Insulin-resistance/Type II Diabetes

Over the last years PPARγ has become the most clinically important drug target in type II diabetes by virtue of its function as a receptor for the widely prescribed insulin sensitizers thiazolidinediones (TZDs). However, the mechanisms of action of PPARγ as the insulin sensitizing effector of TZDs are still at large. Confusingly, while one would expect that reduced PPARγ gene dosage should decrease sensitivity to insulin, mice hemizygous for PPARγ rather display elevated insulin sensitivity, reopening the question about the true role of PPARγ in glucose homeostasis.

We use gene targeting approaches to address two broad questions about the functions of PPARγ in insulin action:

  1. Given that the major insulin consumer is skeletal muscle tissue, whereas PPARγ  is most abundantly expressed in fat, where do the insulin-sensitizing activities of PPARγ originate? One possibility is that minute quantities of PPARγ produced in each insulin-responsive tissue, including muscle, regulate insulin response in a tissue-autonomous fashion. The other possibility, which is our current favorite, is that abundant activity of PPARγ in a central depot, ie fat, accounts for systemic insulin sensitivity in a non-autonomous fashion, for example by regulating the expression of a secreted insulin sensitizing factor. To distinguish between these two possibilities, we use mice carrying a floxed PPARγ allele to generate tissue-specific knockouts of PPARγ  in skeletal muscle and fat and compare their glucose and insulin tolerance.

  2. What will be the physiological outcome of complete PPARγ deficiency in the adult? Since constitutive PPARγ deficiency is embryonic and neonatal-lethal, and the CRE-lox system fails to yield complete deletion of PPARγ in any single tissue, we designed a novel inducible PPARγ knockout allele, which enables to keep PPARγ expression intact, until a chosen point in time when we can inactivate it in the whole animal and assess the outcome.

Identification of the tissue/s that account for the insulin-sensitizing activity of PPARγ will enable us to go back to the inducible knockout system, using it as a differential platform to isolate PPARγ target genes from these tissues. One or more of these genes likely underlie the insulin-sensitizing activities of TZDs.