Cross-Talk between PPARgamma and Insulin Signaling and Modulation of Insulin Sensitivity

Abstract

PPARgamma activation in type 2 diabetic patients results in a marked improvement in insulin and glucose parameters, resulting from an improvement of whole-body insulin sensitivity. Adipose tissue is the major mediator of PPARgamma action on insulin sensitivity. PPARgamma activation in mature adipocytes induces the expression of a number of genes involved in the insulin signaling cascade, thereby improving insulin sensitivity. PPARgamma is the master regulator of adipogenesis, thereby stimulating the production of small insulin-sensitive adipocytes. In addition to its importance in adipogenesis, PPARgamma plays an important role in regulating lipid, metabolism in mature adipocytes by increasing fatty acid trapping. Finally, adipose tissue produces several cytokines that regulate energy homeostasis, lipid and glucose metabolism. Disturbances in the production of these factors may contribute to metabolic abnormalities, and PPARgamma activation is also associated with beneficial effects on expression and secretion of a whole range of cytokines.

Figure 1

Mechanism of PPARγ activation. Upon ligand binding to the PPAR/RXR heterodimer, a conformational change leads to release of a corepressor and binding of a coactivator; this regulates the kinetics of the assembly of the transcription complex, resulting in increased affinity for the specific PPAR response element, which modulates gene transcription. RXR; Retinoic X receptor; PPRE; PPAR response element.

Figure 2

Insulin signaling pathway in adipose cells. Binding of insulin to its tyrosine kinase receptor engages a cascade of intracellular phosphorylation events, including activation of phosphatidylinositol-3-kinase and ERK-1/2, that promote multiple biological responses, including glucose uptake, lipid metabolism, survival, differentiation, and modulation of gene transcription.

Figure 3

Effects of TZDs and metformin on activation of insulin signaling proteins in tissues from individuals with type 2 diabetes. The effects of troglitazone, pioglitazone, and rosiglitazone on various proteins involved in insulin signaling in skeletal muscle and adipose tissue are indicated. The effects of metformin are also shown for comparison. GDR indicates the glucose disposal rate, as a measure of insulin sensitivity. IR-PY: insulin receptor tyrosine phosphorylation; IRS1: insulin receptor substrate-1; PY: tyrosine phosphorylation; PI3K: phosphatidylinositol 3 kinase. Adapted from [–33].

Figure 4

Cellular effects of PPARγ activation in adipocytes. TZDs improve whole-body insulin sensitivity by modulating glucose and lipid metabolism in adipose tissue as well as adipokine secretion by adipocytes. FA: fatty acids.