Cilia and Obesity

Abstract

The ciliopathies Bardet-Biedl syndrome and Alström syndrome cause obesity. How ciliary dysfunction leads to obesity has remained mysterious, partly because of a lack of understanding of the physiological roles of primary cilia in the organs and pathways involved in the regulation of metabolism and energy homeostasis. Historically, the study of rare monogenetic disorders that present with obesity has informed our molecular understanding of the mechanisms involved in nonsyndromic forms of obesity. Here, we present a framework, based on genetic studies in mice and humans, of the molecular and cellular pathways underlying long-term regulation of energy homeostasis. We focus on recent progress linking these pathways to the function of the primary cilia with a particular emphasis on the roles of neuronal primary cilia in the regulation of satiety.

Figure 1.

Model of how ciliary signaling may contribute to energy homeostasis. Certain G-protein-coupled receptors (GPCRs) and signaling machinery, such as Sstr3, Mchr1, Drd1, Kiss1r, Htr6, and Adcy3, localize to the cilia membrane of neurons in specific brain regions. Intraflagellar transport (IFT) mutation results in loss of the cilium. In mouse models of Bardet–Biedl syndrome (BBS), both ciliary GPCRs and membrane-associated Lepr localization are perturbed. In Alström syndrome (ALMS) mouse models, GPCRs remain at cilia, but Adcy3 no longer localizes appropriately to cilia. Taken together, these models convey the complexity of the cilium as a signaling center and indicate that there are differing requirements for membrane protein localization to cilia.