Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

Abstract

Impairment of insulin action (insulin resistance) is frequently observed in Type II (non-insulin-dependent) diabetes mellitus as well as in wasting syndromes including neoplastic, inflammatory and chronically infectious diseases [1,2]. Previous studies suggest that inflammatory cytokines, such as tumour necrosis factor-a (TNF-a) [3], interleukin-1 (IL-1) [4], , leukaemia inhibitory factor (LIF) [6] and transforming growth factor-b (TGF-b) [7] are involved in the development of insulin resistance. Clinical studies have shown that TNF-a and IL-6 concentrations are increased in the sera of patients with several cancers and infectious diseases, in which insulin action is impaired [8]. Moreover, infusion of rats Diabetologia (1999) Abstract Aims/hypothesis. Previous studies show that inflammatory cytokines play a part in the development of insulin resistance. Thiazolidinediones were developed as insulin-sensitizing drugs and are ligands for the peroxisome proliferator-activated receptorg (PPARg). We hypothesized that the anti-diabetic mechanism of thiazolidinediones depends on the quantity of PPARg in the insulin resistant state in which inflammatory cytokines play a part. Methods. We isolated rat PPARg1 and g2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPARg mRNA expression in rat mature adipocytes. Results. Various inflammatory cytokines, such as tumour necrosis factor-a (TNF-a), interleukin-1a (IL1a), IL-1b, IL-6 and leukaemia inhibitory factor decreased PPARg mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13-acetate also decreased the expression of PPARg. The suppression of PPARg mRNA expression caused by 10 nmol/l of TNF-a was reversed 60 % and 55 % by treatment with 10 ±4 mol/l of troglitazone and 10 ±4 mol/l of pioglitazone, respectively. The suppression of glucose transporter 4 mRNA expression caused by TNF-a was also reversed by thiazolidinediones. Associated with the change of PPARg mRNA expression, troglitazone improved glucose uptake suppressed by TNF-a. Conclusion/interpretation. Our study suggests that inflammatory cytokines could be factors that regulate PPARg expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPARg mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones. [Diabetologia (1999) 42: 702±710]

Troglitazone Not Only Increases GLUT4 but Also Induces Its Translocation in Rat Adipocytes

“…In in vitro studies, it has been reported that thiazolidinediones increase glucose uptake in 3T3-F442A and 3T3-L1 adipocytes by increasing GLUT4 and/or GLUT1 content (9,10). In mature adipocytes, troglitazone has also been reported to increase GLUT4 mRNA levels (11). These in vitro and in vivo studies could not distinguish between the increases in glucose transporters associated with the enhancement of adipocyte differentiation and those resulting from the direct effects of the thiazolidinedione on mature adipocytes.…”

“…In in vitro studies, it has been reported that thiazolidinediones increased glucose uptake in 3T3-F442A and 3T3-L1 adipocytes by increasing GLUT4 and/or GLUT1 content (9,10). In mature adipocytes, troglitazone has also been reported to increase GLUT4 mRNA levels (11). Furthermore, thiazolidinediones have been suggested to modulate intrinsic activity and translocation of glucose transporters (12).…”

Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-α or its receptors

“…IL-6 could affect functions of lipid and muscle cells [43,44,45]. In contrast lipid tissue is a major source of IL-6 [46,47] and possibly also of sIL-6R [48].…”

Phosphorylation of Extracellular Signal-Regulated Kinase (ERK)-1/2 Is Associated with the Downregulation of Peroxisome Proliferator-Activated Receptor (PPAR)-γ during Polymicrobial Sepsis

“…We have previously demonstrated that PPARγ expression is downregulated in the lung and vascular endothelium in rodent models of septic shock and that treatment with PPARγ ligands reverses the sepsis-induced reduction (1). In adipose tissue, PPARγ expression decreased after mice were challenged in vivo with endotoxin, and cytokine-induced suppression of PPARγ was reversed with synthetic agonists (5,6). However, it remains unclear what mechanisms lead to a decrease in PPARγ activity in sepsis.…”