Functional genetic dissection of nuclear receptor signalling in obesity, diabetes and liver regeneration using spatio-temporally controlled somatic mutagenesis in the mouse

Abstract

The mouse is an excellent animal model for defining human diseases. The null allele mutations (knockouts, KO) have already provided valuable information about their functions, but have also revealed major complications and difficulties: (1) an early embryonic lethality, (2) temporal effect (developmental stage or adult stage), (3) functional redundancy and (4) spatio-effect (cell-autonomous or non-autonomous). To overcome these limitations, spatio-temporally controlled somatic mutagenesis, Cre-ER T/LoxP system, was established. The nuclear receptors (NRs) play central roles in development, organogenesis, metabolism and energy homeostasis through their ability to transduce hormonal signals into modulation of gene activity. Obesity, excess energy storage in adipose tissue, has a strong link to diabetes. Among NRs, retinoid X receptor α (RXRα)-peroxisome proliferator-activated receptor γ (PPARγ) heterodimers can mediate adipocyte differentiation and obesity which has been demonstrated with in vitro cell culture systems and RXR- and PPARγ-specific ligand studies. Therefore an adipocyte-specific temporally controlled somatic mutagenesis system was established and analysed. Furthermore, the functional roles of NRs to control liver regeneration were also studied with similar system in hepatocytes.