Insulin resistance-inducing cytokines differentially regulate SOCS mRNA expression via growth factor- and Jak/Stat-signaling pathways in 3T3-L1 adipocytes.

Abstract

Various cytokines, including tumor necrosis factor (TNF) alpha, growth hormone (GH) and interleukin (IL)-6, induce insulin resistance. Recently, it was demonstrated that induction of suppressor of cytokine signaling (SOCS)-3 by TNFalpha and GH is an important mechanism by which these cytokines impair insulin sensitivity. The current study investigated in 3T3-L1 adipocytes whether TNFalpha and GH also upregulate SOCS-1 and SOCS-6, which have both been shown to inhibit insulin signaling potently, and whether IL-6 might alter synthesis of SOCS-1, -3 and -6. Interestingly, 10 ng/ml TNFalpha, 500 ng/ml GH and 30 ng/ml IL-6 induced SOCS-1 mRNA time-dependently with maximal stimulation detectable after 8 h of TNFalpha and 1 h of GH and IL-6 addition respectively. Furthermore, TNFalpha and GH caused sustained upregulation of SOCS-1 for up to 24 h, whereas stimulation by IL-6 was only transient, with SOCS-1 mRNA returning to basal levels 2 h after effector addition. Induction of SOCS-1 was dose-dependent, and significant stimulation was detectable at concentrations as low as 3 ng/ml TNFalpha, 50 ng/ml GH and 10 ng/ml IL-6. Furthermore, stimulation experiments and studies using pharmacologic inhibitors suggested that the positive effect of TNFalpha, GH and IL-6 on SOCS-1 mRNA is, at least in part, mediated by Janus kinase (Jak) 2. Finally, SOCS-3 expression was dose- and time-dependently induced by IL-6, at least in part via Jak2, but none of the cytokines affected SOCS-6 expression. Taken together, our results show a differential regulation of SOCS mRNA by insulin resistance-inducing hormones, and suggest that SOCS-1, as well as SOCS-3, may be an important intracellular mediator of insulin resistance in fat cells and a potential pharmacologic target for the treatment of impaired insulin sensitivity.

• Authors: M Fasshauer, S Kralisch, M Klier, U Lossner, M Bluher, J Klein, R Paschke
• Journal: The Journal of endocrinology (J Endocrinol) Vol. 181 Issue 1 Pg. 129-38 (Apr 2004) ISSN: 0022-0795 [Print] England
• PMID: 15072573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Cytokines
• Interleukin-6
• Proteins
• Proto-Oncogene Proteins
• RNA, Messenger
• Repressor Proteins
• SOCS3 protein, human
• SOCS6 protein, human
• Socs1 protein, mouse
• Socs3 protein, mouse
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Transcription Factors
• Tumor Necrosis Factor-alpha
• Growth Hormone
• Protein-Tyrosine Kinases
• JAK2 protein, human
• Jak2 protein, mouse
• Janus Kinase 2

Topics

• 3T3 Cells
• Adipocytes (drug effects, metabolism)
• Animals
• Blotting, Western (methods)
• Carrier Proteins (genetics)
• Cytokines (pharmacology)
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Growth Hormone (pharmacology)
• Insulin Resistance
• Interleukin-6 (pharmacology)
• Janus Kinase 2
• Mice
• Precipitin Tests (methods)
• Protein-Tyrosine Kinases (metabolism)
• Proteins (genetics)
• Proto-Oncogene Proteins
• RNA, Messenger (analysis, metabolism)
• Repressor Proteins (genetics)
• Stimulation, Chemical
• Suppressor of Cytokine Signaling 1 Protein
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Time Factors
• Transcription Factors (genetics)
• Tumor Necrosis Factor-alpha (pharmacology)