The Hh signaling pathway is significantly modulated by primary cilia (33). Cilia provide a specialized compartment that aids in the processing of Glioma-associated oncogene homolog (Gli) the family of Zn-finger transcription factors, which are crucial for the transduction of Hh signals. In the absence of Hh ligands such as Sonic Hh (Shh), Gli2 and Gli3 are processed into their activator and repressor forms via proteolytic cleavage (34). This processing is facilitated by the ciliary kinase protein kinase A (PKA), the scaffolding protein kinesin family member 7 (Kif7) and a protease complex. The binding of Shh to its receptor, patched 1 (PTCH1) located on the cilia, alleviates the inhibition of Smoothened (SMO) by PTCH1, leading to the accumulation of SMO within the cilia (35). This accumulation prevents the proteolytic processing of Gli proteins, enriching the Gli2/3 activator form and triggering the expression of Hh target genes.

Primary cilia also influence Wnt signaling, a pathway that involves the regulated proteolysis of the transcription co-activator β-catenin (36). The ciliary protein Kif3a plays a role in inhibiting β-catenin signaling by facilitating its degradation (37). Consequently, the loss of cilia results in enhanced Wnt signaling activity. The interplay between Hh and Wnt signaling is pivotal in determining cell fate during developmental processes. Furthermore, cilia contribute to the orientation of the mitotic spindle and the regulation of oriented cell divisions through planar cell polarity signaling (38).

The master regulator of metabolism, mTOR, is localized to primary cilia and plays a role in regulating ciliary length (39). mTOR supports ciliogenesis and the docking of ciliary vesicles. Of note, the length of cilia can influence mTOR activity by modulating the expression of its inhibitors, such as the DEP domain-containing mTOR-interacting protein, an endogenous suppressor of mTOR signaling. Additionally, the Hippo pathway effectors YAP/TAZ are recruited to primary cilia under conditions of serum starvation (40). This recruitment inhibits the activity of YAP/TAZ, thereby limiting cell proliferation. Ciliogenesis is promoted, whereas deciliation activates YAP/TAZ-dependent transcription, highlighting the complex interplay between cilia and cellular signaling pathways (41).

Primary cilia serve as a niche for growth factor receptors such as platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) and fibroblast growth factor, facilitating the initiation of intracellular signaling cascades that govern cell proliferation and differentiation. Notably, the PDGF receptor α is specifically localized to the primary cilia of fibroblasts, where ligand binding triggers MEK/ERK and mTOR signaling pathways (42). Disruptions in PDGF signaling are linked to ciliopathy phenotypes, highlighting the unique role of ciliary compartmentalization in modulating RTK signaling, potentially eliciting distinct cellular responses compared to activation at the cell surface (43).

GPCRs, pivotal in detecting extracellular signals, are enriched within the membranes of cilia (44). An example includes the somatostatin receptor 3 (SSTR3), which is preferentially localized to neuronal cilia (45). Activation of ciliary GPCRs can induce localized Ca²⁺ signaling, underscoring the importance of ciliary compartmentalization in achieving signaling specificity through subtype-selective GPCR localization (46). Furthermore, cilia facilitate the integration of multiple signaling pathways, including Wnt, Hedgehog and RTK, by housing components of these pathways and enabling crosstalk with GPCRs (47).

Cilia influence the TGFβ superfamily's signaling mechanisms via receptor complexes comprising type I and II serine/threonine kinases (48). Localization of TGFβ receptors to cilia enhances ligand-mediated activation, with ciliary loss leading to impaired signaling. This cilia-mediated control is crucial for regulating developmental and homeostatic processes. The ciliary protein Tectonic plays a significant role in mediating TGFβ signals, interacting with Shh and canonical Wnt pathways (49,50).

Primary cilia enhance Notch signaling pathway activation through the regulated intramembrane proteolysis of Notch receptors, which releases an intracellular fragment that activates gene transcription (51). Both Notch receptors and their ligands, such as Delta, are localized to cilia, emphasizing the cilia's role in facilitating Notch pathway processing. The disruption of ciliogenesis adversely affects Notch-dependent developmental processes, illustrating the functional significance of ciliary regulation in signal transduction (52).

Arcuate nucleus pro-opiomelanocortin (POMC) neurons possess primary cilia interacting with melanocortin 4 receptor (MC4R) to regulate satiety signaling (5,55). Ablating IFT88 in POMC neurons caused cilia loss, reduced POMC firing and decreased α-melanocyte stimulating hormone (α-MSH) release (5). Further analysis found altered trafficking and dysfunctional signaling of the MC4R satiety receptor in cilia-defective POMC neurons. This caused impaired POMC neuron response to α-MSH and defective propagation of satiety signals to downstream nuclei like the paraventricular nucleus. MC4R activation normally induces membrane depolarization, action potential firing and α-MSH secretion in POMC neurons (55). However, optogenetic and electrophysiology experiments revealed loss of these MC4R responses in POMC neurons lacking cilia. This MC4R/POMC signaling axis is critical for appetite regulation (56). Accordingly, disrupting the axis through cilia defects caused hyperphagia, reduced energy expenditure and obesity in mice (Fig. 2).

Obesity is commonly linked with the aging process. The MC4R is crucial in the hypothalamic leptin-melanocortin pathway for combating obesity (57). Research indicates that primary cilia containing MC4R in hypothalamic neurons of rats progressively shorten with age, which correlates with metabolic decline and increased fat accumulation. This phenomenon, a condition termed 'age-associated ciliopathy' is a progressive functional decline in a specific tissue or organ system. This decline results from the deterioration of primary cilia structure, which occurs as a direct consequence of the biological aging process. It is driven by the upregulation of leptin-melanocortin signaling due to excessive nutrient intake. However, dietary restriction or inhibition of ciliogenesis-associated kinase 1 can alleviate or reverse this condition. Genetically induced shortening of MC4R-bearing cilia in hypothalamic neurons results in decreased responsiveness to melanocortin, leading to reduced thermogenesis in brown adipose tissue, lower energy expenditure, increased appetite and subsequent obesity and leptin resistance (58). Therefore, while leptin exerts anti-obesity effects in the short term, prolonged leptin-melanocortin signaling contributes to the age-related shortening of MC4R cilia, heightening the risk of obesity.

Ventral medial hypothalamus SF1 neurons also require primary cilia for regulating food intake (59). SF1 neuronal cilia modulate activity and calcium dynamics through ATP/P2Y purinergic receptor and γ-aminobutyric acid type B receptor signaling (60). Selectively ablating IFT88 in SF1 neurons abolished cilia and altered calcium oscillations. This caused overactivity of SF1 neurons, hyperphagia, reduced energy utilization and pronounced diet-induced obesity (61). Further characterization found changes in genes regulating feeding and metabolism, such as agouti related peptide (AGRP), melanin concentrating hormone and cocaine and amphetamine regulated transcript (62). Thus, ciliary signaling regulates hunger/satiety neuronal function to suppress overeating and weight gain.

Olfactory cilia detect food odors, with their ablation causing hyperphagia (63). Deleting IFT88 eliminates olfactory cilia and receptors like cyclic nucleotide-gated channel α2, a core ion channel essential for olfactory signal transduction, disrupting odor detection and discrimination (64). Electro-olfactogram recordings confirmed loss of odor-evoked responses. Further RNA sequencing revealed reduced expression of adenylate cyclase 3 and other olfactory signaling molecules. Behaviorally, mice lacking olfactory cilia exhibited hyperphagia, glucose intolerance, increased adiposity, liver steatosis and weight gain on a high-fat diet. This demonstrates the key role of olfactory cilia in controlling food seeking behaviors that impact energy balance and obesity susceptibility (65).

Tetratricopeptide repeat domain 21B (THM1) (also known as TTC21B or IFT139) encodes a component of the intraciliary transport-A complex and mutations in this gene are present in 5% of patients with ciliary diseases (66). Research has demonstrated that adult mice lacking Thm1 develop obesity, diabetes, hypertension and fatty liver, with notable sex differences in susceptibility to weight gain and metabolic dysfunction (67). When Thm1 conditional knockout mice were pair-fed with control mice, obesity and related disorders were prevented, indicating that excessive food intake contributes to the obesity phenotype. Thm1 knockdown leads to increased localization of adenylyl cyclase III in primary cilia, resulting in cilia with shortened, bulbous distal tips on neurons in the hypothalamic arcuate nucleus, a key center for regulating feeding and activity. In pre-obese Thm1 conditional knockout mice, expression of the anorexigenic hormone POMC in the arcuate nucleus was reduced by 50%, contributing to hyperphagia (68). Fasting in these mice did not alter the expression of POMC or the Agrp, suggesting an impaired ability to perceive peripheral signaling changes (69). Therefore, ciliary defects due to THM1 gene mutations reduce sensitivity to ingestive signals, disrupting appetite regulation and leading to hyperphagia, obesity and metabolic disorders.

The PI3K-3 phosphoinositide dependent protein kinase 1 (PDK1)-forkhead box (Fox)O1 signaling pathway plays a role in regulating energy homeostasis. When unphosphorylated by PDK1, FoxO1 is active and located in the nucleus, where it represses POMC expression and stimulates Agrp expression (70). Activation of leptin and insulin results in the phosphorylation of FoxO1 and its export from the nucleus, allowing STAT3 to bind to the POMC and Agrp promoters, which activates POMC neurons and inhibits AgRP neurons (71). In conditions of excess energy, leptin signaling activates mTOR, promoting phosphorylation and inhibiting adenosine monophosphate-activated protein kinase (AMPK), thereby suppressing food intake (72).

Primary cilia play a pivotal role in suppressing adipocyte differentiation by modulating Hh pathway signaling. Specifically, the transcriptional repressor is a form of Gli3 (Gli3R) inhibits the expression of peroxisome proliferator-activated receptor γ (PPARγ), a key regulator of adipogenesis (73). Disruption of ciliogenesis through the knockdown of intraflagellar transport protein IFT88 or other ciliary genes results in the absence of primary cilia, preventing the formation of Gli3R (74). Consequently, this leads to the derepression of the PPARγ promoter. RNA interference targeting IFT88 in 3T3-L1 preadipocytes has shown a significant upregulation of PPARγ expression in the absence of cilia, facilitating enhanced differentiation into mature adipocytes (75). This is evidenced by increased lipid droplet formation, as indicated by Oil Red O staining, and elevated expression of adipogenic markers such as fatty acid binding protein 4, lipoprotein lipase, adiponectin and C/EBPα, as confirmed by quantitative PCR and immunoblot analyses (8). Furthermore, the activation of Hh signaling using the agonist purmorphamine or by expressing Gli3R can mitigate the accelerated adipogenesis resulting from ciliary loss.

Adult mesenchymal stem cells, including preadipocytes, have a cellular sensory structure called primary cilia. Preadipocytes with these cilia are prevalent around blood vessels in adipose tissue and become active in response to high-fat diets (76). Disruption of cilia in mouse preadipocytes significantly affects the expansion of white adipose tissue. Researchers have identified that the localization of the omega-3 fatty acid receptor free fatty acid receptor 4/G protein-coupled receptor 120 (FFAR4/GPR120) within cilia, which promotes adipogenesis, depends on tubby-like protein 3, an essential adaptor of the IFT-A complex that mediates the ciliary entry of specific membrane proteins. FFAR4 agonists and omega-3 fatty acids, but not saturated fatty acids, stimulate mitogenesis and adipogenesis by rapidly increasing cyclic (c)AMP production within cilia, resulting in the phosphorylation and nuclear translocation of CCCTC-binding factor (CTCF). Within the nucleus, phosphorylated CTCF acts as a scaffold, recruiting the histone acetyltransferase p300 to form an activation complex at the regulatory regions of key adipogenic genes, such as PPARγ and CCAAT/enhancer-binding protein α (CEBPα). P300 catalyzes local histone hyperacetylation, opening the chromatin. This facilitates the binding of the transcriptional machinery and adipogenic factors, including PPARγ and CEBPα, creating a positive feedback loop, which initiates adipogenesis (8). Dietary omega-3 fatty acids specifically boost the number of adipocytes, facilitating the creation of new adipocytes and promoting the storage of saturated fatty acids to maintain a healthy balance of adipose tissue (8) (Fig. 3).

Fas-binding factor 1 (FBF1) is a core component of ciliary transition fibers that mediates stress-induced cilium-to-promyelocytic leukemia protein-nuclear body signaling to initiate cellular senescence (77). Of note, the absence of FBF1 results in a notable paradox: Fbf1tm1a/tm1a mice, which are a genetically modified model carrying a 'knockout-first' tm1a allele in the FbF1 locus, despite progressively becoming obese, do not develop adverse metabolic complications throughout their lifespan. The lack of FBF1 leads to the upregulation of the ciliary program in white adipose tissue through an A-kinase anchoring protein 9 (AKAP9)-dependent, cilia-regulated PKA signaling pathway. AKAP9, a scaffold protein enriched at the ciliary base, anchors PKA and facilitates its compartmentalized activation (78). Additionally, it significantly enhances adipogenesis through Hh signaling regulated by Bardet-Biedl syndrome proteins. The combined effect of increased ciliogenesis and expansion of adipose tissue highlights a potential explanation for the phenomenon of 'healthy obesity' observed in Fbf1tm1a/tm1a mice (78). This study suggests that targeting preadipocyte cilia could represent a promising strategy for combating metabolic disorders.

Injured skeletal muscle has the ability to regenerate; however, with aging or in the case of muscular dystrophies, muscle tissue tends to be replaced by fat. Following injury, fibro/adipogenic progenitors (FAPs) within the muscle begin to proliferate and differentiate into adipocytes (79). These FAPs actively form primary cilia, which mediate intercellular communication, including Hh signaling. Studies have shown that genetic ablation of cilia in FAPs inhibits intramuscular fat formation both after injury and in a mouse model of Duchenne muscular dystrophy. Furthermore, preventing FAP ciliation not only improved myofiber regeneration post-injury but also mitigated the reduction in myofiber size observed in muscular dystrophy models (80). Hh signaling via FAP cilia controls the expression of tissue inhibitor of metalloproteinases 3 (TIMP3), a secreted inhibitor of metalloproteinases (MMPs), which in turn suppresses MMP14 activity to prevent adipogenesis. Additionally, a pharmacological agent that mimics TIMP3 effectively blocked the differentiation of FAPs into adipocytes, suggesting a potential therapeutic approach to counteract the fatty degeneration of skeletal muscle (80). Thus, it may be concluded that Hh signaling through FAP cilia is crucial in regulating the regenerative processes of skeletal muscle in response to injury.

Research has shown that C3H10T1/2 mesenchymal progenitor cells, crucial for cilia formation, exhibit significantly longer cilia compared to control cells and are unable to differentiate into adipocytes (81). The elongated cilia hinder the accumulation of caveolin-1 and/or monosialodihexosylganglioside (GM3)-positive lipid rafts surrounding the ciliary base. Caveolin-1 is a scaffold protein essential for caveolae formation and insulin receptor stabilization, and GM3 is a ganglioside enriched in lipid rafts that promotes insulin receptor retention, which are all critical components involved in the compartmentalization of insulin signaling. Impaired accumulation of these components at the ciliary base disrupts local lipid raft microdomains, leading to the accumulation of insulin receptor proteins at the ciliary base and subsequent inhibition of insulin-Akt signaling (82). In trichostatin knockout mice, adipogenic progenitor cells have elongated cilia, which disrupts lipid raft dynamics. Knockout mice fed a chronically high-fat diet displayed reduced body fat and smaller adipocytes compared to wild-type mice (82). Therefore, primary cilia may play a role in regulating adipogenic signaling by controlling lipid raft dynamics around the cilia (Fig. 3).

Primary cilia on pancreatic islet cells are pivotal for the maintenance of normal glucose homeostasis, with defects in cilia contributing to impaired insulin secretion and the exacerbation of metabolic dysfunction associated with obesity (83,84). These non-motile cilia are present on all types of islet endocrine cells, including insulin-producing β-cells, glucagon-secreting α-cells, somatostatin-releasing δ-cells, and pancreatic polypeptide-containing PP cells. PP cells are a distinct islet endocrine subtype that regulates exocrine and endocrine pancreatic activity via autocrine and paracrine signaling. These cilia project into the central lumen of the pancreatic ducts (85).

Positioned strategically, cilia play a critical role in sensing fluid flow and modulating Ca²⁺ signaling dynamics, crucial for stimulus-secretion coupling in β-cells (86). The influx of Ca²⁺ in response to glucose metabolism acts as a fundamental trigger for the biphasic secretion of insulin. Experimental deletion of the intraflagellar transport protein IFT88, or disruption of other genes involved in ciliogenesis specifically within β-cells, has been shown to impair glucose-induced Ca²⁺ influx. Such perturbation in Ca²⁺ signaling leads to the loss of both first and second-phase insulin releases in response to glucose, as demonstrated in static islet incubations (87). This diminished insulin secretion capacity was corroborated in vivo through observed impaired glucose tolerance tests in conditional IFT88 knockout mice.

Furthermore, islet cilia enhance insulin secretion by facilitating the proper localization of insulin secretory granules at the plasma membrane (83). The absence of cilia disrupts the normal clustering of insulin granules near the ciliary base, a region where they are primed for glucose-responsive exocytosis. Super-resolution imaging techniques have highlighted the preferential localization of granules in proximity to ciliary bases (88). The absence of cilia interrupts the trafficking of these granules along microtubules, leading to aberrant docking and compromised insulin release. Additionally, primary cilia are implicated in supporting exosome secretion, a process that aids in the trafficking of secretory granules, thereby optimizing insulin secretion (80,89). Cilia have been shown to support exosome secretion from β-cells by acting as the trigger for a specific paracrine signaling cascade. They ensure that the specific signaling receptors, particularly Ephrin type-A receptor 2 (EphA2), are selectively packaged into exosomes to regulate the function of neighboring cells. Cilia defects prevent EphA2 from ever reaching the endosomal sorting complexes required for transport pathway, a conserved membrane trafficking system that mediates the sorting, degradation, or recycling of ubiquitinated membrane proteins (87). This impairment in an auxiliary secretion route likely further aggravates deficits in granule docking and release.

In summary, primary cilia orchestrate multiple aspects of stimulus-secretion coupling, including Ca²⁺ signaling dynamics, the trafficking and docking of insulin granules and exosome functionality. The disruption of these processes by diabetes and obesity-induced cilia defects significantly compromises insulin release and glucose regulation, propagating a detrimental cycle where hyperglycemia induces further cilia loss, exacerbating insulin secretion impairment and amplifying metabolic disease challenges. Unraveling these intricate mechanisms sheds light on new avenues for understanding β-cell dysfunction and its relevance to metabolic diseases.

Primary cilia play a crucial role in suppressing inflammatory pathways, the dysregulation of which can disrupt metabolic homeostasis and contribute to the development of obesity (90). Notably, specific hypothalamic neurons, equipped with primary cilia, modulate inflammation through signaling mediated by somatostatin and leptin receptors (91). The SSTR3, selectively localized to neuronal cilia, is a Gai-coupled receptor, inhibits adenylyl cyclase, and reduces cAMP levels and PKA activity. The suppression of the cAMP/PKA pathway which alters the availability and function of the transcriptional co - activator CBP/p300. CBP/p300 is a pair of highly homologous histone acetyltransferases that facilitate gene activation by acetylating histones and recruiting transcription machinery. This suppression inhibits NF-κB - mediated cytokine production (92,93). The absence of SSTR3 in hypothalamic arcuate nucleus POMC neurons amplifies the inflammatory response to lipopolysaccharides, leading to increased release of cytokines such as IL-6, IL-1β and TNFα. Furthermore, SSTR3 activation within POMC neuron cilia curtails inflammation-induced ceramide production and endoplasmic reticulum stress, underscoring the anti-inflammatory effects vital for preserving the normal function and satiety signaling of POMC neurons. Disruption of this ciliary SSTR3 pathway perturbs satiety signaling and feeding behaviors, impacting energy balance (94).

In the context of obesity, hyperleptinemia triggers the relocalization of the leptin receptor (LepR) away from neuronal cilia within the mediobasal hypothalamus (MBH), impairing leptin sensing (58). This alteration in LepR trafficking, evidenced through immunofluorescence staining and live cell imaging, leads to diminished leptin pathway activation, as indicated by reduced STAT3 phosphorylation (95). Mice exhibiting disrupted ciliary trafficking of LepR develop leptin resistance, characterized by overeating, decreased energy expenditure and exacerbated dietary-induced obesity. However, restoring the proper ciliary localization of LepR in MBH neurons can reestablish leptin sensitivity and ameliorate obesity-related phenotypes, highlighting the significance of LepR signaling integrity in hypothalamic neuronal cilia for maintaining normal appetite regulation (58).

Adipocyte cilia also mitigate inflammation by modulating responses to cytokines such as TNF (78). In obese mice on a high-fat diet, adipocyte cilia become shortened, losing SSTR3 localization. Compared to their lean counterparts, obese visceral fat exhibits reduced cilia prevalence and length, with cilia loss intensifying TNFα-induced inflammation (75). This is characterized by increased NF-κB pathway activity, elevated production of pro-inflammatory cytokines and higher levels of macrophage markers like F4/80, establishing the role of adipocyte cilia in curbing inflammation during obesity (96).

Beyond these tissue-specific mechanisms, the chronic low-grade inflammation that drives increased fat storage and fatty liver disease involves critical inter-organ communication. The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is supported by a spleen-liver axis that modulates systemic inflammation. This process is characterized by an enrichment of splenic myeloid-derived suppressor cells (MDSCs) and natural killer T (NKT) cells, along with a loss of hepatic T and B cells. Correlation analysis confirms a selective, strong positive correlation between the distribution of spleen and liver MDSC and NKT cells, indicating that the spleen-liver axis modulates obesity-induced immune dysregulation in a cell-specific manner, as demonstrated by recent research (97). Furthermore, spleen-derived signals can directly amplify hepatic inflammation. Leukotriene B4 (LTB4) released by the spleen enhances liver TNF production both in vivo and in vitro, identifying LTB4 as a spleen-derived endocrine signal that promotes hepatic TNF production during systemic inflammation (98). All these findings focusing on pro-inflammatory processes lend credence to the significance of the liver-spleen axis in non-alcoholic fatty liver disease/MASLD pathogenesis (99). This axis represents a critical systemic circuit through which inflammatory signals are amplified and disseminated, contributing to the metabolic dysfunction driven by ciliary defects in metabolic tissues.

Overall, by regulating key inflammatory, metabolic and endocrine pathways in the hypothalamus and adipose tissue, primary cilia suppress local and systemic abnormalities that can disturb energy homeostasis and promote obesity. Further studies are needed to elucidate the complex molecular intersections between ciliary dysfunction and inflammation in metabolic disease.

When cells face nutrient deprivation, they encounter an energetic crisis that is managed through metabolic reorganization and adjustments in organelle functions. Primary cilia, which are microtubule-based organelles on the cell surface, have the capability to integrate various metabolic and signaling cues. Primary cilia have been shown to sense glutamine availability and respond by elongating via an asparagine synthetase (ASNS), dependent mechanism that promotes ciliary tubulin acetylation and stabilization, thereby enhancing ciliary length under nutrient replete conditions (100). During nutrient deprivation, cilia elongate, which occurs independently of mTOR complex 1 (mTORC1), even when mitochondrial function, ATP supply and AMPK activation are compromised. Of note, the removal or supplementation of glutamine, under both in vivo and in vitro nutritional stress, is necessary and sufficient to regulate mitochondrial mitophagy. This process depends on the production of glutamate from ASNS, leading to either the elongation or retraction of cilia. Cells with IFT88 gene mutations that lack cilia show glutamate-dependent mitochondrial anaphase during metabolic stress, due to reduced ASNS expression and activity at the ciliary base (100). These findings suggest that primary cilia are responsive to cellular glutamine levels through ASNS during periods of metabolic stress.

Given that certain commensal microbes metabolize nutrients in manners protective against obesity, the regulation of their populations through cilia-mediated antimicrobial secretion directly impacts nutritional absorption. Additionally, cilia within the biliary tract facilitate the circulation of bile necessary for the digestion and absorption of lipids and fat-soluble vitamins. Disruptions to motile cilia in the biliary system can alter bile flow and contribute to gallstone disease (101).

In summary, through the coordinated regulation of epithelial barrier function, antimicrobial release, microbiome composition, bile flow and nutrient absorption, intestinal cilia exert a profound influence on metabolism related to obesity. Elucidating these intricate roles underscores the importance of intestinal cilia in maintaining metabolic health and offers potential avenues for targeting obesity and its associated metabolic disorders.

Insufficient adaptive β-cell compensation is a hallmark of T2D (102). Primary cilia, which are versatile sensory appendages, play a crucial role in regulating diverse cellular functions. Studies have identified a notably higher number of downregulated genes associated with cilia in the pancreatic islets of diabetes-susceptible New Zealand Obese mice compared to diabetes-resistant B6-ob/ob mice (103). Among the 327 mouse cilia genes with altered expression, 81 had human homologs that were also impacted in islets from diabetic individuals. In non-diabetic mouse and human islets, there was a significant overlap in the upregulation of ciliary genes linked to cell-cycle progression. Suppression of KIF3A, a critical gene for ciliogenesis, through short hairpin RNA, disrupted cell division in MIN6 β-cells and primary pancreatic islet cells in both mice and humans, as shown by decreased bromodeoxyuridine incorporation (103). Collectively, these results highlight the vital role of ciliary gene regulation in islet functionality and the risk of developing T2D.