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      Mechanisms Involved in Childhood Obesity-Related Bone Fragility

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          Abstract

          Childhood obesity is one of the major health problems in western countries. The excessive accumulation of adipose tissue causes inflammation, oxidative stress, apoptosis, and mitochondrial dysfunctions. Thus, obesity leads to the development of severe co-morbidities including type 2 diabetes mellitus, liver steatosis, cardiovascular, and neurodegenerative diseases which can develop early in life. Furthermore, obese children have low bone mineral density and a greater risk of osteoporosis and fractures. The knowledge about the interplay bone tissue and between adipose is still growing, although recent findings suggest that adipose tissue activity on bone can be fat-depot specific. Obesity is associated to a low-grade inflammation that alters the expression of adiponectin, leptin, IL-6, Monocyte Chemotactic Protein 1 (MCP1), TRAIL, LIGHT/TNFSF14, OPG, and TNFα. These molecules can affect bone metabolism, thus resulting in osteoporosis. The purpose of this review was to deepen the cellular mechanisms by which obesity may facilitate osteoporosis and bone fractures.

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          Pediatric Obesity—Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline

          The European Society of Endocrinology and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society.
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            Effects of obesity on bone metabolism

            Jay Cao (2011)
            Obesity is traditionally viewed to be beneficial to bone health because of well-established positive effect of mechanical loading conferred by body weight on bone formation, despite being a risk factor for many other chronic health disorders. Although body mass has a positive effect on bone formation, whether the mass derived from an obesity condition or excessive fat accumulation is beneficial to bone remains controversial. The underline pathophysiological relationship between obesity and bone is complex and continues to be an active research area. Recent data from epidemiological and animal studies strongly support that fat accumulation is detrimental to bone mass. To our knowledge, obesity possibly affects bone metabolism through several mechanisms. Because both adipocytes and osteoblasts are derived from a common multipotential mesenchymal stem cell, obesity may increase adipocyte differentiation and fat accumulation while decrease osteoblast differentiation and bone formation. Obesity is associated with chronic inflammation. The increased circulating and tissue proinflammatory cytokines in obesity may promote osteoclast activity and bone resorption through modifying the receptor activator of NF-κB (RANK)/RANK ligand/osteoprotegerin pathway. Furthermore, the excessive secretion of leptin and/or decreased production of adiponectin by adipocytes in obesity may either directly affect bone formation or indirectly affect bone resorption through up-regulated proinflammatory cytokine production. Finally, high-fat intake may interfere with intestinal calcium absorption and therefore decrease calcium availability for bone formation. Unraveling the relationship between fat and bone metabolism at molecular level may help us to develop therapeutic agents to prevent or treat both obesity and osteoporosis. Obesity, defined as having a body mass index ≥ 30 kg/m2, is a condition in which excessive body fat accumulates to a degree that adversely affects health [1]. The rates of obesity rates have doubled since 1980 [2] and as of 2007, 33% of men and 35% of women in the US are obese [3]. Obesity is positively associated to many chronic disorders such as hypertension, dyslipidemia, type 2 diabetes mellitus, coronary heart disease, and certain cancers [4-6]. It is estimated that the direct medical cost associated with obesity in the United States is ~$100 billion per year [7]. Bone mass and strength decrease during adulthood, especially in women after menopause [8]. These changes can culminate in osteoporosis, a disease characterized by low bone mass and microarchitectural deterioration resulting in increased bone fracture risk. It is estimated that there are about 10 million Americans over the age of 50 who have osteoporosis while another 34 million people are at risk of developing the disease [9]. In 2001, osteoporosis alone accounted for some $17 billion in direct annual healthcare expenditure. Several lines of evidence suggest that obesity and bone metabolism are interrelated. First, both osteoblasts (bone forming cells) and adipocytes (energy storing cells) are derived from a common mesenchymal stem cell [10] and agents inhibiting adipogenesis stimulated osteoblast differentiation [11-13] and vice versa, those inhibiting osteoblastogenesis increased adipogenesis [14]. Second, decreased bone marrow osteoblastogenesis with aging is usually accompanied with increased marrow adipogenesis [15,16]. Third, chronic use of steroid hormone, such as glucocorticoid, results in obesity accompanied by rapid bone loss [17,18]. Fourth, both obesity and osteoporosis are associated with elevated oxidative stress and increased production of proinflammatory cytokines [19,20]. At present, the mechanisms for the effects of obesity on bone metabolism are not well defined and will be the focus of this review.
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              Mechanisms of disease: is osteoporosis the obesity of bone?

              Osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. With aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. Secondary causes of osteoporosis, including diabetes mellitus, glucocorticoids and immobility, are associated with bone-marrow adiposity. In this review, we ask a provocative question: does fat infiltration in the bone marrow cause low bone mass or is it a result of bone loss? Unraveling the interface between bone and fat at a molecular and cellular level is likely to lead to a better understanding of several diseases, and to the development of drugs for both osteoporosis and obesity.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                03 May 2019
                2019
                : 10
                : 269
                Affiliations
                [1] 1Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro , Bari, Italy
                [2] 2Neonatal Intensive Care Unit, Di Venere Hospital , Bari, Italy
                [3] 3Department of Emergency and Organ Transplantation, Section of Human Anatomy and Histology, University of Bari , Bari, Italy
                [4] 4Department of Basic and Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro , Bari, Italy
                [5] 5Department of Pharmacy-Drug Science, University of Bari Aldo Moro , Bari, Italy
                Author notes

                Edited by: Guillaume Mabilleau, Université d'Angers, France

                Reviewed by: Tetsuya Izawa, Doshisha University, Japan; Basem M. Abdallah, University of Southern Denmark, Denmark

                *Correspondence: Giacomina Brunetti giacomina.brunetti@ 123456uniba.it

                This article was submitted to Bone Research, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2019.00269
                6509993
                31130918
                fdc0a336-9cac-4db1-907b-a4d6a4afa5ac
                Copyright © 2019 Faienza, D'Amato, Chiarito, Colaianni, Colucci, Grano, Corbo and Brunetti.

                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
                : 02 January 2019
                : 11 April 2019
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 196, Pages: 10, Words: 9254
                Funding
                Funded by: Ministero dell’Istruzione, dell’Università e della Ricerca 10.13039/501100003407
                Categories
                Endocrinology
                Mini Review

                Endocrinology & Diabetes
                osteoporosis,low grade inflammation,osteoimmunology,osteoclast,cytokines
                Endocrinology & Diabetes
                osteoporosis, low grade inflammation, osteoimmunology, osteoclast, cytokines

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