Molekylära mekanismer bakom funktionerna av nya fetma gener

We are using animal models to characterizing the expression and function of number of genes that have been linked to obesity but with little information on their function, except that most of them are hypothalamic (Willer et al., Nat Genet. 2009). SNPs in FTO, TMEM18, KCTD15, GNPDA2, MTCH2 and NEGR1 are associated with BMI. For example, we showed by in situ hybridization and gene regulation studies that FTO is highly expressed in nuclei responsible for regulating appetite and food intake, such as the nucleus of the solitary tract, area postrema, arcuate, paraventricular and supraoptic nuclei, as well as in the bed nucleus of the stria terminalis (Fredriksson et al, 2008, Endocrinology). This paper has become highly cited. Co-labelling showed that the FTO gene is predominantly expressed in neurons while it was virtually not found in glia cells. We also mapped the expression of FTO, both with in situ (Olszewski et al, BMC Neuroscience, 2009, and with our own new specific antibody that the FTO expression is differentially regulated within the feeding nuclei within reward- and hunger-related sites. Interestingly, our in situ hybridization showed colocalization of FTO with anorexigenic oxytocin. Food deprivation upregulated FTO mRNA, while leucine downregulated it. Consumption of palatable diets or macronutrient preference did not affect FTO expression. However, the propensity to ingest more energy without an effect on body weight was associated with lower FTO mRNA levels. Furthermore, we found that a 4-fold higher number of FTO cells displayed c-Fos at meal termination as compared to initiation in the paraventricular and arcuate nuclei of re-fed mice. We suggest that FTO is important for energy intake rather than feeding reward and that it participates in termination of feeding. Interestingly, baseline FTO expression was not only linked with energy intake but also energy metabolism. We currently using our animal models, including transgenic mice to in detail map number of other genes in order to try to unravel their functional role for obesity.

Kontakt

Gruppledare:

Prof. Helgi Schiöth

e-mail: helgi.schioth@neuro.uu.se

Kontakt

Christian Benedict

Christian Benedict, forskare, docent

e-mail: christian.benedict@neuro.uu.se

Twitter: https://twitter.com/christi17855128

Facebook: Sleep science (public group)