Leptin-promoted cilia assembly is critical for normal energy balance

Abstract

The majority of mammalian cells have nonmotile primary cilia on their surface that act as antenna-like sensory organelles. Genetic defects that result in ciliary dysfunction are associated with obesity in humans and rodents, which suggests that functional cilia are important for controlling energy balance. Here we demonstrated that neuronal cilia lengths were selectively reduced in hypothalami of obese mice with leptin deficiency and leptin resistance. Treatment of N1 hypothalamic neuron cells with leptin stimulated cilia assembly via inhibition of the tumor suppressors PTEN and glycogen synthase kinase 3β (GSK3β). Induction of short cilia in the hypothalamus of adult mice increased food intake and decreased energy expenditure, leading to a positive energy balance. Moreover, mice with short hypothalamic cilia exhibited attenuated anorectic responses to leptin, insulin, and glucose, which indicates that leptin-induced cilia assembly is essential for sensing these satiety signals by hypothalamic neurons. These data suggest that leptin governs the sensitivity of hypothalamic neurons to metabolic signals by controlling the length of the cell's antenna. IntroductionMost mammalian cells have single nonmotile primary cilia, which were once thought to be vestigial but are now considered to be important signaling centers (1, 2). Accumulating evidence suggests a strong association between genetic ciliopathies and obesity in humans and animals (3). Obesity is a common manifestation observed in human genetic ciliopathies such as Bardet-Biedl syndrome (BBS) and Alström syndrome (4). Mice that lack BBS proteins and ciliary proteins such as the kinesin-2 subunit KIF3A and the intraflagellar transport protein 88 homolog (IFT88) are obese and hyperphagic (5-7). Furthermore, selective depletion of KIF3A in neurons, particularly in anorexigenic proopiomelanocortinproducing (POMC-producing) neurons, yields an obese phenotype (7), which suggests that neuronal cilia play a critical role in the maintenance of energy balance. Based on the association between genetic ciliopathies and obesity (3), we hypothesized that acquired or other types of genetic obesity may accompany ciliary defects in the hypothalamus, a key brain area involved in the sensation of peripheral metabolic signals and the orchestration of whole-body energy metabolism.

Leptin Elongates Hypothalamic Neuronal Cilia via Transcriptional Regulation and Actin Destabilization

“…Consistent with the results of our previous study (13), leptin treatment (100 nM for 6 or 12 h) increased the ciliary lengths of the N1 cells up to ϳ3.0 m under serum-free conditions (Fig. 1A), although treatment did not alter the number of ciliated cells (Fig.…”

“…Hypothalamic neurons are a primary target for the in vivo actions of leptin (25). Moreover, altered metabolism or leptin treatment selectively causes ciliary changes in hypothalamic neurons (13). Thus, leptin-mediated regulation of ciliary length may specifically occur in hypothalamic neurons.…”

“…under Serum-free Conditions-We first investigated the effects of leptin on hypothalamic neuronal cilia using N1 hypothalamic neuronal cells as these cells are well ciliated and express functional leptin receptors (13). Upon 90% confluence, N1 cells were further cultured in DMEM with or without serum (10% FBS) for 48 h until ciliary analysis.…”

“…Moreover, the remarkable shortening of hypothalamic neuronal primary cilia was observed in diet-induced obese mice with leptin resistance. In contrast, artificially inducing the short phenotype in the hypothalamic cilia of adult mice leads to increased food intake and body weight and an impaired anorexigenic response to physiological satiety signals, such as leptin, insulin, and glucose (13). These data suggest that ciliary length in hypothalamic neurons is important for regulating appetite and body weight.…”

“…Selective inhibition of ciliogenesis in neurons and particularly in the proopiomelanocortin-producing hypothalamic neurons also causes obesity (12), thus indicating the critical role of hypothalamic neuronal cilia in the control of energy balance. We recently reported that obese mice with leptin deficiency demonstrate the short cilia phenotype in the hypothalamus, which is reversed by leptin treatment (13). Moreover, the remarkable shortening of hypothalamic neuronal primary cilia was observed in diet-induced obese mice with leptin resistance.…”