Hypothalamic primary cilium: A hub for metabolic homeostasis

Abstract

Obesity is a global health problem that is associated with adverse consequences such as the development of metabolic disorders, including cardiovascular disease, neurodegenerative disorders, and type 2 diabetes. A major cause of obesity is metabolic imbalance, which results from insufficient physical activity and excess energy intake. Understanding the pathogenesis of obesity, as well as other metabolic disorders, is important in the development of methods for prevention and therapy. The coordination of energy balance takes place in the hypothalamus, a major brain region that maintains body homeostasis. The primary cilium is an organelle that has recently received attention because of its role in controlling energy balance in the hypothalamus. Defects in proteins required for ciliary function and formation, both in humans and in mice, have been shown to cause various metabolic disorders. In this review, we provide an overview of the critical functions of primary cilia, particularly in hypothalamic areas, and briefly summarize the studies on the primary roles of cilia in specific neurons relating to metabolic homeostasis.

Fig. 1. Schematic structure of primary cilia.

Immunofluorescence images of primary cilia (green, ADCY3) in hypothalamic cells (a) and arcuate nuclei (b). Scale = 20 μm. Schematic structure of primary cilia (c). The primary cilium is an antenna-like organelle that receives diverse signals from the extracellular environment. It is comprised of the ciliary membrane surrounding the microtubule-based axoneme. The nine parallel microtubule doublets of the axoneme, which show “9 + 0” rings, form the backbone of the appendage, while the basal body acts as a microtubule-organizing center. The components that are transported from the basal body to the ciliary tip by anterograde transport rely on the intraflagellar transport (IFT) protein attached to the motor protein kinesin 2. In contrast, retrograde transport from the ciliary tip to the cytoplasm depends on dynein motor proteins. The ciliary membrane is highly enriched with several receptors, including G protein-coupled receptors (GPCRs).

Fig. 2. Hypothalamic nuclei involved in the regulation of energy balance.

Energy homeostasis is regulated by a complex feedback loop involving endocrine and neuronal signals originating from peripheral organs and intrahypothalamic communications. The ARC is a key nucleus that houses POMC and AgRP/NPY neurons, which integrate the aforementioned signals. These neurons project to various nuclei, including the PVN, VMH, and LH. In turn, the ARC receives input from the VMH and LH. The NTS receives projections from the ARC, PVN, VMH, and LH and regulates multiple metabolic effectors of energy balance. 3 V, third ventricle; AgRP, agouti-related protein; ARC, arcuate nucleus; LH, lateral hypothalamus; ME, median eminence; NPY, neuropeptide Y; NTS, nucleus of tractus solitarius; POMC, proopiomelanocortin; PVN, paraventricular nucleus; SF-1, steroidogenic factor 1; and VMH, ventromedial hypothalamus.

Fig. 3. Ciliary genes in the hypothalamic nuclei involved in metabolic dysfunction.

Simplified overview of metabolic changes as a consequence of the mutation of ciliary genes in the indicated hypothalamic neurons. Notably, primary cilia play a distinct homeostatic role in each hypothalamic nucleus.