions characterized by insulin resistance, like obesity and diabetes, are associated with increased oxidative stress. Moreover, experimental systems revealed cellular mechanisms for the induction of insulin resistance by ROS/RNS, implying a causative role for oxidants in impairing insulin action. With global concerns on the magnitude and burden of the diabetes and obesity pandemics, it is hoped that better understanding of how ROS/RNS modify insulin action may advance novel therapeutic strategies.
- MAP kinases, IKK and insulin signaling in human omental versus subcutaneous adipose tissue in obesity: MAP kinases and IkB kinase were suggested to link various conditions thought to develop in adipose tissue in obesity with insulin resistance. Yet, whether in obesity these kinases are affected in a fat depot differential manner is unknown. We evaluate the amount of protein and mRNAs of p38MAPK, ERK, JNK1 and IKKb in omental and subcutaneous fat in human obesity. Our results shed light on the role of those kinases in the development of insulin resistance and diabetes
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Publications:- A. Rudich, H. Kanety and N. Bashan. Adipose stress-sensing kinases – linking obesity to malfunction. Trends Endocrinol. Metab 18: 291-299 (2007)
- N. Bashan, K. Dorfman, T. Tarnovscki, I. Harman-Boehm, I. F. Liberty, M. Blüher, S. Ovadia, T. Maymon-Zilberstein, R. Potashnik, M. Stumvoll, E. Avinoach, and A. Rudich. Mitogen-activated protein kinases, Inhibitory-κB kinase, and insulin signaling in human omental Versus subcutaneous adipose tissue in obesity Endocrinology 148: 2955-2962 (2007)
- I. Harman-Boehm, M. Blüher, H. Redel, N. Sion-Vardy, S. Ovadia, E. Avinoach, I. Shai, N. Klöting, M. Stumvoll, N. Bashan and A. Rudich. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the co-morbidities of obesity J. Clin. Endocrinol. Metab 92: 2240-2247 (2007)
- D. Pessler, P. H. Pekala, J. Kovsan, A. Bloch-Damti, A. Rudich and N. Bashan. GLUT4 repression in response to oxidative stress is associated with reciprocal alterations in C/EBP alpha and delta isoforms in 3T3-L1 adipocytes Arch. Physiol. Biochem 112: 3-12 (2006)
- R. Ben-Romano, A. Rudich, S. Etzion, R. Potashnik, E. Kagan, U. Greenbaum, and N. Bashan.. Nelfinavir induces adipocyte insulin resistance through the induction of oxidative stress: Differential protective effect of antioxidant agents Antiviral Therapy 11: 1051-1060 (2006)
- A. Bloch-Damti A, Potashnik R, Gual P, Le Marchand-Brustel Y, Tanti JF, Rudich A and Bashan N.. Differential roles of IRS1 phosphorylated on Ser307 or Ser632 in the induction of insulin resistance by oxidative stress . Accepted for publication in Diabetologia 49: 2463-73 (2006)
- Bloch-Damti, O., and Bashan N. Proposed Mechanisms for the induction of insulin resistance by oxidative stress. Antioxidants&Redox signaling 7: 1553-1567 (2005)
- Rudich, A., Ben-Romano, R., Etzion, S., and Bashan, N. Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors Acta Physiol. Scan. 183: 75-88 (2005)
- Wolach, M. Ashkenazi, R. Grossmann, R. Gavrieli, Z, Friedman, N. Bashan, D. Roos. . Diurnal flucttuation of leukocyte G6PD activity. A possible explanation for the normal neutrophil bactericidal activity and the low incidence of pyrogenic infections in patients with severe G6PD deficiency in Israel. Ped. Res 55: 807-813 (2004)
- Ben-Romano, R., Rudich, A., Tirosh , A., Potashnik, R., Sasaoka, T., Riesenberg, K., Schlaeffer, S., and Bashan, N. Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC Accepted for publication in Diabetologia 47: 1107-17 (2004)
- R. Potashnik, O. Damti-Bloch, N. Bashan and A. Rudich. Protein degradation of insulin receptor substrate 1 by oxidative stress- implication for insulin resistance Diabetologia 46: 639-648 (2003)
- R. Ben-Romano , A. Rudich , D. Török , S. Vanounou , K. Riesenberg , F. Schlaeffer
A. Klip , and N. Bashan.. Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors. AIDS 17: 1 (2003)
- Talior, I., Yarkoni, M., Bashan, N., and elder-Finkelman H. Increased glucose uptake promotes oxidative stress and PKC-delta activation in adipocytes of obese, insulin-resistance mice Endocrinol. Metab 285: 295-302 (2003)
- A. Rudich, J. Kovsan, I. Kachko, H. Ovadia and N. Bashan. Modification of insulin action by reactive oxygen species. Physiol. Review 89: (1928)
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