title: Mouse models of PPAR-gamma deficiency: dissecting PPAR-gamma's role in metabolic homoeostasis.
abstract: The identification of humans with mutations in PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) has underlined its importance in the pathogenesis of the metabolic syndrome. Genetically modified mice provide powerful tools to dissect the mechanisms by which PPAR-gamma regulates metabolic processes. Ablation of PPAR-gamma in vivo is lethal and thus dissection of PPAR-gamma 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-gamma impairment and are useful to elucidate how PPAR-gamma regulates specific metabolic processes. These murine models have confirmed the involvement of PPAR-gamma in adipose tissue development, maintenance and distribution. The mechanism involved in PPAR-gamma regulation of glucose homoeostasis is obscure as both agonism and partial impairment of PPAR-gamma increase insulin sensitivity. While adipose tissue is likely to be the primary target for the insulin-sensitizing effects of PPAR-gamma, some murine models suggest PPAR-gamma expressed outside adipose tissue may also contribute actively to maintain glucose homoeostasis. Interestingly, mutations in PPAR-gamma 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-gamma have provided useful in vivo systems to dissect the function of PPAR-gamma, but additionally have revealed a picture of complexity. These models have confirmed a key role for PPAR-gamma in the metabolic syndrome; however, they challenge the concept that insulin resistance is the main factor linking the clinical manifestations of the metabolic syndrome.
authors.affiliation: Department of Clinical Biochemistry, University of Cambridge, Box 232, Addenbrooke's Hospital, Level 4, Cambridge CB2 2QR, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Gray
authors.forename: E
authors.initials: E
authors.lastname: Dalla Nora
authors.forename: A J
authors.initials: AJ
authors.lastname: Vidal-Puig
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis; D008055:Lipids / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D047495:PPAR gamma / Q000172:deficiency* / Q000235:genetics; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D008055:Lipids; D047495:PPAR gamma; D020033:Protein Isoforms