A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice

Ács, Péter; Bauer, Peter; Mayer, Balázs; Bera, Tapan K.; MacAllister, Rhonda; Mezey, Éva; Pastan, Ira

doi:10.1007/s00429-014-0741-9

Cited by 31 publications

(27 citation statements)

References 59 publications

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“…However, the underlying molecular mechanisms remain poorly defined343536. Similarly, ANKRD26 mice displayed obesity phenotypes potentially linked to defects in primary cilia37. Finally, mutations in HYLS1 have been detected in individuals with hydrolethalus syndrome38, a putative ciliopathy, and HYLS1 and its worm homologue HYLS-1 have been reported to be required for ciliogenesis in vertebrates and C. elegans , respectively33.…”

Section: Resultsmentioning

confidence: 99%

The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate

et al. 2016

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Transition fibres (TFs), together with the transition zone (TZ), are basal ciliary structures thought to be crucial for cilium biogenesis and function by acting as a ciliary gate to regulate selective protein entry and exit. Here we demonstrate that the centriolar and basal body protein HYLS-1, the C. elegans orthologue of hydrolethalus syndrome protein 1, is required for TF formation, TZ organization and ciliary gating. Loss of HYLS-1 compromises the docking and entry of intraflagellar transport (IFT) particles, ciliary gating for both membrane and soluble proteins, and axoneme assembly. Additional depletion of the TF component DYF-19 in hyls-1 mutants further exacerbates TZ anomalies and completely abrogates ciliogenesis. Our data support an important role for HYLS-1 and TFs in establishment of the ciliary gate and underline the importance of selective protein entry for cilia assembly.

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Section: Resultsmentioning

confidence: 99%

The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate

et al. 2016

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“…Ankrd26 is expressed in the CNS, including the hypothalamic ARC and paraventricular nucleus (PVN); in the pancreas and skeletal and smooth muscle cells; in the myocardium; and to a lesser extent in adipose tissue and the liver . A subsequent study revealed that STAT3 phosphorylation in response to leptin in the ARC was similar between Ankrd26 − / − mice and wild‐type littermates . However, the response to α‐melanocyte–stimulating hormone (α‐MSH) that is released from POMC + neurons and signals to melanocortin‐4 receptor (MC4R) in the PVN was significantly reduced.…”

Section: Primary Ciliary Function and Obesitymentioning

confidence: 99%

“…34 A subsequent study revealed that STAT3 phosphorylation in response to leptin in the ARC was similar between Ankrd26 −/− mice and wild-type littermates. 50 However, the response to ␣-melanocyte-stimulating hormone (␣-MSH) that is released from POMC + neurons and signals to melanocortin-4 receptor (MC4R) in the PVN was significantly reduced. Closer investigation revealed that ACIII + cilia were absent from the PVN.…”

Section: Primary Ciliary Function and Obesitymentioning

confidence: 99%

The role of primary cilia in obesity and diabetes

Volta

Gerdes

2016

Annals of the New York Academy of Sciences

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One in 12 people worldwide suffers from diabetes and more than 90% of affected adult individuals are diagnosed with type 2 diabetes mellitus (T2DM). Obesity adds to the personal risk to develop T2DM, and both metabolic diseases are rampantly increasing worldwide. Over recent years, primary cilia have moved into the focus of basic and clinical research, after several human diseases have been identified as ciliopathies (i.e., they are linked to ciliary dysfunction). A subset of ciliopathies presents with obesity and diabetes, either as core symptoms or major complications. Several studies have shown a role for ciliary signaling in the satiety signaling centers of the hypothalamus and in other metabolically active tissues, such as pancreatic islets. Here, we discuss recent advances and perspectives in ciliary metabolic research.

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“…In humans, association studies between the MCHR1 gene and parameters of obesity are conflicting, which may be because of epigenetic effects (165) . Studying the obese/hyperphagic Ankrd26-knockout mouse, Acs et al (78) recently demonstrated absence of Adcy3-containing primary cilia in the paraventricular nucleus, a part of the hypothalamus involved in food intake regulation. Similarly, disrupting the function of the Alms1 gene leads to a large decrease of ciliated neurons in the hypothalamus as determined by the absence of Adcy3, Mchr1 and somatostatin receptor 3 (Sstr3) (166) .…”

Section: The Cilium In Neuronal Food Intake Regulationmentioning

confidence: 99%

The cilium: a cellular antenna with an influence on obesity risk

et al. 2016

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Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype-phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro-and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

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A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice

Cited by 31 publications

References 59 publications

The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate

The hydrolethalus syndrome protein HYLS-1 regulates formation of the ciliary gate

The role of primary cilia in obesity and diabetes

The cilium: a cellular antenna with an influence on obesity risk

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