PMID- 36807310 OWN - NLM STAT- MEDLINE DCOM- 20230515 LR - 20230825 IS - 1600-0765 (Electronic) IS - 0022-3484 (Print) IS - 0022-3484 (Linking) VI - 58 IP - 3 DP - 2023 Jun TI - GPR40 deficiency worsens metabolic syndrome-associated periodontitis in mice. PG - 575-587 LID - 10.1111/jre.13107 [doi] AB - BACKGROUND AND OBJECTIVE: G protein-coupled receptor 40 (GPR40) is a receptor for medium- and long-chain free fatty acids (FFAs). GPR40 activation improves type 2 diabetes mellitus (T2DM), metabolic syndrome (MetS), and the complications of T2DM and MetS. Periodontitis, a common oral inflammatory disease initiated by periodontal pathogens, is another complication of T2DM and MetS. Since FFAs play a key role in the pathogenesis of MetS which exacerbates periodontal inflammation and GPR40 is a FFA receptor with anti-inflammatory properties, it is important to define the role of GPR40 in MetS-associated periodontitis. MATERIALS AND METHODS: We induced MetS and periodontitis by high-fat diet and periodontal injection of lipopolysaccharide (LPS), respectively, in wild-type and GPR40-deficient mice and determined alveolar bone loss and periodontal inflammation using micro-computed tomography, histology, and osteoclast staining. We also performed in vitro study to determine the role of GPR40 in the expression of proinflammatory genes. RESULTS: The primary outcome of the study is that GPR40 deficiency increased alveolar bone loss and enhanced osteoclastogenesis in control mice and the mice with both MetS and periodontitis. GPR40 deficiency also augmented periodontal inflammation in control mice and the mice with both MetS and periodontitis. Furthermore, GPR40 deficiency led to increased plasma lipids and insulin resistance in control mice but had no effect on the metabolic parameters in mice with MetS alone. For mice with both MetS and periodontitis, GPR40 deficiency increased insulin resistance. Finally, in vitro studies with macrophages showed that deficiency or inhibition of GPR40 upregulated proinflammatory genes while activation of GPR40 downregulated proinflammatory gene expression stimulated synergistically by LPS and palmitic acid. CONCLUSION: GPR40 deficiency worsens alveolar bone loss and periodontal inflammation in mice with both periodontitis and MetS, suggesting that GPR40 plays a favorable role in MetS-associated periodontitis. Furthermore, GPR40 deficiency or inhibition in macrophages further upregulated proinflammatory and pro-osteoclastogenic genes induced by LPS and palmitic acid, suggesting that GPR40 has anti-inflammatory and anti-osteoclastogenic properties. CI - (c) 2023 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. FAU - Li, Yanchun AU - Li Y AD - Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. FAU - Lu, Zhongyang AU - Lu Z AD - Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. FAU - Kirkwood, Cameron L AU - Kirkwood CL AD - Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA. FAU - Kirkwood, Keith L AU - Kirkwood KL AUID- ORCID: 0000-0003-4519-8973 AD - Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, New York, USA. AD - Department of Head & Neck/Plastic & Reconstructive Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. FAU - Wank, Stephen A AU - Wank SA AD - National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA. FAU - Li, Ai-Jun AU - Li AJ AD - Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, USA. FAU - Lopes-Virella, Maria F AU - Lopes-Virella MF AD - Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. AD - Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA. FAU - Huang, Yan AU - Huang Y AUID- ORCID: 0000-0003-2789-5580 AD - Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. AD - Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, USA. LA - eng GR - R01 DE016353/DE/NIDCR NIH HHS/United States GR - R01 DE027070/DE/NIDCR NIH HHS/United States GR - DE027070/NH/NIH HHS/United States GR - DE016353/NH/NIH HHS/United States PT - Journal Article DEP - 20230217 PL - United States TA - J Periodontal Res JT - Journal of periodontal research JID - 0055107 RN - 0 (Lipopolysaccharides) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Fatty Acids, Nonesterified) RN - 0 (Palmitic Acids) SB - IM MH - Mice MH - Animals MH - *Metabolic Syndrome/complications/metabolism MH - *Insulin Resistance MH - *Alveolar Bone Loss/pathology MH - *Diabetes Mellitus, Type 2/complications MH - Lipopolysaccharides/adverse effects MH - X-Ray Microtomography MH - *Periodontitis/metabolism MH - Inflammation MH - Receptors, G-Protein-Coupled/genetics/metabolism MH - Anti-Inflammatory Agents MH - Fatty Acids, Nonesterified MH - Palmitic Acids/adverse effects PMC - PMC10182248 MID - NIHMS1884143 OTO - NOTNLM OT - fatty acid receptor OT - inflammation OT - metabolic syndrome OT - periodontitis COIS- CONFLICT OF INTEREST The authors declare that they have no conflict of interest. EDAT- 2023/02/23 06:00 MHDA- 2023/05/15 06:42 PMCR- 2024/06/01 CRDT- 2023/02/22 11:32 PHST- 2023/01/13 00:00 [revised] PHST- 2022/04/12 00:00 [received] PHST- 2023/01/30 00:00 [accepted] PHST- 2024/06/01 00:00 [pmc-release] PHST- 2023/05/15 06:42 [medline] PHST- 2023/02/23 06:00 [pubmed] PHST- 2023/02/22 11:32 [entrez] AID - 10.1111/jre.13107 [doi] PST - ppublish SO - J Periodontal Res. 2023 Jun;58(3):575-587. doi: 10.1111/jre.13107. Epub 2023 Feb 17.