The cilium: a cellular antenna with an influence on obesity risk

Abstract

Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype-phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro-and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

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

“…A genetically heterogeneous class of disorders, termed ciliopathies, is characterized by mutations in genes that encode more than 40 proteins that contribute to the establishment and/or function of the primary cilium (19). Phenotypes shared among members of this class of disorders include renal and retinal dysfunction as well as developmental malformations, such as polydactyly and defects of the CNS.…”

“…Phenotypes shared among members of this class of disorders include renal and retinal dysfunction as well as developmental malformations, such as polydactyly and defects of the CNS. Some ciliopathies-that is, Bardet-Biedl syndrome (BBS) and Alström syndrome-also present with comorbid severe obesity (18,19). Hyperphagia, presumably of hypothalamic origin, is a primary contributor to the obesity observed in individuals with ciliopathies (53,54).…”

“…Rpgrip1l is a component of the transition zone of the primary cilium (17). The primary cilium-functioning as a cellular antenna-plays a key role in coordinating a wide range of signal transduction systems, including those related to body weight homeostasis (18,19). Mice that are ABBREVIATIONS: BBS, Bardet-Biedl syndrome; BrdU, 5-bromo-29deoxyuridine; CUX1, cut-like homeobox 1; FBS, fetal bovine serum; FTO, a-ketoglutarate-dependent dioxygenase; HFD, high-fat diet; Hh, hedgehog; IBMX, isobutylmethylxanthine; PGAT, perigonadal adipose tissue; RPGRIP1L, retinitis pigmentosa GTPase regulator-interacting protein 1 like; SAg, smoothened agonist; SCAT, subcutaneous adipose tissue; siCtr, control small interfering RNA; siRNA, small interfering RNA; SNP, single nucleotide polymorphism heterozygous for a null Rpgrip1l allele are hyperphagic and obese (16,20).…”

To beat, or not to beat, that is question! The spectrum of ciliopathies

“…Non‐motile cilia play a role in the pathogenesis of certain types of obesity and diabetes, through appetite control via neuronal food intake regulation and food odor perception, adipogenesis, insulin metabolism, and resistance to leptin …”

Mechanisms for nonmitotic activation of Aurora-A at cilia

“…Ciliary disorders of the skeleton are found in Jeune asphyxiating thoracic dystrophy [119, 120], Ellisvan Creveld syndrome, Sensen-Brenner syndrome (cranioectodermal dysplasia) and several others [121]. Some ciliary proteins contribute to regulation of metabolism and vascular development, with dysfunctions in components of the ciliary proteome leading to an increased risk of obesity [122-124] and predispose to the development of atherosclerotic plaques [125, 126]. …”