Browsing by Author "Nagy, Tim R."

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    Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice
    (National Academy of Science, 2013) Berbari, Nicolas F.; Pasek, Raymond C.; Malarkey, Erik B.; Yazdi, S.M. Zaki; McNair, Andrew D.; Lewis, Wesley R.; Nagy, Tim R.; Kesterson, Robert A.; Yoder, Bradley K.; Biology, School of Science
    Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.
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    Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone
    (Federation of American Society of Experimental Biology (FASEB), 2019-01) Lewis, Wesley R.; Bales, Katie L.; Revell, Dustin Z.; Croyle, Mandy J.; Engle, Staci E.; Song, Cheng Jack; Malarkey, Erik B.; Uytingco, Cedric R.; Shan, Dan; Antonellis, Patrick J.; Nagy, Tim R.; Kesterson, Robert A.; Mrug, Michal M.; Martens, Jeffrey R.; Berbari, Nicolas F.; Gross, Alecia K.; Yoder, Bradley K.; Biology, School of Science
    The transition zone (TZ) is a domain at the base of the cilium that is involved in maintaining ciliary compartment-specific sensory and signaling activity by regulating cilia protein composition. Mutations in TZ proteins result in cilia dysfunction, often causing pleiotropic effects observed in a group of human diseases classified as ciliopathies. The purpose of this study is to describe the importance of the TZ component Meckel-Grüber syndrome 6 (Mks6) in several organ systems and tissues regarding ciliogenesis and cilia maintenance using congenital and conditional mutant mouse models. Similar to MKS, congenital loss of Mks6 is embryonic lethal, displaying cilia loss and altered cytoskeletal microtubule modifications but only in specific cell types. Conditional Mks6 mutants have a variable cystic kidney phenotype along with severe retinal degeneration with mislocalization of phototransduction cascade proteins. However, other phenotypes, such as anosmia and obesity, which are typically associated with cilia and TZ dysfunction, were not evident. These data indicate that despite Mks6 being a core TZ component, it has tissue- or cell type-specific functions important for cilia formation and cilia sensory and signaling activities.