Saturday, December 8, 2012

Hindsight: PPARg and Adipose Tissue

Back in 2006 there was a tremendous interest in the biology of peroxisome proliferator-activated receptor gamma (PPARg).

Not only had this nuclear hormone receptor been well recognised as a key regulator of adipocyte differentiation, but the introduction of thiazolidinediones (“glitazones”) in diabetes treatment sparked a tremendous amount of work in this ligand.

In a paper I co-athored with my French colleague Bart Staels, published in the Journal of Clinical Endocrinology and Metabolism in 2006, we reviewed the literature on the role of PPARg in regulating lipid and glucose metabolism in adipose tissue.

Our review included all articles we could find on the role of PPARg in adipose tissue of healthy individuals and those with obesity, metabolic syndrome, or type 2 diabetes published between 1990 and 2006.

As we discuss in detail in the article, PPARg is highly expressed in adipose tissue, where its activation with thiazolidinediones alters fat topography and adipocyte phenotype and up-regulates genes involved in fatty acid metabolism and triglyceride storage.

In addition, PPARg activation is associated with potentially beneficial effects on the expression and secretion of a range of factors, including adiponectin, resistin, IL-6, TNFalpha, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and angiotensinogen, as well as a reduction in plasma nonesterified fatty acid supply.

This effects of PPARg-agonists also extends to macrophages, where they suppress production of inflammatory mediators.

Thus, we speculated that PPARg-activating ligands may have a role in preventing progression of insulin resistance to diabetes and endothelial dysfunction to atherosclerosis.

Since then the optimism about this class of medications has been tempered by the fact that larger clinical trials have raised concerns particularly about cardiovascular complications in patients with heart failure.

At the time, however, this state-of-the-art review received considerable attention with over 230 citations to date.

Edmonton, Alberta

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