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Robert Mooney, Ph.D.

Professor of Pathology and Laboratory Medicine

Clinical Chemistry
Mechanisms of obesity-dependent insulin resistance in type 2 diabetes

URMC Labs
601 Elmwood Ave., Rm 1-2111
Rochester, NY 14642-8608
Tel: (585) 275-7811
Fax: (585) 756-4468

Robert_Mooney@urmc.rochester.edu

Director of the Biochemical Genetics Laboratory. Director of the Pathways of Human Disease graduate program in Pathology. Dr. Mooney has also served as Director of the Hemaglobinopathy Laboratory in the Department of Medicine, and Director of Clinical Laboratories at Monroe Community Hospital

Qualifications

Ph.D. Biochemistry, Johns Hopkins University 1980
Clinical Lab Officer Intern, USAF, Lackland Air Force Base, Texas 1973-74
Fellow, Clinical Biochemistry, Washington University School of Medicine 1980-83
Board Certification, American Board of Clinical Chemistry 1985

Research Overview

Obesity is increasing at an alarming rate in the industrialized world. This is a serious health concern because there is a strong association between obesity and insulin resistance, type 2 diabetes, hypertension, cancer, and cardiovascular disease. Our lab is particularly interested in the link between obesity and type 2 diabetes. Type 2 diabetes currently afflicts 6-7% of the U.S. population. It is characterized by defective insulin action (insulin resistance) leading to poor control of blood glucose (sugar) levels. The disease can lead to heart disease, blindness, kidney failure, amputations, and nerve damage. Traditionally considered a disease of advanced age, an epidemic of diabetes in children is of great concern. Sedentary lifestyle and poor eating habits leading to obesity are contributing to the increased incidence of diabetes at all ages. At least 70% of diabetics are obese.

It has now become apparent that obesity-dependent insulin resistance and type 2 diabetes have characteristics of a chronic inflammatory state. This link between inflammation and insulin resistance is the focus of the two major projects in our lab. First, we are defining the role of pro-inflammatory cytokines as mediators of insulin resistance in target tissues, particularly in the liver. Second, we are testing the hypothesis that tissue macrophages are an important source of these pro-inflammatory cytokines in obesity.

Defective insulin receptor signaling in insulin target tissues (muscle, liver, and fat cells) is a hallmark of type 2 diabetes. With a clear association between obesity and diabetes, we are testing the hypothesis that cytokines (particularly interleukin-6) contribute to inhibition of insulin receptor signaling in target tissues leading to insulin resistance. Consistent with this model, IL-6 levels are 2-3 times higher in the blood of diabetics than controls. We have shown that IL-6 causes insulin resistance in liver cells and in vivo by inhibiting insulin receptor signal transduction. More recently, we have demonstrated that a family of regulatory proteins, SOCS (Suppressors of Cytokine Signaling) proteins, are induced by IL-6 in liver cells. Importantly, we have also demonstrated that SOCS proteins bind to the insulin receptor and inhibit its signaling. Thus, we propose that excessive amounts of IL-6 in the blood of obese individuals reacts with IL-6 receptors on liver cells and induces expression of SOCS proteins. These proteins bind to the insulin receptor and inhibit receptor signaling, producing insulin resistance. We are currently testing this model of obesity-dependent insulin resistance at the cellular level and with experimental animals.

Little is understood about the cause of the pro-inflammatory state of insulin resistance and type 2 diabetes. Particularly important would be an understanding of the cell type(s) responsible for the pro-inflammatory cytokines and the mechanism by which obesity activates the cells to produce cytokines. We are actively investigating the role of tissue macrophages, particularly liver-specific Kupffer cells, in this pathologic process. Techniques being employed in these investigations are Kupffer cell isolation and primary cell culture, bone marrow transplantation, in vivo gene expression (adenovirus mediated) and gene suppression (sh-RNA), and assessments of in vivo insulin action using parameters of insulin signal transduction.

In summary, our research focuses on obesity-dependent insulin resistance and diabetes. With collaborations within the medical center and nationally, we are pursuing investigations using both cell and animal models with the goal of understanding the mechanism of insulin receptor dysregulation in this critical disease. Ultimately, it is anticipated that these investigations will direct us to targeted drug therapies or other medical interventions to improve diabetes care.

Publications


Mooney RA. Counterpoint: Interleukin-6 does not have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol. 2007 Feb;102(2):816-8; discussion 818-9.

Mooney, R.A. Point-Counterpoint: Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 2007 Feb;102, 814-816.

Chagnon MJ, Elchebly M, Uetani N, Dombrowski L, Cheng A, Mooney RA, Marette A, Tremblay ML. Altered glucose homeostasis in mice lacking the receptor protein tyrosine phosphatase sigma. Can J Physiol Pharmacol. 2006 Jul;84(7):755-63.

Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology. 2005 Aug;146(8):3417-27. Epub 2005 Apr 21.

LeVea CM, Reeder JE, Mooney RA. EGF-dependent cell cycle progression is controlled by density-dependent regulation of Akt activation. Exp Cell Res. 2004 Jul 1;297(1):272-84.

Klover PJ, Mooney RA. Hepatocytes: critical for glucose homeostasis. Int J Biochem Cell Biol. 2004 May;36(5):753-8.

Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes. 2003 Nov;52(11):2784-9.

Arnold GL, Hyman SL, Mooney RA, Kirby RS. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord. 2003 Aug;33(4):449-54.

Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, Miller RK. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol. 2003 Jun;101(6):1266-74.

Mooney RA, LeVea CM. The leukocyte common antigen-related protein LAR: candidate PTP for inhibitory targeting. Curr Top Med Chem. 2003;3(7):809-19.

Pearce DA, McCall K, Mooney RA, Chattopadhyay S, Curran TM.
Altered amino acid levels in sera of a mouse model for juvenile neuronal ceroid lipofuscinoses. Clin Chim Acta. 2003 Jun;332(1-2):145-8.

Senn, J.J., Klover, P.J., Nowak, I., Koniaris, L., Zimmers-Koniaris, T., Furlanetto, R.W. and Mooney, R.A. (2003) Suppressor of Cytokine Signaling-3, a potential mediator of interleukin-6 dependent insulin resistance in hepatocytes. J. Biol Chem. 278, 13740-13746.

Senn, J.J., Klover, P.J., Nowak, I., and Mooney, R.A. (2002) Interleukin 6 induces cellular insulin resistance in hepatocytes. Diabetes 51(12): 3391-9.

Symons, J., LeVea, C., and Mooney R. (2002) Expression of the leucocyte common antigen-related (LAR) tyrosine phosphatase is regulated by cell density through functional E-cadherin complexes. Biochem. J. 365, 513-519.

Mooney, R.A., Senn, J.J., Cameron, S.J., Inamdar, N., Boivin, L.M., Shang, Y., and Furlanetto, R.W. (2001) Suppressors of Cytokine Signaling-1 and 6 associate with and inhibit the insulin receptor: a potential mechanism for cytokine-mediated insulin resistance. J. Biol. Chem. 276, 25889-25893.

LeVea, C.M., McGary, C.T., Symons J.R., and Mooney, R.A. (2000) PTP LAR expression compared to prognostic indices in metastatic and non-metastatic breast cancer. Breast Cancer Res and Treatment. 64,221-228.