MedWire News: The ability of pioglitazone to reduce non-esterified fatty acids (NEFAs) is due to its ability to sensitize adipose tissue to insulin, researchers have shown.

“It is generally believed that thiazolidinediones ameliorate lipotoxicity and insulin resistance at least in part by reducing circulating levels of NEFAs,” write Michal Pravenec (Czech Academy of Sciences, Prague) and co-workers.

However, the exact mechanism by which thiazolidinediones alter NEFA levels remains unclear.

Pre-clinical studies have shown that rosiglitazone reduces NEFA production by promoting glyceroneogenesis and promoting fatty acid re-esterification in adipocytes. In contrast, long-term administration of thiazolidinediones has been shown to increase NEFA release from adipose tissues.

To investigate further, Pravenec and team studied rats with hypertension and the metabolic syndrome that were treated with pioglitazone for 4 months.

This treatment increased the basal release of NEFA three-fold and the release of NEFA in response to adrenaline 2.6 times. Treatment also almost completely eliminated the re-esterification of NEFA in epididymal adipose tissue.

In addition, pioglitazone treatment increased the amount of mitochondrial DNA found in adipose tissue over three-fold, suggesting significantly increased general fat oxidation. Specifically, the researchers found that pioglitazone significantly increased palmitate oxidation in the soleus muscle.

Despite all these changes, however, pioglitazone treatment significantly decreased both fasting and postprandial circulating NEFA concentrations.

The authors suggest that “long-term administration of pioglitazone may promote reduced NEFA levels in part by increasing adipose tissue sensitivity to the anti-lipolytic effects of insulin, increasing CD36-mediated cellular uptake of fatty acids and by enhancing NEFA oxidation in skeletal muscle or other tissues as well.”

The results are published in the International Journal of Obesity.

Free abstract