Obesity and aging have divergent genomic fingerprints.

Aging is associated with increased visceral fat, and recent studies suggested that in turn, visceral fat could influence longevity. We therefore tested whether obesity could be a condition of premature aging. Whole-genome microarray analysis of gene expression between obese mice, aged mice and their respective controls, revealed that long-term adaptations in gene expression in visceral fat upon aging are different from those occurring during fat accretion in young adult animals, suggesting specific, divergent and non overlapping pathways of regulation.

Atypical transcriptional regulators and cofactors of PPARgamma.

Regulation of peroxisome proliferator-activated receptor gamma (PPARgamma) activity is the result of several events. The first control level is the regulation of the expression of PPARgamma. Examples of this regulation, during adipogenesis, is the transactivation of the PPARgamma promoter by transcription factors of the classical pathway, such as C/EBPs or ADD1/SREBP1, but also newly identified factors, such as E2Fs. When preadipocytes re-enter the cell cycle, PPARgamma expression is induced coincident with an increase in DNA synthesis, suggesting the involvement of the E2F family of cell cycle regulators. E2F1 induces PPARgamma transcription during clonal expansion, whereas E2F4 represses PPARgamma expression during terminal adipocyte differentiation. Hence, E2Fs represent the link between proliferative signaling pathways, triggering clonal expansion, and terminal adipocyte differentiation through regulation of PPARgamma expression. A second regulatory level of PPARgamma action is interaction with cofactors. We will focus our attention on the atypical PPARgamma modulators. We have described an interaction between PPARgamma and the retinoblastoma protein, RB, which is both dependent upon ligand binding by PPARgamma and upon the phosphorylation status of RB. The interaction between PPARgamma and RB decreases the transcriptional activity of PPARgamma through recruitment of the histone deacetylase HDAC3. Inhibition of HDAC activity consequently results in a strong activation of PPARgamma.

Alterations in the incisor development in the Tabby mouse.

The X-linked tabby (Ta) syndrome in the mouse is homologous to the hypohidrotic ectodermal dysplasia (HED) in humans. As in humans with HED, Ta mice exhibit hypohidrosis, characteristic defects of hairs and tooth abnormalities. To analyze the effects of Ta mutation on lower incisor development, histology, morphometry and computer-aided 3D reconstructions were combined. We observed that Ta mutation had major consequences for incisor development leading to abnormal tooth size and shape, change in the balance between prospective crown- and root-analog tissues and retarded cytodifferentiations. The decrease in size of Ta incisor was observed at ED13.5 and mainly involved the width of the tooth bud. At ED14.5-15.5, the incisor appeared shorter and narrower in the Ta than in the wild type (WT). Growth alterations affected the diameter to a greater extent than the length of the Ta incisor. From ED14.5, changes in the shape interfered with the medio-lateral asymmetry and alterations in the posterior growth of the cervical loop led to a loss of the labio-lingual asymmetry until ED17.0. Although the enamel organ in Ta incisors was smaller than in the WT, a larger proportion of the dental papilla was covered by preameloblasts-ameloblasts. These changes apparently resulted from reduced development of the lingual part of the enamel organ and might be correlated with a possible heterogeneity in the development of the enamel organ, as demonstrated for upper incisors. Our observations suggest independent development of the labial and lingual parts of the cervical loop. Furthermore, it appeared that the consequences of Ta mutation could not be interpreted only as a delay in tooth development.