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• _3 value "Thus, animals lacking functional PPAR-gamma in skeletal muscle do not show TZD-induced skeletal muscle insulin sensitization. During the glucose clamp studies, we also measured circulating FFA levels (Fig. 5b) and HGP (Fig. 5c); because the effects of both TZDs were the same in the MKO animals (Fig. 5b), the data were combined. Basal FFA levels were elevated and poorly suppressed by insulin in the untreated MKO animals, whereas TZD administration decreased basal FFA levels below control values and enhanced the suppressive effects of insulin. In the untreated MKO animals, HGP was slightly elevated in the basal state, and the suppressive effects of insulin were significantly (P = 0.019) attenuated (Fig. 5c). After TZD treatment, basal HGP was decreased and the suppressive effects of insulin were restored (P = 0.006). TZDs also led to an increase of 2.9-fold (P = 0.0001) in intrahepatic triglyceride content, consistent with findings in other TZD-treated mouse models of insulin resistance38. Thus, TZDs exert their expected effects in adipose tissue and liver, but not muscle, in MKO animals. Plasma glucose, insulin, triglyceride and FFA levels were all decreased in vivo in the TZD-treated animals (Table 1). Thus, despite the fact that TZD treatment did not improve insulin sensitization in skeletal muscle, most of the other symptoms of Syndrome X were ameliorated, highlighting the importance of adipose tissue and liver as target organs for TZDs. Protein and gene expression measurements Using quantitative PCR to measure mRNA expression of selected genes in skeletal muscle, we found that PPAR-alpha mRNA and AMPK protein levels were unchanged in MKO animals compared with controls, and were unaffected by TZD treatment (data not shown). Pyruvate dehydrogenase kinase-4 (PDK-4) and uncoupling protein-3 (UCP-3) mRNA levels were also comparable in MKO mice compared with controls (data not shown), but TZD administration caused a significant 85% decrease in UCP-3 and a 60% decrease in PDK-4 mRNA in all groups (P = 0.0003 and 0.02, respectively)." provenance.