The identification of humans with mutations in PPAR-γ (peroxisome-proliferator-activated receptor-γ) has underlined its importance in the pathogenesis of the metabolic syndrome. Genetically modified mice provide powerful tools to dissect the mechanisms by which PPAR-γ regulates metabolic processes. Ablation of PPAR-γ in vivo is lethal and thus dissection of PPAR-γ function using mouse models has relied on the development of tissue and isoform-specific ablation and mouse models of human mutations. These models exhibit phenotypes of partial PPAR-γ impairment and are useful to elucidate how PPAR-γ regulates specific metabolic processes. These murine models have confirmed the involvement of PPAR-γ in adipose tissue development, maintenance and distribution. The mechanism involved in PPAR-γ regulation of glucose homoeostasis is obscure as both agonism and partial impairment of PPAR-γ increase insulin sensitivity. While adipose tissue is likely to be the primary target for the insulin-sensitizing effects of PPAR-γ, some murine models suggest PPAR-γ expressed outside adipose tissue may also contribute actively to maintain glucose homoeostasis. Interestingly, mutations in PPAR-γ that cause severe insulin resistance in humans when expressed in mice do not result in insulin insensitivity. However, these murine models can recapitulate the effects in fuel partitioning, post-prandial lipid handling and vasculature dysfunction observed in humans. In summary, these murine models of PPAR-γ have provided useful in vivo systems to dissect the function of PPAR-γ, but additionally have revealed a picture of complexity. These models have confirmed a key role for PPAR-γ in the metabolic syndrome; however, they challenge the concept that insulin resistance is the main factor linking the clinical manifestations of the metabolic syndrome.

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