[PDF][PDF] Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice

G Stratigopoulos, JFM Carli, DR O'Day, L Wang… - Cell metabolism, 2014 - cell.com
G Stratigopoulos, JFM Carli, DR O'Day, L Wang, CA LeDuc, P Lanzano, WK Chung
Cell metabolism, 2014cell.com
Common polymorphisms in the first intron of FTO are associated with increased body weight
in adults. Previous studies have suggested that a CUX1-regulatory element within the
implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L.
Given the role of ciliary genes in energy homeostasis, we hypothesized that mice
hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l+/− mice
are hyperphagic and fatter, and display diminished suppression of food intake in response …
Summary
Common polymorphisms in the first intron of FTO are associated with increased body weight in adults. Previous studies have suggested that a CUX1-regulatory element within the implicated FTO region controls expression of FTO and the nearby ciliary gene, RPGRIP1L. Given the role of ciliary genes in energy homeostasis, we hypothesized that mice hypomorphic for Rpgrip1l would display increased adiposity. We find that Rpgrip1l+/− mice are hyperphagic and fatter, and display diminished suppression of food intake in response to leptin administration. In the hypothalamus of Rpgrip1l+/− mice, and in human fibroblasts with hypomorphic mutations in RPGRIP1L, the number of AcIII-positive cilia is diminished, accompanied by impaired convening of the leptin receptor to the vicinity of the cilium, and diminished pStat3 in response to leptin. These findings suggest that RPGRIP1L may be partly or exclusively responsible for the obesity susceptibility signal at the FTO locus.
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