Hypomorphism for RPGRIP1L, a Ciliary Gene Vicinal to the FTO Locus, Causes Increased Adiposity in Mice

Abstract

Summary Common polymorphisms in the first intron of FTO are associated with a 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, 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 ciliais 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.

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

“…We have previously shown that Rpgrip1l hypomorphism increases food intake and adiposity (21). Based on our finding that the obesity-risk alleles at rs8050136 and rs1421085 correlate with decreased RPGRIP1L/FTO expression in human neuronal cells, we examined the effects on adiposity of RPGRIP1L/FTO compound hypomorphism in vivo.…”

“…The increased food intake of Rpgrip1l +/-mice is accompanied by diminished responses of arcuate neurons to i.p. administration of leptin (21). We examined leptin sensitivity in Rpgrip1l +/-Fto +/-and Fto +/-mice at 5 weeks of age, when no differences in body mass or composition were present ( Figure 3D).…”

“…We previously reported that, in the hypothalamus of the Rpgrip1l +/-mouse and in human fibroblasts with biallelic hypomorphic mutations of RPGRIP1L (from patients with Joubert syndrome), the number of adenylyl cyclase 3-positive (AC3-positive) cilia is diminished, accompanied by impaired leptin-stimulated convening of LEPR to the vicinity of the cilium and diminished hypothalamic pSTAT3 generation in response to leptin (21). Congenital systemic deletion of Ac3 results in obesity in mice (32).…”

“…A prediction from these findings is that the relative increase in P200 and decrease in P110 resulting from low cathepsin L activity leads to reduced RPGRIP1L/FTO expression and increased food intake. RPGRIP1L/FTO expression is decreased in leptin-deficient (Lep ob ) mice and upregulated by leptin administration in these animals, indicating that RPGRIP1L/FTO may have anorectic effects via the canonical leptin signaling pathway (18,19 (19,21). Based on these findings, we hypothesized that the FTO obesity-risk allele at rs8050136 alters CUX1 binding, leading to decreased hypothalamic RPGRIP1L/FTO, diminished leptin sensitivity, and increased food intake.…”

Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation

“…Murine models have proven to be highly useful in bridging the gap between the identification of a variant as being associated with an adiposity phenotype and the understanding of how that variant actually influences energy balance. For example, the robust correlation between BMI and polymorphisms in the first intron of the human fat mass and obesity-associated (FTO) gene has been followed by loss and gain of function studies in genetically modified mice, supporting the notion that a number of neighboring genes including IRX3 (which is the gene most likely mediating the effect of the human SNP), RPGRIP1L, and FTO itself can all play a role in the control of energy balance and body composition (7)(8)(9)(10)(11)(12)(13). A strong association between increased BMI and a region of human chromosome 2, near to the gene TMEM18, has been repeatedly demonstrated in both adults and children (2,(14)(15)(16)(17)(18).…”