title: Palmitic acid and DGAT1 deficiency enhance osteoclastogenesis, while oleic acid-induced triglyceride formation prevents it.
abstract: Both obesity and diabetes mellitus are associated with alterations in lipid metabolism as well as a change in bone homeostasis and osteoclastogenesis. We hypothesized that increased fatty acid levels affect bone health by altering precursor cell differentiation and osteoclast activation. Here we show that palmitic acid (PA, 16:0) enhances receptor activator of NF-κB ligand (RANKL)-stimulated osteoclastogenesis and is sufficient to induce osteoclast differentiation even in the absence of RANKL. TNFα expression is crucial for PA-induced osteoclastogenesis, as shown by increased TNFα mRNA levels in PA-treated cells and abrogation of PA-stimulated osteoclastogenesis by TNFα neutralizing antibodies. In contrast, oleic acid (OA, 18:1) does not enhance osteoclast differentiation, leads to increased intracellular triglyceride accumulation, and inhibits PA-induced osteoclastogenesis. Adenovirus-mediated expression of diacylglycerol acyl transferase 1 (DGAT1), a gene involved in triglyceride synthesis, also inhibits PA-induced osteoclastogenesis, suggesting a protective role of DGAT1 for bone health. Accordingly, Dgat1 knockout mice have larger bone marrow-derived osteoclasts and decreased bone mass indices. In line with these findings, mice on a high-fat PA-enriched diet have a greater reduction in bone mass and structure than mice on a high-fat OA-enriched diet. Thus, we propose that TNFα mediates saturated fatty acid-induced osteoclastogenesis that can be prevented by DGAT activation or supplementation with OA.
authors.affiliation: Division of Periodontics, Columbia University College of Dental Medicine, New York, NY, USA.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Drosatos-Tampakaki
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Drosatos
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Siegelin
authors.forename: Shan
authors.initials: S
authors.lastname: Gong
authors.forename: Salmiyeh
authors.initials: S
authors.lastname: Khan
authors.forename: Thomas
authors.initials: T
authors.lastname: Van Dyke
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: P Christian
authors.initials: PC
authors.lastname: Schulze
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schulze-Späte
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D051048:Diacylglycerol O-Acyltransferase; D004041:Dietary Fats / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D019301:Oleic Acid / Q000494:pharmacology*; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D019308:Palmitic Acid / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D014280:Triglycerides; D019301:Oleic Acid; D019308:Palmitic Acid; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase
keywords: DGAT1; OSTEOCLASTOGENESIS; PALMITIC ACID; TNFα; TRIGLYCERIDES