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      Running Against the Wnt: How Wnt/β-Catenin Suppresses Adipogenesis

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          Abstract

          Mesenchymal stem cells (MSCs) give rise to adipocytes, osteocytes, and chondrocytes and reside in various tissues, including bone marrow and adipose tissue. The differentiation choices of MSCs are controlled by several signaling pathways, including the Wnt/β-catenin signaling. When MSCs undergo adipogenesis, they first differentiate into preadipocytes, a proliferative adipocyte precursor cell, after which they undergo terminal differentiation into mature adipocytes. These two steps are controlled by the Wnt/β-catenin pathway, in such a way that when signaling is abrogated, the next step in adipocyte differentiation can start. This sequence suggests that the main role of Wnt/β-catenin signaling is to suppress differentiation while increasing MSC and preadipocytes cell mass. During later steps of MSC differentiation, however, active Wnt signaling can promote osteogenesis instead of keeping the MSCs undifferentiated and proliferative. The exact mechanisms behind the various functions of Wnt signaling remain elusive, although recent research has revealed that during lineage commitment of MSCs into preadipocytes, Wnt signaling is inactivated by endogenous Wnt inhibitors. In part, this process is regulated by histone-modifying enzymes, which can lead to increased or decreased Wnt gene expression. The role of Wnt in adipogenesis, as well as in osteogenesis, has implications for metabolic diseases since Wnt signaling may serve as a therapeutic target.

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          Most cited references71

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          Wnt/beta-catenin signaling: components, mechanisms, and diseases.

          Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.
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            Mechanisms linking obesity to insulin resistance and type 2 diabetes.

            Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet beta-cells - the cells that release insulin - failure to control blood glucose levels results. Abnormalities in beta-cell function are therefore critical in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention.
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              WNT signaling in bone homeostasis and disease: from human mutations to treatments.

              Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                09 February 2021
                2021
                : 9
                : 627429
                Affiliations
                [1] 1Faculty of Medicine, University Medical Centre Utrecht , Utrecht, Netherlands
                [2] 2Department of Developmental Biology, Howard Hughes Medical Institute , Stanford, CA, United States
                [3] 3School of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University , Stanford, CA, United States
                Author notes

                Edited by: Delilah Hendriks, Hubrecht Institute (KNAW), Netherlands

                Reviewed by: Ormond MacDougald, University of Michigan, United States; Dominic Bernkopf, University of Erlangen Nuremberg, Germany

                *Correspondence: Roeland Nusse rnusse@ 123456stanford.edu

                This article was submitted to Stem Cell Research, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                10.3389/fcell.2021.627429
                7900430
                33634128
                57780cd2-2fd1-40a0-b75e-42376a1089d5
                Copyright © 2021 de Winter and Nusse.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 November 2020
                : 14 January 2021
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 71, Pages: 9, Words: 7136
                Categories
                Cell and Developmental Biology
                Review

                adipogenesis,wnt signaling,mesenchymal stem cells,preadipocyte,osteogenesis,c/ebp,pparγ

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