Aims/hypothesis The aim of this study was to determine the dependency on peroxisome proliferator-activated receptor-γ (PPAR-γ) of insulin sensitisation and glucose homeostasis by thiazolidinediones using a global Ppar-γ (also known as Pparg)-knockout mouse model. Methods Global Mox2-Cre-Ppar-γ-knockout (MORE-PGKO) mice were treated with rosiglitazone and analysed for insulin sensitivity and glucose metabolism. Metabolic and hormonal variables were determined. Adipose and other tissues were measured and analysed for gene expression. Results Rosiglitazone induced regrowth of fat in female but not male MORE-PGKO mice, and only in specific depots. Insulin sensitivity increased but, surprisingly, was not associated with the typical changes in adipokines, plasma NEFA or tissue triacylglycerol. However, increases in alternatively activated macrophage markers, which have been previously associated with metabolic improvement, were observed in the regrown fat. Rosiglitazone improved glucose homeostasis but not insulin sensitivity in male MORE-PGKO mice, with further increase of insulin associated with an apparent expansion of pancreatic islets. Conclusions/interpretation Stimulating fat growth by rosiglitazone is sufficient to improve insulin sensitivity in female mice with 95% PPAR-γ deficiency. This increase in insulin sensitivity is not likely to be due to changes typically seen in adipokines or lipids but may involve changes in macrophage polarisation that occur independent of PPAR-γ. In contrast, rosiglitazone improves glucose homeostasis in male mice with similar PPAR-γ deficiency by increasing insulin production independent of changes in adiposity. Further, the insulin-sensitising effect of rosiglitazone is dependent on PPAR-γ in this male lipodystrophic model. © Springer-Verlag 2010.