High-fat diet disrupts bone remodeling by inducing local and systemic alterations Carina Cristina Montalvany-Antonucci a , Marina Campos Zicker b , Adaliene Versiani Matos Ferreira c , Soraia Macari d , Erivan Schnaider Ramos-Junior e , Ricardo Santiago Gomez f , Thaís Santos Ferreira Pereira f , Mila Fernandes Moreira Madeira g , Sandra Yasuyo Fukada h , Ildeu Andrade Jr. a , Tarcília Aparecida Silva f, ⁎ a Department of Orthodontics, Faculty of Dentistry, Pontifical Catholic University of Minas Gerais, Belo Horizonte, MG, Brazil b Department of Food Science, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil c Department of Nutrition, Nursing School, Federal University of Minas Gerais, Belo Horizonte, MG, BraziL d Department of Pediatric Dentistry and Orthodontics, Faculty of Dentistry, Federal University of Minas Gerais, MG, Brazil e Department of Biomedical Sciences, Faculty of Dentistry, University of the Pacific, Stockton, CA, USA f Department of Oral Surgery and Pathology, Faculty of Dentistry, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil g Department of Microbiology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil h Department of Pharmacological Science, Faculty of Pharmacy, University of São Paulo, SP, Brazil Received 11 July 2017; received in revised form 30 May 2018; accepted 7 June 2018 Abstract A high-fat (HF) diet leads to detrimental effects on alveolar bone (AB); however, the mechanisms linking adiposity to bone loss are poorly understood. This study investigated if AB resorption induced by an HF diet is associated with the regulation of inflammatory gene expression and if adipocytes can directly interfere with osteoclastogenesis. We also evaluated the effects of diet restriction (DR) on bone phenotype. C57BL6/J mice were fed normal chow or an HF diet for 12 weeks. Samples of maxillae, femur, blood and white adipose tissue were analyzed. In vitro co-culture of bone marrow-derived osteoclasts and mature adipocytes was carried out. The results revealed an increased number of osteoclasts and fewer osteoblasts in animals fed the HF diet, which led to the disruption of trabecular bone and horizontal AB loss. Similar effects were observed in the femur. The metabolic parameters and the deleterious effects of the HF diet on AB and the femur were reversed after DR. The HF diet modulated the expression of 30 inflammatory genes in AB such as Fam3c, InhBa, Tnfs11, Ackr2, Pxmp2 and Chil3, which are related to the inflammatory response and bone remodeling. In vitro, mature adipocytes produced increased levels of adipokines, and co-culture with osteoclasts resulted in augmented osteoclastogenesis. The results indicate that the mechanisms by which an HF diet affects bone involve induction of osteoclastogenesis and inflammatory gene expression. Adipokines apparently are key molecules in this process. Strategies to control diet-induced bone loss might be beneficial in patients with preexisting bone inflammatory conditions. © 2018 Elsevier Inc. All rights reserved. Key words: Bone remodeling; Obesity; High-fat diet; Alveolar bone loss; Diet restriction 1. Introduction Adipose tissue expansion generated by a high-fat (HF) diet is known to cause several systemic disorders such as cardiovascular disease, type 2 diabetes, insulin resistance and metabolic syndrome [1–3]. However, the effects of an HF diet and obesity in bone remodeling are less defined [4–6]. While some results suggested that mechanical loading caused by excess weight has a positive impact on bone mass maintenance [7], recent studies showed that body fat accumulation increases bone resorption [5,6]. Bone remodeling disorders caused by HF consumption have been studied in different experimental models of steady-state conditions [8], periodontal disease [9], ovariectomy [10] and bone healing [11]. The majority of the reports investigated the effects of HF on femurs, tibiae and vertebrae [12–14], while few studies evaluated the impact of HF consumption on alveolar bone (AB) [8,15,16]. AB preservation is essential for tooth support. AB loss can be induced or aggravated by systemic inflammatory conditions as demonstrated by experimental [17,18] and clinical studies [19,20]. Several potential mechanisms have linked adipose tissue accumulation and AB deterio- ration, including (1) increased gingival oxidative stress [21], (2) adipocyte differentiation in detrimental osteoblast formation, (3) local dysbiosis favoring periodontopathogens [22], (4) local and/or systemic increase of receptor activation of NF-kappaB ligand (RankL) [23], (5) release of proinflammatory cytokines and adipokines [24], and (6) the direct influence of bone marrow-driven adipocytes on osteoclast formation via RankL cell-to-cell contact [25]. However, the pathways linking obesity/adipose tissue expansion with AB alteration have not yet been defined [26]. Furthermore, there is little evidence that osteoclast differentiation and activity can be influenced by mature adipocytes. The aims of this study were to investigate the effects of HF diet and diet restriction on AB remodeling and to explore the mechanisms by which Available online at www.sciencedirect.com ScienceDirect Journal of Nutritional Biochemistry 59 (2018) 93 – 103 ⁎ Corresponding author. E-mail address: silva.tarcilia@gmail.com (T.A. Silva). https://doi.org/10.1016/j.jnutbio.2018.06.006 0955-2863/© 2018 Elsevier Inc. All rights reserved.