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. Author manuscript; available in PMC: 2013 Feb 27.
Published in final edited form as: Circ Res. 2012 Jan 6;110(1):8–11. doi: 10.1161/RES.0b013e3182435d88

Figure 1.

Figure 1

High fat diet (HFD), obese or leptin-deficient ob/ob mice exhibit increases free fatty acids (FFA) and cytokines, which activate CDK5. CDK5 phosphorylates Ser273 on PPARγ resulting in dysregulated expression of a series of genes considered to be insulin sensitizers such as adiponectin. This leads to glucose intolerance, insulin resistance and ultimately diabetes. The phosphorylation of PPARγ by CDK5 can be blocked by TZDs or SR1664 thus promoting preserved expression of adiponectin. In the paradigm show here, CDK5 through Ser273-P on PPARγ switches off the rheostat, an effect blocked by SR1664, TZDs, and perhaps some endogenous ligands. TZDs also cause a transition from a state of basal activity, to one that is fully activated leading to PPRE-mediated transactivation of many genes involved in adipogenesis, fluid retention, and alter gene expression in osteoblasts. Here, the volume on the rheostat is turned to its maximum setting. It remains unclear if endogenous ligands can modulate the activity of the rheostat thus regulating the level of PPARγ activation, and if so, why this is impaired in obesity.