Combined Neural Inactivation of Suppressor of Cytokine Signaling-3 and Protein-Tyrosine Phosphatase-1B Reveals Additive, Synergistic, and Factor-Specific Roles in the Regulation of Body Energy Balance

Briancon, Nadege; McNay, David E.; Maratos-Flier, Eleftheria; Flier, Jeffrey S.
December 2010
Diabetes;Dec2010, Vol. 59 Issue 12, p3074
Academic Journal
OBJECTIVE--The adipokine hormone leptin triggers signals in the brain that ultimately lead to decreased feeding and increased energy expenditure. However, obesity is most often associated with elevated plasma leptin levels and leptin resistance. Suppressor of cytokine signaling (SOCS)-3 and protein-tyrosine phosphatase 1B (PTP-1B) are two endogenous inhibitors of tyrosine kinase signaling pathways and suppress both insulin and leptin signaling via different molecular mechanisms. Brain-specific inactivation of these genes individually in the mouse partially protects against diet-induced obesity (DIO) and insulin resistance. The aim of this study was to investigate possible genetic interactions between these two genes to determine whether combined reduction in these inhibitory activities results in synergistic, epistatic, or additive effects on energy balance control. RESEARCH DESIGN AND METHODS--We generated mice with combined inactivation of the genes coding for SOCS-3 and PTP-1B in brain cells, examined their sensitivity to hormone action, and analyzed the contribution of each gene to the resulting phenotype. RESULTS--Surprisingly, the Nestin-Cre mice used to mediate gene inactivation displayed a phenotype. Nonetheless, combined inactivation of SOCS-3 and PTP-1B in brain revealed additive effects on several parameters, including partial resistance to DIO and associated glucose intolerance. In addition, synergistic effects were observed for body length and weight, suggesting possible compensatory mechanisms for the absence of either inhibitor. Moreover, a SOCS-3-specific lean phenotype was revealed on the standard diet. CONCLUSIONS--These results show that the biological roles of SOCS-3 and PTP-1B do not fully overlap and that targeting both factors might improve therapeutic effects of their inhibition in obesity and type 2 diabetes. Diabetes 59:3074-3084, 2010


Related Articles

  • Mechanisms of Muscle Insulin Resistance in Obese Individuals. Dohm, G. Lynis // International Journal of Sport Nutrition & Exercise Metabolism;2001 Supplement, Vol. 11 Issue 4, pS64 

    Deals with a study which reported that insulin resistance in skeletal muscle of obese individuals was associated with decreases in insulin signal transduction and tyrosine kinase activity of the insulin receptor. Methodology used in the study; Results and discussion.

  • Erratum. Increased Insulin Sensitivity and Hypoinsulinemia in APS Knockout Mice. Diabetes 2003;52:2657-2665.  // Diabetes;Aug2015, Vol. 64 Issue 8, p3050 

    A correction to the article "Increased Insulin Sensitivity and Hypoinsulinemia in APS Knockout Mice" that was published in the 2003 issue is presented.

  • Hepatocyte-Specific Ptpn6 Deletion Protects From Obesity-Linked Hepatic Insulin Resistance. Xu, Elaine; Charbonneau, Alexandre; Rolland, Yannève; Bellmann, Kerstin; Pao, Lily; Siminovitch, Katherine A.; Neel, Benjamin G.; Beauchemin, Nicole; Marette, André // Diabetes;Aug2012, Vol. 61 Issue 8, p1949 

    The protein-tyrosine phosphatase Shp1 negatively regulates insulin action on glucose homeostasis in liver and muscle, but its potential role in obesity-linked insulin resistance has not been examined. To investigate the role of Shp1 in hepatic insulin resistance, we generated hepatocyte-specific...

  • Casitas b-Lineage Lymphoma--Deficient Mice Are Protected Against High-Fat Diet-Induced Obesity and Insulin Resistance. Molero, Juan C.; Waring, Samuel G.; Cooper, Adrian; Turner, Nigel; Laybutt, Ross; Cooney, Gregory J.; James, David E. // Diabetes;Mar2006, Vol. 55 Issue 3, p708 

    Casitas b-lineage lymphoma (c-Cbl) is a multiadaptor protein with E3-ubiquitin ligase activity involved in regulating the degradation of receptor tyrosine kinases. We have recently reported that c-Cbl-/- mice exhibit a lean phenotype and enhanced peripheral insulin action likely due to elevated...

  • A Review on Structure Based Drug Design of Protein Tyrosine Phosphatase 1B Inhibitors for Target for obesity and Type 2 Diabetes Mellitus. Shravanti, K.; Pavan Kumar, K.; Bhagavan Raju, M.; Madhusudhanareddy, I.; Atyam, Gupta // Journal of Pharmacy Research;Dec2010, Vol. 3 Issue 12, p2939 

    Type 2 diabetes is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion. Obseity and diabetes are due to the resistance of hormones insulin and leptin. Protein Tyrosine Phosphatase1B (PTP1B) is involved in the negative regulation of...

  • Track 7 Diabetes and hyperlipidemia in obesity P205-P259.  // International Journal of Obesity & Related Metabolic Disorders;May2001 Supplement, Vol. 25, pS88 

    Presents articles related to diabetes and hyperlipidemia in obesity published in the May 3, 2001 issue of the periodical 'International Journal of Obesity.' Diseases caused by diabetes; Effect of diet free fat and endurance training on insulin receptor tyrosine protein kinase in dietary obese...

  • Adipokines and Risk of Type 2 Diabetes in Older Men. Wannamethee, S. Goya; Lowe, Gordon D. O.; Rumley, Ann; Cherry, Lynne; Whincup, Peter H.; Sattar, Naveed // Diabetes Care;May2007, Vol. 30 Issue 5, p1200 

    OBJECTIVE -- The aim was to assess the relationship between adipokines, including interleukin (IL)-6, leptin, and adiponectin, with development of type 2 diabetes and assess the role of obesity and insulin resistance in these relationships. RESEARCH DESIGN AND METHODS -- We conducted a...

  • Comparison of alterations in insulin signalling pathway in adipocytes from Type II diabetic pregnant women and women with gestational diabetes mellitus M. Tomazic et al.: Impaired insulin signalling in GDM and Type II diabetic pregnant women. Tomazic, M.; Janez, A.; Sketelj, A.; Kocijancic, A.; Eckel, J.; Sharma, P. // Diabetologia;Apr2002, Vol. 45 Issue 4, p502 

    Aims/hypothesis. The cellular mechanisms for the insulin resistance in pregnancy and gestational diabetes mellitus are not known. The membrane protein plasma cell glycoprotein PC-1 has been identified as an inhibitor of insulin receptor tyrosine kinase activity and could have a role in insulin...

  • Regulation of insulin receptor function. Youngren, J. F. // Cellular & Molecular Life Sciences;Apr2007, Vol. 64 Issue 7/8, p873 

    Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation events within cells that regulate the activity of...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics