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      Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes

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          Significance

          Sclerostin exerts profound control over skeletal metabolism by regulating the osteoanabolic Wnt/β-catenin signaling pathway. In this study, we demonstrate that in addition to a dramatic increase in bone mass, Sost −/− mice as well as those treated with a sclerostin-neutralizing antibody exhibit a reduction in white adipose tissue mass and are protected from high fat diet feeding. This effect is associated with an increase in fatty acid oxidation and reduced de novo fatty acid synthesis in adipocytes due to increased Wnt/β-catenin signaling.

          Abstract

          Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/β-catenin signaling, but serum sclerostin levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost −/− mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost −/− mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost −/− mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin’s effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue.

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          Most cited references43

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          Romosozumab in postmenopausal women with low bone mineral density.

          Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation.
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            Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST).

            Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.
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              Regulation of Wnt signaling during adipogenesis.

              We have identified Wnt10b as a potent inhibitor of adipogenesis that must be suppressed for preadipocytes to differentiate in vitro. Here, we demonstrate that a specific inhibitor of glycogen synthase kinase 3, CHIR 99021, mimics Wnt signaling in preadipocytes. CHIR 99021 stabilizes free cytosolic beta-catenin and inhibits adipogenesis by blocking induction of CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. Preadipocyte differentiation is inhibited when 3T3-L1 cells are exposed to CHIR 99021 for any 24 h period during the first 3 days of adipogenesis. Consistent with this time frame of inhibition, expression of Wnt10b mRNA is suppressed upon induction of differentiation, with a 50% decline by 6 h and complete inhibition by 36 h. Of the agents used to induce differentiation, exposure of 3T3-L1 cells to methyl-isobutylxanthine or cAMP is sufficient to suppress expression of Wnt10b mRNA. Inhibition of adipogenesis by Wnt10b is likely mediated by Wnt receptors, Frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6. These receptors, like Wnt10b, are highly expressed in preadipocytes and stromal vascular cells. Finally, we demonstrate that disruption of extracellular Wnt signaling by expression of secreted Frizzled related proteins causes spontaneous adipocyte conversion.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                26 December 2017
                11 December 2017
                : 114
                : 52
                : E11238-E11247
                Affiliations
                [1] aDepartment of Orthopaedic Surgery, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [2] bDepartment of Neuroscience, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [3] cCenter for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [4] dProgram in Molecular Medicine, University of Massachusetts Medical School , Worcester, MA 01655;
                [5] eDepartment of Medicine, Division of Endocrinology and Metabolism, University of Massachusetts Medical School , Worcester, MA 01655;
                [6] fDepartment of Medicine, Division of Diabetes, University of Massachusetts Medical School , Worcester, MA 01655;
                [7] gDepartment of Biological Chemistry, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [8] hDepartment of Pediatrics, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [9] iDepartment of Medicine, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [10] jDivision of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiologic Sciences, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [11] kCancer Molecular and Functional Imaging Program, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine , Baltimore, MD 21205;
                [12] l Baltimore Veterans Administration Medical Center , Baltimore, MD 21201
                Author notes
                2To whom correspondence should be addressed. Email: rriddle1@ 123456jhmi.edu .

                Edited by Clifford J. Tabin, Harvard Medical School, Boston, MA, and approved November 15, 2017 (received for review May 12, 2017)

                Author contributions: S.P.K., M.J.W., and R.C.R. designed research; J.L.F., Z.L., P.K., M.L.Z., R.E.T., H.D., S.A., H.L.N., J.K.K., M.A.H., D.L.J.T., M.J.W., and R.C.R. performed research; J.K.K., M.A.H., M.J.W., and R.C.R. analyzed data; and R.C.R. wrote the paper.

                1S.P.K. and J.L.F. contributed equally to this work.

                Article
                PMC5748171 PMC5748171 5748171 201707876
                10.1073/pnas.1707876115
                5748171
                29229807
                16574ce9-b250-4b81-8600-ba4125b2c955
                Copyright @ 2017

                Published under the PNAS license.

                History
                Page count
                Pages: 10
                Funding
                Funded by: U.S. Department of Veterans Affairs (VA) 100000738
                Award ID: BX003724
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: DK099134
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: DK079637
                Funded by: HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 100000062
                Award ID: DK093000
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: NS072241
                Categories
                PNAS Plus
                Biological Sciences
                Medical Sciences
                PNAS Plus

                adipose,sclerostin,Wnt,bone,metabolism
                adipose, sclerostin, Wnt, bone, metabolism

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