The results of this study support the assessment of FGS in community-dwelling older adults to gain insight into physical health status. Interventions directed toward FGS, balance, and BMI may contribute to optimum HRQL in this population.

Primary cilia are cellular appendages critical for diverse types of singling. They are found on most cell types, including cells throughout the central nervous system. Cilia preferentially localize certain G protein-coupled receptors (GPCRs) and are critical for mediating the signaling of these receptors. Several of these neuronal GPCRs have recognized roles in feeding behavior and energy homeostasis. Cell and model systems likeC. elegansandChlamydomonashave implicated both dynamic GPCR cilia localization and cilia length and shape changes as key for signaling. It is unclear if mammalian ciliary GPCRs utilize similar mechanismsin vivoand under what conditions these processes may occur. Here, we assess two neuronal cilia GPCRs, melanin-concentrating hormone receptor 1 (MCHR1) and neuropeptide-Y receptor 2 (NPY2R), as mammalian model ciliary receptors in the mouse brain. We test the hypothesis that dynamic localization to cilia occurs under physiological conditions associated with these GPCRs’ functions. Both receptors are involved in feeding behaviors, and MCHR1 is also associated with sleep and reward. Cilia were analyzed with a computer-assisted approach allowing for unbiased and high throughput analysis. We measured cilia frequency, length, and receptor occupancy. We observed changes in ciliary length, receptor occupancy, and cilia frequency under different conditions for one receptor but not another and in specific brain regions. These data suggest that dynamic cilia localization of GPCRs depends on properties of individual receptors and cells where they are expressed. A better understanding of subcellular localization dynamics of ciliary GPCRs could reveal unknown molecular mechanisms regulating behaviors like feeding.Significance StatementOften, primary cilia localize specific G protein-coupled receptors (GPCRs) for subcellular signaling. Cell lines and model systems indicate that cilia deploy dynamic GPCR localization and change their shape or length to modulate signaling. We used mice to assess neuronal cilia GPCRs under physiological conditions associated with the receptors’ known functions and ciliopathy clinical features like obesity. We show that particular cilia with specific GPCRs appear to dynamically alter their length while others appear relatively stable under these conditions. These results implicate multiple themes across cilia GPCR mediated signaling and indicate that not all cilia modulate GPCR signaling using the same mechanisms. These data will be important for potential pharmacological approaches to target cilia GPCR-mediated signaling.

The hedgehog signaling pathway is best known for its role in developmental patterning of the neural tube and limb bud. More recently, hedgehog signaling has been recognized for its roles in growth of adult tissues and maintenance of progenitor cell niches. However, the role of hedgehog signaling in fully differentiated cells like neurons in the adult brain is less clear. In

A subset of genetic disorders termed ciliopathies are associated with obesity. The mechanisms behind cilia dysfunction and altered energy homeostasis in these syndromes are complex and likely involve deficits in both development and adult homeostasis. Interestingly, several cilia-associated gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis, including their roles in centrally mediated food intake and peripheral tissues, many questions remain. Here, we briefly discuss syndromic ciliopathies and monogenic cilia signaling mutations associated with obesity. We then focus on potential ways neuronal cilia regulate energy homeostasis. We discuss the literature around cilia and leptin-melanocortin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We also discuss the different brain regions where cilia are implicated in energy homeostasis and the potential for cilia dysfunction in neural development to contribute to obesity. We close with a short discussion on the challenges and opportunities associated with studies looking at neuronal cilia and energy homeostasis. This review highlights how neuronal cilia-mediated signaling is critical for proper energy homeostasis.