Several independent, genome-wide association studies have identified a strong correlation between body mass index and polymorphisms in the human FTO gene. Common variants in the first intron define a ...risk allele predisposing to obesity, with homozygotes for the risk allele weighing approximately 3 kilograms more than homozygotes for the low risk allele. Nevertheless, the functional role of FTO in energy homeostasis remains elusive. Here we show that the loss of Fto in mice leads to postnatal growth retardation and a significant reduction in adipose tissue and lean body mass. The leanness of Fto-deficient mice develops as a consequence of increased energy expenditure and systemic sympathetic activation, despite decreased spontaneous locomotor activity and relative hyperphagia. Taken together, these experiments provide, to our knowledge, the first direct demonstration that Fto is functionally involved in energy homeostasis by the control of energy expenditure.
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In this study we show in mice that Ftm (Rpgrip1l) is located at the ciliary basal body. Our data reveal that Ftm is necessary for developmental processes such as the establishment of left-right ...asymmetry and patterning of the neural tube and the limbs. The loss of Ftm affects the ratio of Gli3 activator to Gli3 repressor, suggesting an involvement of Ftm in Shh signalling. As Ftm is not essential for cilia assembly but for full Shh response, Ftm can be considered as a novel component for cilium-related Hh signalling. Furthermore, the absence of Ftm in arthropods underlines the divergence between vertebrate and Drosophila Hh pathways.
Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with ...primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.
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4.
Fischer et al. reply Brüning, Jens C; Rüther, Ulrich; Emmerling, Christian ...
Nature,
04/2010, Letnik:
464, Številka:
7289
Journal Article
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Replying to: J. R. Speakman Nature 464, 10.1038/nature08807 (2010)The human studies on FTO reported an association of an intronic single nucleotide polymorphism (SNP) with obesity. Our report of mice ...with the targeted inactivation of the Fto gene demonstrated a direct role of Fto in energy homeostasis. We have shown that the absence of Fto protein results in leanness and that Fto deficiency affects energy homeostasis. Speakman exemplifies that the experiments performed in mice conflict with results in humans carrying the FTO risk allele presenting hyperphagia and increased caloric intake.
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Nature 458, 894-898 (2009) An intronic single nucleotide polymorphism (SNP) (rs9939609) close to the fat mass and obesity associated gene (FTO) was the first SNP to be discovered with common variants ...linked to body mass index1; at least seven studies in humans have implicated this SNP with variations in food intake and satiety2-8, and four studies have rejected an effect on energy expenditure normalized for body weight2,5,6,8. ... the difference in food intake between genotypes required to generate the observed differences in body fatness was about 0.02 g day^sup -1^ in the females and 0.07 g day^sup -1^ in males. ... there is the same power issue highlighted above with respect to food intake, except that there is even less power in the expenditure measures as the total sample is only 23 individuals.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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