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      ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrp rd6 mouse

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          Abstract

          The knockout (KO) of the adiponectin receptor 1 ( AdipoR1) gene causes retinal degeneration. Here we report that ADIPOR1 protein is primarily found in the eye and brain with little expression in other tissues. Further analysis of AdipoR1 KO mice revealed that these animals exhibit early visual system abnormalities and are depleted of RHODOPSIN prior to pronounced photoreceptor death. A KO of AdipoR1 post-development either in photoreceptors or the retinal pigment epithelium (RPE) resulted in decreased expression of retinal proteins, establishing a role for ADIPOR1 in supporting vision in adulthood. Subsequent analysis of the Mfrp rd6 mouse retina demonstrated that these mice are lacking ADIPOR1 in their RPE layer alone, suggesting that loss of ADIPOR1 drives retinal degeneration in this model. Moreover, we found elevated levels of IRBP in both the AdipoR1 KO and the Mfrp rd6 models. The spatial distribution of IRBP was also abnormal. This dysregulation of IRBP hypothesizes a role for ADIPOR1 in retinoid metabolism.

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          Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.

          Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.
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            Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.

            Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.
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              A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.

              Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.
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                Author and article information

                Contributors
                valsluch@gmail.com
                dennis.rice@novartis.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                25 September 2018
                25 September 2018
                2018
                : 8
                : 14339
                Affiliations
                [1 ]ISNI 0000 0004 0439 2056, GRID grid.418424.f, Department of Ophthalmology, , Novartis Institutes for BioMedical Research, Cambridge, ; Massachusetts, United States
                [2 ]ISNI 0000 0004 0439 2056, GRID grid.418424.f, Global Scientific Operations, , Novartis Institutes for BioMedical Research, Cambridge, ; Massachusetts, United States
                [3 ]ISNI 0000 0004 0374 0039, GRID grid.249880.f, The Jackson Laboratory, Bar Harbor, ; Maine, United States
                Author information
                http://orcid.org/0000-0003-3318-7986
                http://orcid.org/0000-0001-9376-7339
                Article
                32579
                10.1038/s41598-018-32579-9
                6156493
                30254279
                623277b2-c72e-491d-b1d1-0f4f5b0f9e4b
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 20 April 2018
                : 10 September 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);
                Award ID: EY019943
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: CA34196
                Award Recipient :
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