Metabolic regulation and energy homeostasis through the primary Cilium

Abstract

Obesity and diabetes represent a significant healthcare concern. In contrast to genome-wide association studies that, some exceptions notwithstanding, have offered modest clues about pathomechanism, the dissection of rare disorders in which obesity represents a core feature have highlighted key molecules and structures critical to energy regulation. Here we focus on the primary cilium, an organelle whose roles in energy homeostasis have been underscored by the high incidence of obesity and type II diabetes in patients and mouse mutants with compromised ciliary function. We discuss recent evidence linking ciliary dysfunction to metabolic defects and we explore the contribution of neuronal and nonneuronal cilia to these phenotypes.

Figure 1. Hypothalamic neuronal cilia regulate energy metabolism

Neuronal cilia emanating from POMC-expressing neurons regulate obesity phenotypes in the ciliopathies. Under normal conditions, neuronal cilia and the BBSome complex may serve to modulate signaling from the leptin receptor and/or other receptor complexes. Upon perturbation of the cilium, mistrafficking of receptor complexes leads to the inactivation of STAT3 and to dysfunctional cellular signaling.

Figure 2. Evaluation of the role of cilia during energy homeostasis

Several covariates drive obesity phenotypes in the ciliopathies. In the adipose tissue, depletion of BBS proteins leads to the loss of cilia from preadipocytes; the failure to respond to environmental cues through the primary cilium results in the perturbation of adipogenesis. In the pancreas, depletion of IFT proteins results in the transformation of centroacinar cells to ductal-like cells. Insulin, leptin and potentially other, uncharacterized factors regulate neurons in the hypothalamus which are also sensitive to the loss of cilia.