Mol. Cells 2022; 45(4): 169-176
Published online April 6, 2022
https://doi.org/10.14348/molcells.2022.2046
© The Korean Society for Molecular and Cellular Biology
Correspondence to : mskim@amc.seoul.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alstr?m syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.
Keywords ciliopathy, G protein-coupled receptor, hypothalamus, leptin, obesity, primary cilia
Primary cilia are non-motile hair-like structures extruding from the cell surfaces that comprise a 9+0 tubulin-based cytoskeleton core called axoneme and a specialized plasma membrane covering the axoneme (Singla and Reiter, 2006). Primary cilia are assembled from a basal body derived from the mother centriole during the G0 or G1 phase of the cell cycle (Sánchez and Dynlacht, 2016). For cilia growth, ciliary membranes and axonemal proteins are synthesized in the cytoplasmic endoplasmic reticulum-Golgi and transported to the basal body area and then to the ciliary tip. The transport of ciliary proteins is mediated by the intraflagellar transport (IFT) machinery, which is composed of motor proteins (kinesin or dynein) and cargo IFT proteins (Ishikawa and Marshall, 2011; Rosenbaum and Witman, 2002).
Ciliary membranes express a number of signaling receptors, especially G protein-coupled receptors (GPCRs), and signaling molecules as well as ion channels, which is compatible with their functioning as a sensory organelle (Anvarian et al., 2019; Schou et al., 2015). Moreover, the primary cilia in epithelial cells and sensory neurons play an indispensable role in sensing external environments, including light, sound, olfactory signals, chemicals, temperature, mechanical force, flow of body fluids, and among others (Berbari et al., 2009; Singla and Reiter, 2006). Furthermore, primary cilia serve as a platform for cellular signal transduction. Multiple signaling pathways (such as sonic hedgehog, Wnt, PDGF, LKB1-AMPK, autophagy, etc.) are transduced via the primary cilia or are modulated by them (Anvarian et al., 2019; Aznar and Billaud, 2010; Pampliega et al., 2013; Song et al., 2018). A substantial body of evidence now indicates that ciliary defects are closely linked to the development of various causes of obesity. Here, we briefly illustrate how defects in cilia or cilia-related molecules promote obesity, with an emphasis on the central mechanisms involved.
The association between primary cilia and obesity stems from observations in human genetic ciliopathies such as the Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS). BBS patients commonly manifest obesity along with intellectual impairment, renal abnormalities, polydactyly, retinal degeneration, and hypogenitalism (Forsythe and Beales, 2013). These patients are typically born with a normal weight but 90% of cases rapidly gain weight in the first year of life. In addition, type 2 diabetes affects about 45% of BBS patients. To date, mutations in more than 20 genes (
The molecular basis for the onset of obesity in BBS has been the subject of considerable study. A protein complex comprising BBS proteins, the BBSome, has been shown to work as an adaptor of the IFT complex (Liu and Lechtreck, 2018), and it has been suggested that BBS proteins may also mediate the ciliary transport/localization of molecules that are critical for body weight control. In this event, any defects in BBS proteins would likely impair the cilia-mediated functions of those molecules. A promising candidate as a cilia-related body weight regulator is neuropeptide Y receptor type 2 (Y2R), a known receptor of the gut-released anorexigenic peptide PYY3-36 and that localized on the cilia of hypothalamic neurons (Loktev and Jackson, 2013).
ALMS is a rare autosomal recessive disorder caused by
Other obesity-linked monogenic ciliopathies include a syndrome of mental retardation, truncal obesity, retinal dystrophy and micropenis (MORM) induced by ciliary lipid phosphatase inositol polyphosphate-5-phosphatase E (
Almost every cell type contains primary cilia that manifest either transiently or permanently. An important question that arose from this was the nature of the cell types that played a major role in defective cilia-induced obesity. The answer subsequently came from mouse models of defective ciliogenesis that were generated by knocking out genes encoding IFT components (
The hypothalamus, particularly the hypothalamic arcuate nucleus (ARH), is a critical area with regard to the regulation of food intake and energy balance (Roh et al., 2016). Proopiomelanocortin (POMC) neurons in this area represent the neurons with anti-obesity actions (Morton et al., 2006; Schwartz et al., 2000). POMC neurons release α-melanocyte stimulating hormone (αMSH) which suppresses food intake through agonistic activity at the melanocortin 4 receptor (MC4R) (Ollmann et al., 1997). A POMC neuron-specific inhibition of ciliogenesis was reported to cause obesity when it was introduced during the mid-embryonic and early postnatal periods whereas it did not alter body weight when introduced in adulthood (Lee et al., 2020). In terms of the mechanism, the absence of functioning cilia in developing POMC neurons impairs embryonic neurogenesis and postnatal circuit organization, suggesting a critical role of primary cilia in the normal development of these neurons. The ventromedial hypothalamus (VMH) is another important area for body weight control. Mice with cilia dysgenesis in VMH steroidogenic factor-1 (SF1)-expressing neurons also acquire the obesity phenotype owing to an increase in food intake and a decrease in energy expenditure and brown adipose tissue thermogenesis (Sun et al., 2021). The hypothalamic paraventricular nucleus (PVH) also has a critical involvement in the regulation of both body weight and food intake (Roh et al., 2016). Loss of cilia in the MC4R-expressing PVH neurons causes obesity, hyperphagia, and increased body lengths (Siljee et al., 2018). Hence, studies using mouse models of ciliary dysgenesis have demonstrated that defective ciliogenesis in specific hypothalamic neuronal populations causes obesity and hyperphagia.
Conversely, obesity by itself appears to influence cilia formation in hypothalamic neurons. In adulthood, most of these neurons are terminally differentiated and have a single primary cilium on the soma surface. Hypothalamic cilia lengths vary from less than 2 μm to more than 10 μm, with average lengths of 5-6 μm (Han et al., 2014). Notably, the hypothalamic cilia lengths are shorter in obese conditions, with the lengths in the ARH and VMH found to be 30% shorter in obese mice than in age-matched lean controls (Han et al., 2014). More interestingly, maternal HFD feeding during the lactation period dampens ciliogenesis in the offspring’s hypothalamus (Lee et al., 2020). The obesity-associated short cilia phenotype appears to be related to reduced leptin signaling. In terms of the molecular mechanism, leptin promotes cilia growth in hypothalamic neurons via the PTEN/GSK3β signaling-dependent stimulation of IFT protein transcription and actin depolymerization, both of which are critical steps in ciliogenesis (Han et al., 2014; Kang et al., 2015). An obesity-associated short cilia phenotype has not been observed in other brain areas (Han et al., 2014; Lee et al., 2020). Taken together, a bidirectional regulatory process exists between ciliogenesis and obesity in hypothalamic neurons.
Leptin is the most important hormone for preventing obesity and is released by the white adipose tissue in proportion to the fat mass (Frederich et al., 1995). Leptin controls food intake and energy expenditure by acting on the hypothalamus (Halaas et al., 1995). In hypothalamic leptin-target neurons, leptin exerts its signaling effects through the leptin receptor (LepRb) and via downstream signaling pathways including JAK2-STAT3 (Kwon et al., 2016). Several lines of evidence have confirmed that functional cilia are necessary for leptin signaling in the hypothalamus. The acute inhibition of ciliogenesis in the mediobasal hypothalamus in adult mice through the microinjection of small inhibitory RNAs specific to
Determining the mechanism by which the primary cilia transduce leptin signaling in hypothalamic neurons was the core aim of many studies. The ciliary localization of LepRb has not been demonstrated yet and this receptor has only so far been detected around the basal body at the base of the cilium (Han et al., 2014; Stratigopoulos et al., 2014). Hence, leptin signal transduction has been speculated to take place in the periciliary area rather than on the cilium itself. Intriguingly, leptin treatments have been found to trigger the periciliary trafficking of LepRb and the inhibition of this process may disrupt leptin signaling (Stratigopoulos et al., 2014). For example, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGLIP1L), a ciliary transition zone protein, was reported to mediate the periciliary trafficking of LepRb (Fig. 1A).
The relationship between BBS proteins and leptin signaling has also been studied by several research groups but the results seem to be somewhat contradictory.
In addition to LepRb, BBS1 also mediates the transport of the serotonin receptor 5-HT2C to the plasma membrane, especially in POMC neurons (Guo et al., 2019). Hence,
AC3/ADCY3, encoded by the
In line with the aforementioned evidence, a gain-of-function mutation in
MC4R is a Gs-coupled GPCR that is critically linked to body weight homeostasis in mammals (Krashes et al., 2016). MC4R mutations are the most common cause (3%-5%) of monogenic obesity in humans (Bromberg et al., 2009; Lubrano-Berthelier et al., 2006; Siljee et al., 2018). A recent report has identified MC4R as an AC3-interacting receptor at the primary cilium (Siljee et al., 2018; Wang et al., 2021). In the PVH neurons, MC4R colocalizes with AC3 at the cilium and this ability is markedly reduced in human obesity-associated MC4R mutants (p.P230L and p.R236C) (Siljee et al., 2018) (Fig. 1B). Moreover, food intake and body weight gain are increased when ciliary AC3 signaling is inhibited by the overexpression of ciliary Gi-coupled GPCR GPR88 in either Sim1- or MC4R-expressing PVH neurons (Siljee et al., 2018). MC4R agonist (MTII)-induced anorexia is largely dependent on cilia and ciliary AC3 signaling in PVH neurons (Wang et al., 2021). These findings have provided important molecular insights into the intimate association among MC4R, cilia-mediated signaling, and obesity.
TUB, a tubby homolog in human, is a member of the tubby-like protein (TULP) family that is predominantly expressed in neurons (He et al., 2000).
The ankyrin repeat domain 26 (ANKRD26) protein is localized in the ciliary transition fibers (Yan et al., 2020) and its gene is located on chromosome 10p12, a locus that has been associated with the genetic form of obesity in humans (Dong et al., 2005). In line with this,
Accumulated evidence supports that cilia–mediated signaling in specific hypothalamic neuronal populations is critical for the maintenance of energy balance and normal body weight. To date, the proposed role of the primary cilia is to provide a signaling platform for neuropeptides that control the energy balance and feeding behaviors. The current cilia-localized candidate receptors are MC4R, NPY2R, NPY5R, MCHR1, SSTR3, 5HT6, dopamine receptor 1 (D1), and others. The relationship between MC4R and the primary cilia is well-studied in relation to human obesity whereas the physiological and biological roles of other ciliary receptors remain to be elucidated. Moreover, the downstream pathways from cilia signaling that modulate neuronal functions and activity are largely unknown. As adult-induced ablation of cilia in PVH neurons causes slow-onset changes in food intake and body weight (Wang et al., 2021), these effects may require slowly-progressive structural changes in neurons and neuronal circuits. Indeed, in adult-born hippocampal neurons, the cilia modulate glutamatergic synapse formation via the control of dendrite refinement and thereby affect memory formation (Kumamoto et al., 2012). In addition, primary cilia in striatal interneurons regulate synaptic connectivity (Guo et al., 2017). Hence, hypothalamic neuronal cilia may regulate the synaptic integration and neuronal connectivity implicated in weight control. In line with this, the cilia promote axonal projection and dendrite formation in developing POMC neurons by mediating the leptin stimulation of lysosomal proteolysis (Lee et al., 2020).
Although this review article has principally addressed the phenomenon of hypothalamic cilia and obesity, adipocytes transiently express cilia during the early stages of adipogenesis, suggesting that the cilia may have some roles in adipocyte development (Kopinke et al., 2017; Marion et al., 2009; Zhu et al., 2009). Hence, ciliary defects possibly induce obesity through adipocyte mechanisms. In conclusion, the primary cilia in hypothalamic neurons are a tiny but critical organelle for controlling body fatness and defects in these entities can predispose both humans and rodents to obesity.
This study was supported by grants from the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT of Korea (2017R1A2B3007123, 2019R1F1A1060805, 2019R1I1A1A01058091, 2020R1A2C 3004843, 2020R1A4A3078962), and from the Asan Institute for Life Sciences (2019-IP0855-1).
C.H.L., G.M.K., and M.S.K. wrote the manuscript.
The authors have no potential conflicts of interest to disclose.
Mol. Cells 2022; 45(4): 169-176
Published online April 30, 2022 https://doi.org/10.14348/molcells.2022.2046
Copyright © The Korean Society for Molecular and Cellular Biology.
Chan Hee Lee1 , Gil Myoung Kang2
, and Min-Seon Kim3,*
1Department of Biomedical Science, Hallym University, Chuncheon 24252, Korea, 2Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Korea, 3Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
Correspondence to:mskim@amc.seoul.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alstr?m syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.
Keywords: ciliopathy, G protein-coupled receptor, hypothalamus, leptin, obesity, primary cilia
Primary cilia are non-motile hair-like structures extruding from the cell surfaces that comprise a 9+0 tubulin-based cytoskeleton core called axoneme and a specialized plasma membrane covering the axoneme (Singla and Reiter, 2006). Primary cilia are assembled from a basal body derived from the mother centriole during the G0 or G1 phase of the cell cycle (Sánchez and Dynlacht, 2016). For cilia growth, ciliary membranes and axonemal proteins are synthesized in the cytoplasmic endoplasmic reticulum-Golgi and transported to the basal body area and then to the ciliary tip. The transport of ciliary proteins is mediated by the intraflagellar transport (IFT) machinery, which is composed of motor proteins (kinesin or dynein) and cargo IFT proteins (Ishikawa and Marshall, 2011; Rosenbaum and Witman, 2002).
Ciliary membranes express a number of signaling receptors, especially G protein-coupled receptors (GPCRs), and signaling molecules as well as ion channels, which is compatible with their functioning as a sensory organelle (Anvarian et al., 2019; Schou et al., 2015). Moreover, the primary cilia in epithelial cells and sensory neurons play an indispensable role in sensing external environments, including light, sound, olfactory signals, chemicals, temperature, mechanical force, flow of body fluids, and among others (Berbari et al., 2009; Singla and Reiter, 2006). Furthermore, primary cilia serve as a platform for cellular signal transduction. Multiple signaling pathways (such as sonic hedgehog, Wnt, PDGF, LKB1-AMPK, autophagy, etc.) are transduced via the primary cilia or are modulated by them (Anvarian et al., 2019; Aznar and Billaud, 2010; Pampliega et al., 2013; Song et al., 2018). A substantial body of evidence now indicates that ciliary defects are closely linked to the development of various causes of obesity. Here, we briefly illustrate how defects in cilia or cilia-related molecules promote obesity, with an emphasis on the central mechanisms involved.
The association between primary cilia and obesity stems from observations in human genetic ciliopathies such as the Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS). BBS patients commonly manifest obesity along with intellectual impairment, renal abnormalities, polydactyly, retinal degeneration, and hypogenitalism (Forsythe and Beales, 2013). These patients are typically born with a normal weight but 90% of cases rapidly gain weight in the first year of life. In addition, type 2 diabetes affects about 45% of BBS patients. To date, mutations in more than 20 genes (
The molecular basis for the onset of obesity in BBS has been the subject of considerable study. A protein complex comprising BBS proteins, the BBSome, has been shown to work as an adaptor of the IFT complex (Liu and Lechtreck, 2018), and it has been suggested that BBS proteins may also mediate the ciliary transport/localization of molecules that are critical for body weight control. In this event, any defects in BBS proteins would likely impair the cilia-mediated functions of those molecules. A promising candidate as a cilia-related body weight regulator is neuropeptide Y receptor type 2 (Y2R), a known receptor of the gut-released anorexigenic peptide PYY3-36 and that localized on the cilia of hypothalamic neurons (Loktev and Jackson, 2013).
ALMS is a rare autosomal recessive disorder caused by
Other obesity-linked monogenic ciliopathies include a syndrome of mental retardation, truncal obesity, retinal dystrophy and micropenis (MORM) induced by ciliary lipid phosphatase inositol polyphosphate-5-phosphatase E (
Almost every cell type contains primary cilia that manifest either transiently or permanently. An important question that arose from this was the nature of the cell types that played a major role in defective cilia-induced obesity. The answer subsequently came from mouse models of defective ciliogenesis that were generated by knocking out genes encoding IFT components (
The hypothalamus, particularly the hypothalamic arcuate nucleus (ARH), is a critical area with regard to the regulation of food intake and energy balance (Roh et al., 2016). Proopiomelanocortin (POMC) neurons in this area represent the neurons with anti-obesity actions (Morton et al., 2006; Schwartz et al., 2000). POMC neurons release α-melanocyte stimulating hormone (αMSH) which suppresses food intake through agonistic activity at the melanocortin 4 receptor (MC4R) (Ollmann et al., 1997). A POMC neuron-specific inhibition of ciliogenesis was reported to cause obesity when it was introduced during the mid-embryonic and early postnatal periods whereas it did not alter body weight when introduced in adulthood (Lee et al., 2020). In terms of the mechanism, the absence of functioning cilia in developing POMC neurons impairs embryonic neurogenesis and postnatal circuit organization, suggesting a critical role of primary cilia in the normal development of these neurons. The ventromedial hypothalamus (VMH) is another important area for body weight control. Mice with cilia dysgenesis in VMH steroidogenic factor-1 (SF1)-expressing neurons also acquire the obesity phenotype owing to an increase in food intake and a decrease in energy expenditure and brown adipose tissue thermogenesis (Sun et al., 2021). The hypothalamic paraventricular nucleus (PVH) also has a critical involvement in the regulation of both body weight and food intake (Roh et al., 2016). Loss of cilia in the MC4R-expressing PVH neurons causes obesity, hyperphagia, and increased body lengths (Siljee et al., 2018). Hence, studies using mouse models of ciliary dysgenesis have demonstrated that defective ciliogenesis in specific hypothalamic neuronal populations causes obesity and hyperphagia.
Conversely, obesity by itself appears to influence cilia formation in hypothalamic neurons. In adulthood, most of these neurons are terminally differentiated and have a single primary cilium on the soma surface. Hypothalamic cilia lengths vary from less than 2 μm to more than 10 μm, with average lengths of 5-6 μm (Han et al., 2014). Notably, the hypothalamic cilia lengths are shorter in obese conditions, with the lengths in the ARH and VMH found to be 30% shorter in obese mice than in age-matched lean controls (Han et al., 2014). More interestingly, maternal HFD feeding during the lactation period dampens ciliogenesis in the offspring’s hypothalamus (Lee et al., 2020). The obesity-associated short cilia phenotype appears to be related to reduced leptin signaling. In terms of the molecular mechanism, leptin promotes cilia growth in hypothalamic neurons via the PTEN/GSK3β signaling-dependent stimulation of IFT protein transcription and actin depolymerization, both of which are critical steps in ciliogenesis (Han et al., 2014; Kang et al., 2015). An obesity-associated short cilia phenotype has not been observed in other brain areas (Han et al., 2014; Lee et al., 2020). Taken together, a bidirectional regulatory process exists between ciliogenesis and obesity in hypothalamic neurons.
Leptin is the most important hormone for preventing obesity and is released by the white adipose tissue in proportion to the fat mass (Frederich et al., 1995). Leptin controls food intake and energy expenditure by acting on the hypothalamus (Halaas et al., 1995). In hypothalamic leptin-target neurons, leptin exerts its signaling effects through the leptin receptor (LepRb) and via downstream signaling pathways including JAK2-STAT3 (Kwon et al., 2016). Several lines of evidence have confirmed that functional cilia are necessary for leptin signaling in the hypothalamus. The acute inhibition of ciliogenesis in the mediobasal hypothalamus in adult mice through the microinjection of small inhibitory RNAs specific to
Determining the mechanism by which the primary cilia transduce leptin signaling in hypothalamic neurons was the core aim of many studies. The ciliary localization of LepRb has not been demonstrated yet and this receptor has only so far been detected around the basal body at the base of the cilium (Han et al., 2014; Stratigopoulos et al., 2014). Hence, leptin signal transduction has been speculated to take place in the periciliary area rather than on the cilium itself. Intriguingly, leptin treatments have been found to trigger the periciliary trafficking of LepRb and the inhibition of this process may disrupt leptin signaling (Stratigopoulos et al., 2014). For example, retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGLIP1L), a ciliary transition zone protein, was reported to mediate the periciliary trafficking of LepRb (Fig. 1A).
The relationship between BBS proteins and leptin signaling has also been studied by several research groups but the results seem to be somewhat contradictory.
In addition to LepRb, BBS1 also mediates the transport of the serotonin receptor 5-HT2C to the plasma membrane, especially in POMC neurons (Guo et al., 2019). Hence,
AC3/ADCY3, encoded by the
In line with the aforementioned evidence, a gain-of-function mutation in
MC4R is a Gs-coupled GPCR that is critically linked to body weight homeostasis in mammals (Krashes et al., 2016). MC4R mutations are the most common cause (3%-5%) of monogenic obesity in humans (Bromberg et al., 2009; Lubrano-Berthelier et al., 2006; Siljee et al., 2018). A recent report has identified MC4R as an AC3-interacting receptor at the primary cilium (Siljee et al., 2018; Wang et al., 2021). In the PVH neurons, MC4R colocalizes with AC3 at the cilium and this ability is markedly reduced in human obesity-associated MC4R mutants (p.P230L and p.R236C) (Siljee et al., 2018) (Fig. 1B). Moreover, food intake and body weight gain are increased when ciliary AC3 signaling is inhibited by the overexpression of ciliary Gi-coupled GPCR GPR88 in either Sim1- or MC4R-expressing PVH neurons (Siljee et al., 2018). MC4R agonist (MTII)-induced anorexia is largely dependent on cilia and ciliary AC3 signaling in PVH neurons (Wang et al., 2021). These findings have provided important molecular insights into the intimate association among MC4R, cilia-mediated signaling, and obesity.
TUB, a tubby homolog in human, is a member of the tubby-like protein (TULP) family that is predominantly expressed in neurons (He et al., 2000).
The ankyrin repeat domain 26 (ANKRD26) protein is localized in the ciliary transition fibers (Yan et al., 2020) and its gene is located on chromosome 10p12, a locus that has been associated with the genetic form of obesity in humans (Dong et al., 2005). In line with this,
Accumulated evidence supports that cilia–mediated signaling in specific hypothalamic neuronal populations is critical for the maintenance of energy balance and normal body weight. To date, the proposed role of the primary cilia is to provide a signaling platform for neuropeptides that control the energy balance and feeding behaviors. The current cilia-localized candidate receptors are MC4R, NPY2R, NPY5R, MCHR1, SSTR3, 5HT6, dopamine receptor 1 (D1), and others. The relationship between MC4R and the primary cilia is well-studied in relation to human obesity whereas the physiological and biological roles of other ciliary receptors remain to be elucidated. Moreover, the downstream pathways from cilia signaling that modulate neuronal functions and activity are largely unknown. As adult-induced ablation of cilia in PVH neurons causes slow-onset changes in food intake and body weight (Wang et al., 2021), these effects may require slowly-progressive structural changes in neurons and neuronal circuits. Indeed, in adult-born hippocampal neurons, the cilia modulate glutamatergic synapse formation via the control of dendrite refinement and thereby affect memory formation (Kumamoto et al., 2012). In addition, primary cilia in striatal interneurons regulate synaptic connectivity (Guo et al., 2017). Hence, hypothalamic neuronal cilia may regulate the synaptic integration and neuronal connectivity implicated in weight control. In line with this, the cilia promote axonal projection and dendrite formation in developing POMC neurons by mediating the leptin stimulation of lysosomal proteolysis (Lee et al., 2020).
Although this review article has principally addressed the phenomenon of hypothalamic cilia and obesity, adipocytes transiently express cilia during the early stages of adipogenesis, suggesting that the cilia may have some roles in adipocyte development (Kopinke et al., 2017; Marion et al., 2009; Zhu et al., 2009). Hence, ciliary defects possibly induce obesity through adipocyte mechanisms. In conclusion, the primary cilia in hypothalamic neurons are a tiny but critical organelle for controlling body fatness and defects in these entities can predispose both humans and rodents to obesity.
This study was supported by grants from the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT of Korea (2017R1A2B3007123, 2019R1F1A1060805, 2019R1I1A1A01058091, 2020R1A2C 3004843, 2020R1A4A3078962), and from the Asan Institute for Life Sciences (2019-IP0855-1).
C.H.L., G.M.K., and M.S.K. wrote the manuscript.
The authors have no potential conflicts of interest to disclose.
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