Lrp4 expression by adipocytes and osteoblasts differentially impacts sclerostin's endocrine effects on body composition and glucose metabolism
| Autor: | Thomas L. Clemens, Zhu Li, Ryan C. Riddle, Michael J. Wolfgang, Priyanka Kushwaha, Hao Da, Lin Mei, Wen Cheng Xiong, Conor Beil, Soo-Hyun Kim |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Carbohydrate metabolism Biochemistry 03 medical and health sciences chemistry.chemical_compound Mice Internal medicine Adipocyte medicine Adipocytes Animals Homeostasis Molecular Biology Cells Cultured LDL-Receptor Related Proteins Adaptor Proteins Signal Transducing Osteoblasts 030102 biochemistry & molecular biology Fatty acid metabolism Chemistry Fatty Acids LRP6 LRP5 Osteoblast Epistasis Genetic Cell Biology 030104 developmental biology Endocrinology medicine.anatomical_structure Metabolism Body Composition Sclerostin Adipocyte hypertrophy |
| Popis: | Sclerostin exerts profound local control over bone acquisition and also mediates endocrine communication between fat and bone. In bone, sclerostin's anti-osteoanabolic activity is enhanced by low-density lipoprotein receptor-related protein 4 (Lrp4), which facilitates its interaction with the Lrp5 and Lrp6 Wnt co-receptors. To determine whether Lrp4 similarly affects sclerostin's endocrine function, we examined body composition as well as glucose and fatty acid metabolism in mice rendered deficient of Lrp4 in the adipocyte (AdΔLrp4) or the osteoblast (ObΔLrp4). AdΔLrp4 mice exhibit a reduction in adipocyte hypertrophy and improved glucose and lipid homeostasis, marked by increased glucose and insulin tolerance and reduced serum fatty acids, and mirror the effect of sclerostin deficiency on whole-body metabolism. Indeed, epistasis studies place adipocyte-expressed Lrp4 and sclerostin in the same genetic cascade that regulates adipocyte function. Intriguingly, ObΔLrp4 mice, which exhibit dramatic increases in serum sclerostin, accumulate body fat and develop impairments in glucose tolerance and insulin sensitivity despite development of a high bone mass phenotype. These data indicate that expression of Lrp4 by both the adipocyte and osteoblast is required for normal sclerostin endocrine function and that the impact of sclerostin deficiency on adipocyte physiology is distinct from the effect on osteoblast function. |
| Databáze: | OpenAIRE |
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