The role of Rpgrip1l, a component of the primary cilium, in adipocyte development and function

Abstract

Genetic variants within the FTO (α-ketoglutarate-dependent dioxygenase) gene have been strongly associated with a modest increase in adiposity as a result of increased food intake. These risk alleles are associated with decreased expression of both FTO and neighboring RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein 1 like). RPGRIP1L encodes a protein that is critical to the function of the primary cilium, which conveys extracellular information to the cell. Rpgrip1l mice exhibit increased adiposity, in part, as a result of hyperphagia. Here, we describe the effects of Rpgrip1l in adipocytes that may contribute to the adiposity phenotype observed in these animals and possibly in humans who segregate for FTO risk alleles. Loss of Rpgrip1l in 3T3-L1 preadipocytes increased the number of cells that are capable of differentiating into mature adipocytes. Knockout of Rpgrip1l in mature adipocytes using Adipoq-Cre did not increase adiposity in mice that were fed chow or a high-fat diet. We also did not observe any effects of Rpgrip1l knockdown in mature 3T3-L1 adipocytes. Thus, to the extent that Rpgrip1l affects cell-autonomous adipose tissue function, it may do so as a result of the effects conveyed in preadipocytes in which the primary cilium is functionally important. We propose that decreased RPGRIP1L expression in preadipocytes in humans who segregate for FTO obesity risk alleles may increase the storage capacity of adipose tissue.-Martin Carli, J. F., LeDuc, C. A., Zhang, Y., Stratigopoulos, G., Leibel, R. L. The role of Rpgrip1l, a component of the primary cilium, in adipocyte development and function.

Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development

“…The inconsistencies in correlation of allelic variation to expression of FTO and vicinal genes may be attributed to the possibility that different haplotypes within intron 1 affect different genes and, thereby, different physiological process. This possibility would be consistent with multiple mechanisms (72) at different levels of penetrance and within different race/ethnicities, underlying such a statistically strong effect of noncoding alleles on adiposity. The present study focuses on the action of RPGRIP1L in neurons, in which expression of RPGRIP1L, but not IRX3/IRX5, is correlated in an FTO intronic allele dose-dependent manner (8).…”

Recruitment of CTCF to anFtoenhancer is responsible for transgenerational inheritance of obesity

“…4F). Several of these genes, including Rpgrip1l, Irx3, Irx5, Slc6a2, and Mmp2, have been shown to be involved in the regulation of body size and obesity by affecting appetite and food consumption ( 31-35 ), which agrees with observations indicating that BPA-F4 mice have increased food consumption (Fig. 1F).…”

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

“…Furthermore, the loss of function of ciliary protein retinitis pigmentosa GTPase regulator-interacting protein 1 like (RPGRIP1L), which localizes to the primary cilium transition zone and is required for Hh signaling, contributes to the 3T3-L1 preadipocytes differentiating into mature adipocytes. This effect, however, is not observed in mature 3T3-L1 adipocytes, which indicates the specific function of primary cilia in adipogenesis [107,108]. In combination, these results reveal the important function of primary cilia in suppressing preadipocyte differentiation.…”