Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells

Endocrinology. 1995 Apr;136(4):1474-81. doi: 10.1210/endo.136.4.7895657.

Abstract

Tumor necrosis factor-alpha (TNF alpha) is a cytokine implicated in the development of septic shock, cachexia, and other pathological states. Recent studies indicated a direct role for adipose expression of TNF alpha in obesity-linked insulin resistance and diabetes. Pioglitazone, CP-86,325 (CP), AD-5075, CS-045, ciglitazone, and englitazone are members of a new class of insulin-sensitizing thiazolidinedione derivatives with in vivo antidiabetic activities. To test whether these agents antagonize the effect of TNF alpha, 3T3-L1 cells were induced to differentiate in the presence of TNF alpha with or without thiazolidinedione derivatives. Incubation of 3T3-L1 cells with TNF alpha alone completely inhibited adipocyte conversion and expression of fatty acid-binding protein messenger RNA (mRNA). However, coincubation of TNF alpha-treated cells with CP (1 microM), AD-5075 (1 microM), pioglitazone (10 microM), or CS-045 (10 microM) blocked these effects. Long term incubation of 3T3-L1 adipocytes with a low dose of TNF alpha (50 pM) significantly decreased the levels of the adipocyte/muscle-specific glucose transporter (GLUT4) and the CCAAT enhancer-binding protein mRNAs, but did not affect expression of the ubiquitously expressed glucose transporter (GLUT1) or lipoprotein lipase mRNAs. Incubation of 3T3-L1 adipocytes with TNF alpha also inhibited insulin-stimulated 2-deoxyglucose uptake as well as expression of GLUT4 protein. Furthermore, in 3T3-L1 adipocytes, incubation with TNF alpha attenuated the expression of fatty acid-binding protein mRNA in a time- and dose-dependent manner. These inhibitory effects were partially or completely blocked by coincubation of the cells with CP. These results implicate that the insulin-sensitizing agents may exert their antidiabetic activities by antagonizing the inhibitory effects of TNF alpha.

MeSH terms

  • 3T3 Cells / cytology
  • 3T3 Cells / drug effects*
  • 3T3 Cells / metabolism
  • Animals
  • Carrier Proteins / genetics
  • Cell Differentiation / drug effects*
  • Deoxyglucose / metabolism
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Gene Expression / drug effects
  • Glucose / metabolism*
  • Glucose Transporter Type 1
  • Glucose Transporter Type 4
  • Hypoglycemic Agents / pharmacology*
  • Insulin / pharmacology*
  • Mice
  • Monosaccharide Transport Proteins / genetics
  • Muscle Proteins*
  • Neoplasm Proteins*
  • Nerve Tissue Proteins*
  • RNA, Messenger / metabolism
  • Thiazoles / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Carrier Proteins
  • Fabp5 protein, mouse
  • Fabp7 protein, mouse
  • Fatty Acid-Binding Protein 7
  • Fatty Acid-Binding Proteins
  • Glucose Transporter Type 1
  • Glucose Transporter Type 4
  • Hypoglycemic Agents
  • Insulin
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Slc2a1 protein, mouse
  • Slc2a4 protein, mouse
  • Thiazoles
  • Tumor Necrosis Factor-alpha
  • Deoxyglucose
  • Glucose