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Smith C, Lin X, Parker L, Yeap BB, Hayes A, Levinger I. The role of bone in energy metabolism: A focus on osteocalcin. Bone 2024; 188:117238. [PMID: 39153587 DOI: 10.1016/j.bone.2024.117238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 08/19/2024]
Abstract
Understanding the mechanisms involved in whole body glucose regulation is key for the discovery of new treatments for type 2 diabetes (T2D). Historically, glucose regulation was largely focused on responses to insulin and glucagon. Impacts of incretin-based therapies, and importance of muscle mass, are also highly relevant. Recently, bone was recognized as an endocrine organ, with several bone proteins, known as osteokines, implicated in glucose metabolism through their effects on the liver, skeletal muscle, and adipose tissue. Research efforts mostly focused on osteocalcin (OC) as a leading example. This review will provide an overview on this role of bone by discussing bone turnover markers (BTMs), the receptor activator of nuclear factor kB ligand (RANKL), osteoprotegerin (OPG), sclerostin (SCL) and lipocalin 2 (LCN2), with a focus on OC. Since 2007, some, but not all, research using mostly OC genetically modified animal models suggested undercarboxylated (uc) OC acts as a hormone involved in energy metabolism. Most data generated from in vivo, ex vivo and in vitro models, indicate that exogenous ucOC administration improves whole-body and skeletal muscle glucose metabolism. Although data in humans are generally supportive, findings are often discordant likely due to methodological differences and observational nature of that research. Overall, evidence supports the concept that bone-derived factors are involved in energy metabolism, some having beneficial effects (ucOC, OPG) others negative (RANKL, SCL), with the role of some (LCN2, other BTMs) remaining unclear. Whether the effect of osteokines on glucose regulation is clinically significant and of therapeutic value for people with insulin resistance and T2D remains to be confirmed.
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Affiliation(s)
- Cassandra Smith
- Nutrition & Health Innovation Research Institute, School of Health and Medical Sciences, Edith Cowan University, Perth, Western Australia, Australia; Medical School, The University of Western Australia, Perth, Western Australia, Australia; Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia
| | - Xuzhu Lin
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
| | - Lewan Parker
- Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, VIC, Australia
| | - Bu B Yeap
- Medical School, The University of Western Australia, Perth, Western Australia, Australia; Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia
| | - Alan Hayes
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Victoria University and Western Health, St Albans, VIC, Australia; Department of Medicine - Western Health, The University of Melbourne, Footscray, VIC, Australia.
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Celik B, Leal AF, Tomatsu S. Potential Targeting Mechanisms for Bone-Directed Therapies. Int J Mol Sci 2024; 25:8339. [PMID: 39125906 PMCID: PMC11312506 DOI: 10.3390/ijms25158339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 07/23/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
Bone development is characterized by complex regulation mechanisms, including signal transduction and transcription factor-related pathways, glycobiological processes, cellular interactions, transportation mechanisms, and, importantly, chemical formation resulting from hydroxyapatite. Any abnormal regulation in the bone development processes causes skeletal system-related problems. To some extent, the avascularity of cartilage and bone makes drug delivery more challenging than that of soft tissues. Recent studies have implemented many novel bone-targeting approaches to overcome drawbacks. However, none of these strategies fully corrects skeletal dysfunction, particularly in growth plate-related ones. Although direct recombinant enzymes (e.g., Vimizim for Morquio, Cerezyme for Gaucher, Elaprase for Hunter, Mepsevii for Sly diseases) or hormone infusions (estrogen for osteoporosis and osteoarthritis), traditional gene delivery (e.g., direct infusion of viral or non-viral vectors with no modifications on capsid, envelope, or nanoparticles), and cell therapy strategies (healthy bone marrow or hematopoietic stem cell transplantation) partially improve bone lesions, novel delivery methods must be addressed regarding target specificity, less immunogenicity, and duration in circulation. In addition to improvements in bone delivery, potential regulation of bone development mechanisms involving receptor-regulated pathways has also been utilized. Targeted drug delivery using organic and inorganic compounds is a promising approach in mostly preclinical settings and future clinical translation. This review comprehensively summarizes the current bone-targeting strategies based on bone structure and remodeling concepts while emphasizing potential approaches for future bone-targeting systems.
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Affiliation(s)
- Betul Celik
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA;
- Nemours Children’s Health, 1600 Rockland Rd., Wilmington, DE 19803, USA;
| | - Andrés Felipe Leal
- Nemours Children’s Health, 1600 Rockland Rd., Wilmington, DE 19803, USA;
- Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá 110231, Colombia
| | - Shunji Tomatsu
- Nemours Children’s Health, 1600 Rockland Rd., Wilmington, DE 19803, USA;
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1193, Japan
- Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19144, USA
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Fuller KN, Bohne EM, Mey JT, Blackburn BK, Miranda VR, Varady KA, Danielson KK, Haus JM. Plasma undercarboxylated osteocalcin dynamics with glycemic stress reflects insulin sensitivity and beta-cell function in humans with and without T2DM. Metabol Open 2023; 20:100264. [PMID: 38115864 PMCID: PMC10728569 DOI: 10.1016/j.metop.2023.100264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 12/21/2023] Open
Abstract
This study aimed to better understand the relationship between bone-related biomarkers and nutrient stress in the context of metabolic health. We investigated plasma osteocalcin (OC) during an oral glucose challenge and experimental hyperinsulinemia in Type 2 diabetes (T2DM) and lean healthy controls (LHC). Older individuals with obesity and T2DM (n = 9) and young LHCs (n = 9) underwent a 75g oral glucose tolerance test (OGTT) and a 40 mU/m2/min hyperinsulinemic-euglycemic clamp. Plasma undercarboxylated OC (ucOC) and total OC were measured at baseline, 60mins, and 120mins of the OGTT and clamp via ELISA. In addition, plasma alkaline phosphatase (ALP), leptin, adiponectin, Vitamin D and insulin were measured and indices of insulin sensitivity and β-cell function were derived. The T2DM group had lower (p<0.05) ucOC and ucOC:total OC ratio than LHC during both the OGTT and clamp. Further, baseline ucOC was positively correlated to indices of β-cell function and negatively correlated to indices of insulin resistance when both groups were combined (all p<0.05). Suppression of OC observed in T2DM may be related to glucose intolerance and insulin resistance. Similarly, our data suggest that the observed phenotypic differences between groups are likely a product of long-term glucose dysregulation rather than acute flux in glucose or insulin.
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Affiliation(s)
- Kelly N.Z. Fuller
- Department of Pediatrics, Section of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Erin M. Bohne
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, IL, USA
| | - Jacob T. Mey
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Brian K. Blackburn
- Applied Health Sciences and Kinesiology, Humboldt State University, Arcata, CA, USA
| | | | - Krista A. Varady
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, IL, USA
| | - Kirstie K. Danielson
- Division of Endocrinology and Metabolism, University of Illinois at Chicago, IL, USA
| | - Jacob M. Haus
- School of Kinesiology, University of Michigan, Ann Arbor, MI, USA
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Halle JL, Counts BR, Paez HG, Baumfalk DR, Zhang Q, Mohamed JS, Glazer ES, Puppa MJ, Smuder AJ, Alway SE, Carson JA. Recovery from FOLFOX chemotherapy-induced systemic and skeletal muscle metabolic dysfunction in mice. Am J Physiol Endocrinol Metab 2023; 325:E132-E151. [PMID: 37378624 PMCID: PMC10393342 DOI: 10.1152/ajpendo.00096.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 05/22/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023]
Abstract
FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy is used to treat colorectal cancer and can acutely induce metabolic dysfunction. However, the lasting effects on systemic and skeletal muscle metabolism after treatment cessation are poorly understood. Therefore, we investigated the acute and lasting effects of FOLFOX chemotherapy on systemic and skeletal muscle metabolism in mice. Direct effects of FOLFOX in cultured myotubes were also investigated. Male C57BL/6J mice completed four cycles (acute) of FOLFOX or PBS. Subsets were allowed to recover for 4 wk or 10 wk. Comprehensive Laboratory Animal Monitoring System (CLAMS) metabolic measurements were performed for 5 days before study endpoint. C2C12 myotubes were treated with FOLFOX for 24 hr. Acute FOLFOX attenuated body mass and body fat accretion independent of food intake or cage activity. Acute FOLFOX decreased blood glucose, oxygen consumption (V̇o2), carbon dioxide production (V̇co2), energy expenditure, and carbohydrate (CHO) oxidation. Deficits in V̇o2 and energy expenditure remained at 10 wk. CHO oxidation remained disrupted at 4 wk but returned to control levels after 10 wk. Acute FOLFOX reduced muscle COXIV enzyme activity, AMPK(T172), ULK1(S555), and LC3BII protein expression. Muscle LC3BII/I ratio was associated with altered CHO oxidation (r = 0.75, P = 0.03). In vitro, FOLFOX suppressed myotube AMPK(T172), ULK1(S555), and autophagy flux. Recovery for 4 wk normalized skeletal muscle AMPK and ULK1 phosphorylation. Our results provide evidence that FOLFOX disrupts systemic metabolism, which is not readily recoverable after treatment cessation. FOLFOX effects on skeletal muscle metabolic signaling did recover. Further investigations are warranted to prevent and treat FOLFOX-induced metabolic toxicities that negatively impact survival and life quality of patients with cancer.NEW & NOTEWORTHY The present study demonstrates that FOLFOX chemotherapy induces long-lasting deficits in systemic metabolism. Interestingly, FOLFOX modestly suppressed skeletal muscle AMPK and autophagy signaling in vivo and in vitro. The FOLFOX-induced suppression of muscle metabolic signaling recovered after treatment cessation, independent of systemic metabolic dysfunction. Future research should investigate if activating AMPK during treatment can prevent long-term toxicities to improve health and quality of life of patients with cancer and survivors.
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Affiliation(s)
- Jessica L Halle
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Brittany R Counts
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Hector G Paez
- Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Dryden R Baumfalk
- Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida, United States
| | - Quan Zhang
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Junaith S Mohamed
- Laboratory of Muscle and Nerve, Department of Diagnostic and Health Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Evan S Glazer
- Department of Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - Melissa J Puppa
- College of Health Sciences, The University of Memphis, Memphis, Tennessee, United States
| | - Ashley J Smuder
- Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, Florida, United States
| | - Stephen E Alway
- Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
| | - James A Carson
- Integrative Muscle Biology Laboratory, Division of Regenerative and Rehabilitation Sciences, College of Health Professions, University of Tennessee Health Science Center, Memphis, Tennessee, United States
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Choi W, Ro Y, Choe E, Hong L, Kim D, Kim S, Yoon I, Kim D. Comparison of prepartum blood parameters in dairy cows with postpartum ketosis and new risk prediction candidates. Front Vet Sci 2023; 10:1161596. [PMID: 37252395 PMCID: PMC10213766 DOI: 10.3389/fvets.2023.1161596] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 04/21/2023] [Indexed: 05/31/2023] Open
Abstract
Introduction Ketosis is a predominant metabolic problem and a risk factor for several postpartum diseases. This retrospective study aimed to evaluate the complete blood count (CBC), plasma biochemistry, and osteocalcin and identify significant prepartum and early postpartum values expressed in ketotic cows. Methods In 135 Holstein Friesian cows, 210 parturitions of 114 primiparous and 96 multiparous cows were examined. According to the plasma concentrations of β-hydroxybutyrate (BHB; ≥ 1.4 mmol/L) or non-esterified fatty acids (NEFA; ≥ 0.7 mmol/L) in the postpartum period, cows were divided into healthy cows (CON) and ketotic cows (KET). Analyses of CBC and biochemistry profiles were performed from -6 to 4 weeks of parturition every 2 weeks (prepartum; BW-5, BW-3, and BW-1, postpartum; BW1 and BW3), and osteocalcin ELISA tests were performed using blood samples from -2 to 2 weeks of parturition (BW-1 and BW1). Results In primiparous KET (n = 114) before parturition, lower lymphocyte (Lym) in BW-5 and BW-3, lower red blood cell (RBC) in BW-5, higher mean corpuscular volume (MCV) in BW-1, and higher NEFA in BW-3 were significant compared with CON. Primiparous KET showed lower carboxylated osteocalcin (cOC) levels and a significant decrease after parturition. In multiparous KET (n = 96) before parturition, lower neutrophil (Neu) in BW-5, higher hemoglobin (HGB) in BW-5, higher MCV in BW-5 and BW-1, higher MCH in BW-5, lower total cholesterol (TC) in BW-5, higher triglyceride (TG) in BW-3, higher NEFA in BW-1, higher glucose (Glu) in BW-3, lower γ-glutamyl transferase (GGT) in BW-5, lower inorganic phosphate (iP) in BW-3, and higher body condition score (BCS) in BW-5 and BW-3 were significant compared with CON. Multiparous KET showed decreased cOC and uncarboxylated osteocalcin (ucOC) after parturition, which was lower than that in the CON group. Discussion The blood parameters expressing different values between CON and KET in prepartum or early postpartum periods are presumed to show individual nutrition and health states, liver function, and overweight status. These parameters could be valuable indicators that can be used to prevent the occurrence of ketosis and improve management practices by recognizing these differences in ketotic cows before calving.
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Affiliation(s)
- Woojae Choi
- Department of Farm Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Younghye Ro
- Farm Animal Clinical Training and Research Center, Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea
| | - Eunhui Choe
- Farm Animal Clinical Training and Research Center, Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea
| | - Leegon Hong
- Department of Farm Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Dohee Kim
- Department of Farm Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Seongdae Kim
- Department of Farm Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Ilsu Yoon
- Department of Farm Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Danil Kim
- Department of Farm Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
- Farm Animal Clinical Training and Research Center, Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Republic of Korea
- Research Institute for Veterinary Science, Seoul National University, Seoul, Republic of Korea
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Dall RD, Cheung MM, Shewokis PA, Altasan A, Volpe SL, Amori R, Singh H, Sukumar D. Combined vitamin D and magnesium supplementation does not influence markers of bone turnover or glycemic control: A randomized controlled clinical trial. Nutr Res 2023; 110:33-43. [PMID: 36640582 DOI: 10.1016/j.nutres.2022.12.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 12/12/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
High-dose vitamin D supplementation can increase total osteocalcin concentrations that may reduce insulin resistance in individuals at risk for prediabetes or diabetes mellitus. Magnesium is a cofactor in vitamin D metabolism and activation. The purpose of this study was to determine the combined effect of vitamin D and magnesium supplementation on total osteocalcin concentrations, glycemic indices, and other bone turnover markers after a 12-week intervention in individuals who were overweight and obese, but otherwise healthy. We hypothesized that combined supplementation would improve serum total osteocalcin concentrations and glycemic indices more than vitamin D supplementation alone or a placebo. A total of 78 women and men completed this intervention in 3 groups: a vitamin D and magnesium group (1000 IU vitamin D3 and 360 mg magnesium glycinate), a vitamin D group (1000 IU vitamin D3), and a placebo group. Despite a significant increase in serum 25-hydroxyvitamin D concentrations in the vitamin D and magnesium group compared with the placebo group (difference = 5.63; CI, -10.0 to -1.21; P = .001) post-intervention, there were no differences in serum concentrations of total osteocalcin, glucose, insulin, and adiponectin or the homeostatic model assessment of insulin resistance (HOMA-IR) among groups (P > .05 for all). Additionally, total osteocalcin (β = -0.310, P = .081), bone-specific alkaline phosphatase (β = 0.004, P = .986), and C-terminal cross-linked telopeptide (β = 0.426, P = .057), were not significant predictors of HOMA-IR after the intervention. Combined supplementation was not associated with short-term improvements in glycemic indices or bone turnover markers in participants who were overweight and obese in our study. This trial was registered at clinicaltrials.gov (NCT03134417).
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Affiliation(s)
- Rosemary D Dall
- Department of Nutrition Sciences, Drexel University, Philadelphia, PA, USA
| | - May M Cheung
- City University of New York - Brooklyn College, Brooklyn, New York, USA
| | | | - Asma Altasan
- Department of Nutrition Sciences, Drexel University, Philadelphia, PA, USA
| | - Stella L Volpe
- Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
| | - Renee Amori
- St. Luke's University Health Network, Bethlehem, PA, USA
| | | | - Deeptha Sukumar
- Department of Nutrition Sciences, Drexel University, Philadelphia, PA, USA.
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Liu J, Wei Y, Zang P, Wang W, Feng Z, Yuan Y, Zhou H, Zhang Z, Lei H, Yang X, Liu J, Lu B, Shao J. Circulating osteocalcin is associated with time in range and other metrics assessed by continuous glucose monitoring in type 2 diabetes. Diabetol Metab Syndr 2022; 14:109. [PMID: 35927761 PMCID: PMC9351112 DOI: 10.1186/s13098-022-00863-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 06/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Osteocalcin, a protein secreted mainly by mature osteoblasts, has been shown to be involved in glucose metabolism through various pathways. However, few studies has explored the association between osteocalcin and Time in range (TIR). Continuous glucose monitoring (CGM) -derived metrics, such as TIR and other indexes have been gradually and widely used in clinical practice to assess glucose fluctuations. The main purpose of this study was to investigate the correlation between osteocalcin and indexes from CGM in patients with type 2 diabetes mellitus (T2DM). METHOD The total number of 376 patients with T2D were enrolled, all of them performed three consecutive days of monitoring. They were divided into four groups on account of the quartile of osteocalcin. Time in range, Time below range (TBR), Time above range(TAR) and measures of glycemic variability (GV) were assessed for analysing. After a 100 g standard steamed bread meal, blood glucose (Glu0h Glu0.5 h, Glu1h, Glu2h, GLu3h), C-peptide (Cp0h, Cp0.5 h, Cp1h, Cp2h, Cp3h), serum insulin (INS0h, INS0.5 h, INS1h, INS2h, INS3h) concentrations at different time points were obtained. HOMA-IS, HOMA-βwas calculated to evaluate insulin sensitivity and insulin secreting of the participants. RESULTS Patients with higher osteocalcin level had higher TIR (P < 0.05). Spearman correlation analysis showed that osteocalcin was positively correlated with TBR (although the P value for TBR was greater than 0.05) (r = 0.227, P < 0.001 r = 0.068, P = 0.189) and negatively correlated with TAR (- 0.229, P < 0.001). Similarly, there was a negative correlation between osteocalcin and glycemic variability (GV) indicators, including SD, MBG, MODD, ADDR, and MAGE (P value of MAGE > 0.05). Multiple stepwise regression showed that osteocalcin was an independent contributor to TIR, TAR and HOMA-IS. CONCLUSION Circulating osteocalcin is positively correlated with TIR and negatively correlated with MODD, ADDR, and MAGE. Osteocalcin may have a beneficial impact on glucose homeostasis in T2DM patients.
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Affiliation(s)
- Jun Liu
- Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Yinghua Wei
- Department of Endocrinology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Pu Zang
- Department of Endocrinology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Wei Wang
- Department of Endocrinology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Zhouqin Feng
- Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Yanyu Yuan
- Department of Endocrinology, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Hui Zhou
- Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Zhen Zhang
- Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Haiyan Lei
- Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China
| | - Xinyi Yang
- Department of Endocrinology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China
| | - Jun Liu
- Department of Endocrinology, Jinling Hospital, Nanjing Medical University, Nanjing, China
| | - Bin Lu
- Department of Endocrinology, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, China.
| | - Jiaqing Shao
- Department of Endocrinology, Jinling Hospital, Southern Medical University, Nanjing, China.
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Naguib M, Ali N, ElSaraf N, Rashed L, Azzam H. Does Serum Osteocalcin Level Affect Carotid Atherosclerosis in Post-Menopausal Diabetic Females? A Case-Control Study. Int J Gen Med 2022; 15:4513-4523. [PMID: 35509602 PMCID: PMC9059994 DOI: 10.2147/ijgm.s353492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 04/11/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose To determine the association between serum osteocalcin and carotid intima media thickness (CIMT) in a group of post-menopausal females with type 2 diabetes (T2DM). Patients and Methods This cross-sectional study enrolled 75 postmenopausal women with T2DM and 40 age matched postmenopausal healthy females. Age, body mass index, blood pressure were recorded for all subjects. Laboratory tests including fasting blood glucose (FBG), glycated hemoglobin (HbA1c) and lipid profile were measured. Serum osteocalcin was measured using ELISA. Bone mineral density (BMD) was measured by DEXA scan. CIMT was assessed with B-mode ultrasonography. Results Patients with T2DM had significantly lower serum osteocalcin compared to control (63.73±27.20 vs 136.16±21.96 pg/mL, P<0.001). Patients with osteoporosis had significantly lower osteocalcin level compared to those with normal BMD. Patients with T2DM had a significant negative correlation between serum osteocalcin and CIMT (r= -0.332; P=0.003), FBG (r= -0.732; P< 0.001), HbA1c (r=-0.672; P< 0.001), and HOMA-IR (r= -0.672; P< 0.001). However, multiple linear regression analysis revealed that CIMT in patients with diabetes was only significantly associated with age (P= 0.001), duration of diabetes (P< 0.001), SBP (P< 0.001), HOMA-IR (P=0.033), LDL (P=0.005), and HDL (P< 0.001). Furthermore, serum insulin (β= -0.183, P=0.033), FBG (β= -0.604, P< 0.001) and LDL (β= -0.195, P= 0.02) were independently negatively correlated with serum osteocalcin. Conclusion In this study, Postmenopausal women with diabetes had significantly lower osteocalcin compared to non-diabetic women. Although serum osteocalcin was negatively correlated with CIMT, multivariate regression analysis revealed that osteocalcin level was only independently related to worse glycemic parameters in postmenopausal women with T2DM.
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Affiliation(s)
- Mervat Naguib
- Diabetes and Endocrinology Unite, Internal Medicine Department, Faculty of Medicine Kasr Al-Ainy Hospital Cairo University, Cairo, Egypt
| | - Nadia Ali
- Internal Medicine Department, Ahmed Maher Hospital, Cairo, Egypt
| | - Nashwa ElSaraf
- Internal Medicine Department, Faculty of Medicine Kasr Al-Ainy Hospital Cairo University, Cairo, Egypt
| | - Lila Rashed
- Department of Biochemistry, Faculty of Medicine Cairo University, Cairo, Egypt
| | - Hebatoallah Azzam
- Radiology Department, Faculty of Medicine Kasr Al-Ainy Hospital Cairo University, Cairo, Egypt
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Qian Z, Liu C, Li H, Yang H, Wu J, Liu J, Li Y, Chen X, Xu J, Li X. Osteocalcin Alleviates Lipopolysaccharide-Induced Acute Inflammation via Activation of GPR37 in Macrophages. Biomedicines 2022; 10:1006. [PMID: 35625743 PMCID: PMC9138386 DOI: 10.3390/biomedicines10051006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/24/2022] [Accepted: 04/24/2022] [Indexed: 11/16/2022] Open
Abstract
The G protein-coupled receptor 37 (GPR37) has been reported to be expressed in macrophages and the activation of GPR37 by its ligand/agonist, and it can regulate macrophage-associated functions and inflammatory responses. Since our previous work identified that osteocalcin (OCN) acts as an endogenous ligand for GPR37 and can elicit various intracellular signals by interacting with GPR37, we thus hypothesized that OCN may also play a functional role in macrophage through the activation of GPR37. To verify the hypothesis, we conducted a series of in vivo and in vitro studies in lipopolysaccharide (LPS)-challenged mice and primary cultured macrophages. Our results reveal that the OCN gene deletion (OCN-/-) and wild type (WT) mice showed comparable death rates and inflammatory cytokines productions in response to a lethal dose of LPS exposure. However, the detrimental effects caused by LPS were significantly ameliorated by exogenous OCN treatments in both WT and OCN-/- mice. Notably, the protective effects of OCN were absent in GPR37-/- mice. In coordination with the in vivo results, our in vitro studies further illustrated that OCN triggered intracellular responses via GPR37 in peritoneal macrophages by regulating the release of inflammatory factors and macrophage phagocytic function. Finally, we exhibited that the adoptive transfer of OCN-treated macrophages from WT mice significantly inhibits the release of pro-inflammatory cytokines in GPR37-/- mice exposed to LPS. Taken together, these findings suggest a protective role of OCN against LPS-caused acute inflammation, by the activation of GPR37 in macrophages, and provide a potential application of the activation of the OCN/GPR37 regulatory axis as a therapeutic strategy for inflammatory diseases.
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Affiliation(s)
- Zhengjiang Qian
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
| | - Chunhua Liu
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
| | - Hongchao Li
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
| | - Haiyang Yang
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianhao Wu
- Department of Traditional Chinese Medicine, Shenzhen University General Hospital, Shenzhen 518055, China; (J.W.); (J.L.); (J.X.)
| | - Jing Liu
- Department of Traditional Chinese Medicine, Shenzhen University General Hospital, Shenzhen 518055, China; (J.W.); (J.L.); (J.X.)
| | - Yanjiao Li
- Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China;
| | - Xuhui Chen
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518000, China;
| | - Jianyang Xu
- Department of Traditional Chinese Medicine, Shenzhen University General Hospital, Shenzhen 518055, China; (J.W.); (J.L.); (J.X.)
| | - Xiang Li
- Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, CAS Key Laboratory of Brain Connectome and Manipulation, Shenzhen Key Laboratory of Viral Vectors for Biomedicine, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen 518055, China; (Z.Q.); (C.L.); (H.L.); (H.Y.)
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10
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Lai Y, Masatoshi H, Ma Y, Guo Y, Zhang B. Role of Vitamin K in Intestinal Health. Front Immunol 2022; 12:791565. [PMID: 35069573 PMCID: PMC8769504 DOI: 10.3389/fimmu.2021.791565] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Intestinal diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancer (CRC) generally characterized by clinical symptoms, including malabsorption, intestinal dysfunction, injury, and microbiome imbalance, as well as certain secondary intestinal disease complications, continue to be serious public health problems worldwide. The role of vitamin K (VK) on intestinal health has drawn growing interest in recent years. In addition to its role in blood coagulation and bone health, several investigations continue to explore the role of VK as an emerging novel biological compound with the potential function of improving intestinal health. This study aims to present a thorough review on the bacterial sources, intestinal absorption, uptake of VK, and VK deficiency in patients with intestinal diseases, with emphasis on the effect of VK supplementation on immunity, anti-inflammation, intestinal microbes and its metabolites, antioxidation, and coagulation, and promoting epithelial development. Besides, VK-dependent proteins (VKDPs) are another crucial mechanism for VK to exert a gastroprotection role for their functions of anti-inflammation, immunomodulation, and anti-tumorigenesis. In summary, published studies preliminarily show that VK presents a beneficial effect on intestinal health and may be used as a therapeutic drug to prevent/treat intestinal diseases, but the specific mechanism of VK in intestinal health has yet to be elucidated.
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Affiliation(s)
- Yujiao Lai
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Hori Masatoshi
- Department of Veterinary Pharmacology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Yanbo Ma
- Department of Animal Physiology, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China
| | - Yuming Guo
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Bingkun Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing, China
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11
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Huang TH, Nosaka K, Chen TC. Changes in blood bone markers after the first and second bouts of whole-body eccentric exercises. Scand J Med Sci Sports 2021; 32:521-532. [PMID: 34951069 DOI: 10.1111/sms.14118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 12/04/2021] [Accepted: 12/21/2021] [Indexed: 12/01/2022]
Abstract
The present study compared the first (EC1) and second (EC2) bouts of whole-body eccentric exercises to examine the effects of the magnitude of muscle damage on changes in blood bone markers. Fifteen sedentary young men performed nine eccentric exercises of arm, leg and trunk muscles, and repeated them two weeks later. Blood samples were taken before and two hours and one to five days following each bout to analyze plasma creatine kinase (CK) activity and myoglobin concentration, serum tartrate resistant acid phosphatase (TRAP), type 1 C-terminal telopeptide (CTX-1), procollagen type I N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BAP), undercarboxylated-osteocalcin (ucOCN), carboxylated-osteocalcin (cOCN), and leptin concentrations. All except ucOCN changed significantly (P<0.05) after both bouts. When comparing bouts for peak changes, P1NP (bone formation marker) and CTX-1 (bone resorption marker) increased less after EC2 (peak: 137±96% and 7±6%, respectively) than after EC1 (146±80% and 30±21%, respectively), whereas BAP (bone formation marker) increased more after EC2 (18±16%) than after EC1 (4±15%) (P<0.05). Leptin (49±58%) and cOCN (14±10%) increased more (P<0.05) after EC2 than after EC1 (-30±15%, 9±26%). Significant (P<0.05) correlations were evident between peak CK activity and peak CTX-1 (r=0.847), P1NP (r=0.815), BAP (r=-0.707), ucOCN (r=0.627), cCON (r=-0.759) and leptin (r=-0.740) changes after EC1, but many of these correlations disappeared after EC2. This was also found for the relationships between other muscle damage markers (myoglobin, muscle soreness and muscle strength) and the bone markers. It was concluded that bone turnover was affected by eccentric exercise, but muscle damage was unfavorable for bone formation.
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Affiliation(s)
- Tsang-Hai Huang
- Institute of Physical Education, Health and Leisure Studies, National Cheng Kung University, Tainan City, Taiwan
| | - Kazunori Nosaka
- Centre for Exercise and Sports Science Research, School of Medical and Health Sciences, Edith Cowan University, Western Australia, Australia
| | - Trevor C Chen
- Department of Physical Education and Sport Sciences, National Taiwan Normal University, Taipei City, Taiwan
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12
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Berger JM, Karsenty G. Osteocalcin and the Physiology of Danger. FEBS Lett 2021; 596:665-680. [PMID: 34913486 PMCID: PMC9020278 DOI: 10.1002/1873-3468.14259] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 11/29/2021] [Accepted: 12/07/2021] [Indexed: 12/02/2022]
Abstract
Bone biology has long been driven by the question as to what molecules affect cell differentiation or the functions of bone. Exploring this issue has been an extraordinarily powerful way to improve our knowledge of bone development and physiology. More recently, a second question has emerged: does bone have other functions besides making bone? Addressing this conundrum revealed that the bone-derived hormone osteocalcin affects a surprisingly large number of organs and physiological processes, including acute stress response. This review will focus on this emerging aspect of bone biology taking osteocalcin as a case study and will show how classical and endocrine functions of bone help to define a new functional identity for this tissue.
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Affiliation(s)
- Julian Meyer Berger
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, NY, 10032, USA
| | - Gerard Karsenty
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, NY, 10032, USA
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Katra B, Fedak D, Matejko B, Małecki MT, Wędrychowicz A. The enteroendocrine-osseous axis in patients with long-term type 1 diabetes mellitus. Bone 2021; 153:116105. [PMID: 34245933 DOI: 10.1016/j.bone.2021.116105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/22/2021] [Accepted: 06/29/2021] [Indexed: 11/16/2022]
Abstract
INTRODUCTION The relationship between the gut and skeleton is increasingly recognized as a component of the regulation of carbohydrate metabolism. The aim of our study was to assess the relationship between bone mineral density (BMD), incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), intestinotrophic peptide glucagon-like peptide-2 (GLP-2) and osteocalcin isoforms in patients with long-term type 1 diabetes (T1D) when compared to healthy controls. METHODS Eighty two patients with long term T1D, treated in the Department of Metabolic Diseases and 53 healthy controls were recruited to the study. Long term disease duration was defined as lasting for more than 10 years. The control group was selected among age- and sex-matched healthy people. Fasting blood samples were collected to measure levels of incretin hormones (GLP-1, GLP-2, GIP), two forms of osteocalcin (uncarboxylated (ucOC), and carboxylated (cOC)), and additional biochemical parameters associated with glucose and bone metabolism (HbA1c, calcium, phosphorus, 25(OH)D3, PTH). RESULTS Patients with T1D had higher BMI than in controls (p = 0.02). There was no difference in BMD at the lumbar spine and the femoral neck between patients with long-term T1D and healthy ones. Z-score values in both groups were within normal ranges. The level of GIP was significantly higher in T1D patients (p = 0.0002) in comparison to the healthy ones. The levels of GLP-1 and GLP-2 did not differ between T1D patients and controls. In the T1D group, strong, positive associations were found between serum levels of GLP-1 and cOC (r = 0.546, p < 0.001) and between GLP-1 and total OC (r = 0.51, p < 0.001), also after adjusting for BMI (p < 0.001 and p < 0.001, respectively). Significant positive associations were also found between serum levels of GLP-2 and cOC (r = 0.27, p = 0.013) and between GLP-2 and total OC (r = 0.25, p = 0.018), also in a multivariate regression (p = 0.009, p = 0,175, respectively). Moreover, in T1D patients, GLP-1 correlated positively with the femoral neck BMD (g/cm2) (r = 0.265, p = 0.016) and this association was statistically significant after adjusting for BMI (p = 0.011). These correlations were not present in the control group. The only significant correlation observed in the control group was between OC and BMD of the neck (p = 0.049 for neck BMD g/cm2, and p = 0.041 for neck Z-score). CONCLUSIONS Our data suggests an effect of gut hormones on bone in long-term T1D, which could be associated with OC activity, however we did not find a direct connection with glucose metabolism. GLP-1 could have a possible, protective role on bone mineral density in patients with T1D. The data from our study suggests that gut hormones could be considered as a new link in the skeleton - pancreatic endocrine loop in patients with T1D.
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Affiliation(s)
- Barbara Katra
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Danuta Fedak
- Department of Diagnostics, Jagiellonian University Medical College, Kraków, Poland
| | - Bartłomiej Matejko
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Maciej T Małecki
- Department of Metabolic Diseases, Jagiellonian University Medical College, Kraków, Poland
| | - Anna Wędrychowicz
- Department of Pediatric and Adolescent Endocrinology, Pediatric Institute, Jagiellonian University Medical College, Kraków, Poland.
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Cooper ID, Brookler KH, Crofts CAP. Rethinking Fragility Fractures in Type 2 Diabetes: The Link between Hyperinsulinaemia and Osteofragilitas. Biomedicines 2021; 9:1165. [PMID: 34572351 PMCID: PMC8472634 DOI: 10.3390/biomedicines9091165] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/27/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) and/or cardiovascular disease (CVD), conditions of hyperinsulinaemia, have lower levels of osteocalcin and bone remodelling, and increased rates of fragility fractures. Unlike osteoporosis with lower bone mineral density (BMD), T2DM bone fragility "hyperinsulinaemia-osteofragilitas" phenotype presents with normal to increased BMD. Hyperinsulinaemia and insulin resistance positively associate with increased BMD and fragility fractures. Hyperinsulinaemia enforces glucose fuelling, which decreases NAD+-dependent antioxidant activity. This increases reactive oxygen species and mitochondrial fission, and decreases oxidative phosphorylation high-energy production capacity, required for osteoblasto/cytogenesis. Osteocytes directly mineralise and resorb bone, and inhibit mineralisation of their lacunocanalicular space via pyrophosphate. Hyperinsulinaemia decreases vitamin D availability via adipocyte sequestration, reducing dendrite connectivity, and compromising osteocyte viability. Decreased bone remodelling and micropetrosis ensues. Trapped/entombed magnesium within micropetrosis fossilisation spaces propagates magnesium deficiency (MgD), potentiating hyperinsulinaemia and decreases vitamin D transport. Vitamin D deficiency reduces osteocalcin synthesis and favours osteocyte apoptosis. Carbohydrate restriction/fasting/ketosis increases beta-oxidation, ketolysis, NAD+-dependent antioxidant activity, osteocyte viability and osteocalcin, and decreases excess insulin exposure. Osteocalcin is required for hydroxyapatite alignment, conferring bone structural integrity, decreasing fracture risk and improving metabolic/endocrine homeodynamics. Patients presenting with fracture and normal BMD should be investigated for T2DM and hyperinsulinaemia.
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Affiliation(s)
- Isabella D. Cooper
- Translational Physiology Research Group, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK
| | - Kenneth H. Brookler
- Research Collaborator, Aerospace Medicine and Vestibular Research Laboratory, Mayo Clinic, Scottsdale, AZ 85259, USA;
| | - Catherine A. P. Crofts
- School of Public Health and Interdisciplinary Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland 0627, New Zealand;
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Liu X, Yeap BB, Brock KE, Levinger I, Golledge J, Flicker L, Brennan-Speranza TC. Associations of Osteocalcin Forms With Metabolic Syndrome and Its Individual Components in Older Men: The Health In Men Study. J Clin Endocrinol Metab 2021; 106:e3506-e3518. [PMID: 34003927 DOI: 10.1210/clinem/dgab358] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT The osteoblast-derived polypeptide, osteocalcin (OC), has been associated with lower risk of type 2 diabetes and metabolic syndrome (MetS) in several epidemiological studies. Animal studies have indicated the undercarboxylated form of OC (ucOC) drives its association with metabolic outcomes. OBJECTIVE We compared associations of ucOC and carboxylated OC (cOC) with MetS and its components in older men. METHODS A cross-sectional analysis of 2575 men aged ≥70 years and older resident in Perth, Western Australia. ucOC was assayed using a hydroxyapatite-binding method, and cOC calculated by subtracting ucOC from total OC. Main outcome measures were MetS and its components. RESULTS Both lower serum ucOC and cOC levels, and the proportion of cOC (%cOC) were associated with less favorable metabolic parameters (higher waist circumference, triglyceride, glucose, blood pressure, and lower high-density lipoprotein cholesterol), whereas inverse associations were found with %ucOC. Men in the lowest quintile of ucOC had higher risk of MetS compared to men in the highest quintile (Q1 ≤ 7.7 vs Q5 > 13.8 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). Men in the lowest quintile of cOC had higher risk of MetS compared to those in the highest quintile (≤ 5.8 vs > 13.0 ng/mL; OR = 2.4; 95% CI, 1.8-3.2). CONCLUSION Lower concentrations of serum ucOC or cOC were associated with less favorable metabolic parameters and a higher risk of MetS. In contrast, a lower proportion of ucOC was associated with better metabolic parameters and lower MetS risk. Further research is warranted to determine whether ucOC and cOC are suitable biomarkers for cardiometabolic risk in men.
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Affiliation(s)
- Xiaoying Liu
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Bu B Yeap
- Medical School, University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Western Australia, Australia
| | - Kaye E Brock
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Melbourne, Victoria, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, James Cook University, Townsville, Queensland, Australia
- Department of Vascular and Endovascular Surgery, Townsville University Hospital, Townsville, Queensland, Australia
| | - Leon Flicker
- Medical School, University of Western Australia, Perth, Western Australia, Australia
- Western Australian Centre for Health and Ageing, University of Western Australia, Perth, Western Australia, Australia
| | - Tara C Brennan-Speranza
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
- School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
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Osteocalcin Is Independently Associated with C-Reactive Protein during Lifestyle-Induced Weight Loss in Metabolic Syndrome. Metabolites 2021; 11:metabo11080526. [PMID: 34436467 PMCID: PMC8400285 DOI: 10.3390/metabo11080526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/16/2021] [Accepted: 08/04/2021] [Indexed: 12/11/2022] Open
Abstract
Bone-derived osteocalcin has been suggested to be a metabolic regulator. To scrutinize the relation between osteocalcin and peripheral insulin sensitivity, we analyzed changes in serum osteocalcin relative to changes in insulin sensitivity, low-grade inflammation, and bone mineral density following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). Participants with MetS were randomized to a weight loss program or to a control group. Before and after the 6-month intervention period, clinical and laboratory parameters and serum osteocalcin levels were determined. Changes in body composition were analyzed by dual-energy X-ray absorptiometry (DXA). In participants of the intervention group, weight loss resulted in improved insulin sensitivity and amelioration of inflammation. Increased serum levels of osteocalcin correlated inversely with BMI (r = −0.63; p< 0.001), total fat mass (r = −0.58, p < 0.001), total lean mass (r = −0.45, p < 0.001), C-reactive protein (CRP) (r = −0.37; p < 0.01), insulin (r = −0.4; p < 0.001), leptin (r = −0.53; p < 0.001), triglycerides (r = −0.42; p < 0.001), and alanine aminotransferase (ALAT) (r = −0.52; p < 0.001). Regression analysis revealed that osteocalcin was independently associated with changes in CRP but not with changes in insulin concentration, fat mass, or bone mineral density, suggesting that weight loss-induced higher serum osteocalcin is primarily associated with reduced inflammation.
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Jin S, Chang XC, Wen J, Yang J, Ao N, Zhang KY, Suo LN, Du J. Decarboxylated osteocalcin, a possible drug for type 2 diabetes, triggers glucose uptake in MG63 cells. World J Diabetes 2021; 12:1102-1115. [PMID: 34326958 PMCID: PMC8311485 DOI: 10.4239/wjd.v12.i7.1102] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/05/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Uncarboxylated osteocalcin (GluOC) has been reported to improve glucose metabolism, prevent type 2 diabetes, and decrease the severity of obesity in mice with type 2 diabetes. GluOC can increase glucose uptake in a variety of cells. Glucose metabolism is the main source of energy for osteoblast proliferation and differentiation. We hypothesized that decarboxylated osteocalcin (dcOC), a kind of GluOC, can increase glucose uptake in MG63 cells (osteoblast-like osteosarcoma cells) and influence their proliferation and differentiation.
AIM To investigate the effects of dcOC on glucose uptake in human osteoblast-like osteosarcoma cells and the possible signaling pathways involved.
METHODS MG63 cells (human osteoblast-like osteosarcoma cells) were treated with dcOC (0, 0.3, 3, 10, or 30 ng/mL) for 1 and 72 h, and glucose uptake was measured by flow cytometry. The effect of dcOC on cell proliferation was measured with a CCK-8 assay, and alkaline phosphatase (ALP) enzyme activity was measured. PI3K was inhibited with LY294002, and hypoxia-inducible factor 1 alpha (HIF-1α) was silenced with siRNA. Then, GPRC6A (G protein-coupled receptor family C group 6 subtype A), total Akt, phosphorylated Akt, HIF-1α, and glucose transporter 1 (GLUT1) levels were measured by Western blot to elucidate the possible pathways by which dcOC modulates glucose uptake.
RESULTS The glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after short-term (1 h) treatment with dcOC at different concentrations (0.3, 3, and 10 ng/mL groups, P < 0.01; 30 ng/mL group, P < 0.05). Glucose uptake of MG63 cells was significantly increased compared with that of the paired control cells after long-term (72 h) treatment with dcOC at different concentrations (0.3, 3, and 10 ng/mL groups, P < 0.01; 30 ng/mL group, P < 0.05). DcOC triggered Akt phosphorylation in a dose-dependent manner, and the most effective stimulatory concentration of dcOC for short-term (1 h) was 3 ng/mL (P < 0.01). LY294002 abolished the dcOC-mediated (1 h) promotion of Akt phosphorylation and glucose uptake without affecting GLUT1 protein expression. Long-term dcOC stimulation triggered Akt phosphorylation and increased the protein levels of HIF-1α, GLUT1, and Runx2 in a dose-dependent manner. Inhibition of HIF-1α with siRNA abolished the dcOC-mediated glucose uptake and substantially decreased GLUT1 protein expression. DcOC intervention promoted cell proliferation in a time- and dose-dependent manner as determined by the CCK-8 assay. Treatment with both 3 ng/mL and 10 ng/mL dcOC affected the ALP activity in MG63 cells after 72 h (P < 0.01).
CONCLUSION Short- and long-term dcOC treatment can increase glucose uptake and affect proliferation and ALP activity in MG63 cells. This effect may occur through the PI3K/Akt, HIF-1α, and GLUT1 signaling factors.
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Affiliation(s)
- Shi Jin
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Xiao-Cen Chang
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Jing Wen
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Jing Yang
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Na Ao
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Ke-Ying Zhang
- Department of Endocrinology, The Fifth People’s Hospital of Shenyang, Shenyang 110023, Liaoning Province, China
| | - Lin-Na Suo
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Jian Du
- Department of Endocrinology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
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Endocrine role of bone in the regulation of energy metabolism. Bone Res 2021; 9:25. [PMID: 34016950 PMCID: PMC8137703 DOI: 10.1038/s41413-021-00142-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 12/20/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Bone mainly functions as a supportive framework for the whole body and is the major regulator of calcium homeostasis and hematopoietic function. Recently, an increasing number of studies have characterized the significance of bone as an endocrine organ, suggesting that bone-derived factors regulate local bone metabolism and metabolic functions. In addition, these factors can regulate global energy homeostasis by altering insulin sensitivity, feeding behavior, and adipocyte commitment. These findings may provide a new pathological mechanism for related metabolic diseases or be used in the diagnosis, treatment, and prevention of metabolic diseases such as osteoporosis, obesity, and diabetes mellitus. In this review, we summarize the regulatory effect of bone and bone-derived factors on energy metabolism and discuss directions for future research.
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Gerosa L, Lombardi G. Bone-to-Brain: A Round Trip in the Adaptation to Mechanical Stimuli. Front Physiol 2021; 12:623893. [PMID: 33995117 PMCID: PMC8120436 DOI: 10.3389/fphys.2021.623893] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Besides the classical ones (support/protection, hematopoiesis, storage for calcium, and phosphate) multiple roles emerged for bone tissue, definitively making it an organ. Particularly, the endocrine function, and in more general terms, the capability to sense and integrate different stimuli and to send signals to other tissues, has highlighted the importance of bone in homeostasis. Bone is highly innervated and hosts all nervous system branches; bone cells are sensitive to most of neurotransmitters, neuropeptides, and neurohormones that directly affect their metabolic activity and sensitivity to mechanical stimuli. Indeed, bone is the principal mechanosensitive organ. Thanks to the mechanosensing resident cells, and particularly osteocytes, mechanical stimulation induces metabolic responses in bone forming (osteoblasts) and bone resorbing (osteoclasts) cells that allow the adaptation of the affected bony segment to the changing environment. Once stimulated, bone cells express and secrete, or liberate from the entrapping matrix, several mediators (osteokines) that induce responses on distant targets. Brain is a target of some of these mediator [e.g., osteocalcin, lipocalin2, sclerostin, Dickkopf-related protein 1 (Dkk1), and fibroblast growth factor 23], as most of them can cross the blood-brain barrier. For others, a role in brain has been hypothesized, but not yet demonstrated. As exercise effectively modifies the release and the circulating levels of these osteokines, it has been hypothesized that some of the beneficial effects of exercise on brain functions may be associated to such a bone-to-brain communication. This hypothesis hides an interesting clinical clue: may well-addressed physical activities support the treatment of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases?
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Affiliation(s)
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy.,Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Poznań, Poland
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20
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The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases. Antioxidants (Basel) 2021; 10:antiox10040566. [PMID: 33917442 PMCID: PMC8067486 DOI: 10.3390/antiox10040566] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/02/2021] [Accepted: 04/02/2021] [Indexed: 12/17/2022] Open
Abstract
As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with antiaging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Thus, vitamin K can carboxylate osteocalcin (a protein capable of transporting and fixing calcium in bone), activate matrix Gla protein (an inhibitor of vascular calcification and cardiovascular events) and carboxylate Gas6 protein (involved in brain physiology and a cognitive decline and neurodegenerative disease inhibitor). By improving insulin sensitivity, vitamin K lowers diabetes risk. It also exerts antiproliferative, proapoptotic, autophagic effects and has been associated with a reduced risk of cancer. Recent research shows that protein S, another vitamin K-dependent protein, can prevent the cytokine storm observed in COVID-19 cases. The reduced activation of protein S due to the pneumonia-induced vitamin K depletion was correlated with higher thrombogenicity and possibly fatal outcomes in COVID-19 patients. Our review aimed to present the latest scientific evidence about vitamin K and its role in preventing age-associated diseases and/or improving the effectiveness of medical treatments in mature adults ˃50 years old.
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21
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Sedky AA. Improvement of cognitive function, glucose and lipid homeostasis and serum osteocalcin levels by liraglutide in diabetic rats. Fundam Clin Pharmacol 2021; 35:989-1003. [PMID: 33683755 DOI: 10.1111/fcp.12664] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/25/2021] [Accepted: 03/01/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Glucose and lipid abnormalities, oxidative stress (OXS) and reduced brain-derived neurotrophic factor (BDNF) are involved in cognitive dysfunction in diabetes. Glucagon like peptide 1 (GLP1) receptors modulate glucose and lipid metabolism, cognitive function and serum osteocalcin. On the other hand, osteocalcin modulates cognitive function and glucose and lipid metabolism. This study investigated whether the GLP 1 agonist liraglutide improves cognitive function via modulation of serum osteocalcin and glucose and lipid metabolism. METHODS Effects of 4 weeks liraglutide treatment (100 µg/Kg/d and 300 µg/Kg/d) on changes in cognitive function and bone homeostasis, induced by high fat diet/low-dose streptozotocin (HFD-STZ), were determined in rats. Cognitive function was assessed using Morris water maze (MWM) test. Serum and bone biochemical parameters were determined. RESULTS Liraglutide dose-dependently improved cognitive function in diabetic rats (reduced escape latency, and increased time spent in target quadrant in MWM test, compared to diabetic control). Glucose and lipid abnormalities and the associated changes in serum BDNF and oxidative stress makers were improved. Serum BDNF and glutathione were significantly increased, whereas malondialdehyde level was reduced. Serum osteocalcin was significantly increased and correlated with improvement in cognitive dysfunction. Serum and bone receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin ratios were significantly reduced by liraglutide treatment. CONCLUSION Improvement of cognitive dysfunction by liraglutide involves modulation of glucose and lipid metabolism and serum osteocalcin. GLP1 agonists may provide an alternative metabolic approach for cognitive dysfunction in diabetes.
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Lin Y, Zhou M, Dai W, Guo W, Qiu J, Zhang Z, Mo M, Ding L, Ye P, Wu Y, Zhu X, Wu Z, Xu P, Chen X. Bone-Derived Factors as Potential Biomarkers for Parkinson's Disease. Front Aging Neurosci 2021; 13:634213. [PMID: 33732138 PMCID: PMC7959739 DOI: 10.3389/fnagi.2021.634213] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 01/29/2021] [Indexed: 12/17/2022] Open
Abstract
Background: Parkinson’s disease (PD) and osteoporosis are both common aging diseases. It is reported that PD has a close relationship with osteoporosis and bone secretory proteins may be involved in disease progression. Objectives: To detect the bone-derived factors in plasma and cerebrospinal fluid (CSF) of patients with PD and evaluate their correlations with C-reaction protein (CRP) level, motor impairment, and Hoehn-Yahr (HY) stage of the disease. Methods: We included 250 PD patients and 250 controls. Levels of osteocalcin (OCN), osteopontin (OPN), osteoprotegerin (OPG), Sclerostin (SO), Bone morphogenetic protein 2 (BMP2), and Dickkopf-1 (DKK-1) in plasma and CSF were measured by custom protein antibody arrays. Data were analyzed using Mann–Whitney U-test and Spearman’s receptor activator of NF-κB (RANK) correlation. Results: Plasma levels of OCN and OPN were correlated with CRP levels and HY stage and motor impairment of PD. Furthermore, the plasma assessment with CSF detection may enhance their potential prediction on PD. Conclusions: OCN and OPN may serve as potential biomarkers for PD. The inflammation response may be involved in the cross-talk between the two factors and PD.
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Affiliation(s)
- Yuwan Lin
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Miaomiao Zhou
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wei Dai
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenyuan Guo
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jiewen Qiu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhiling Zhang
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingshu Mo
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Liuyan Ding
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Panghai Ye
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yijuan Wu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiaoqin Zhu
- Department of Physiology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Zhuohua Wu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pingyi Xu
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiang Chen
- Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Wang JS, Mazur CM, Wein MN. Sclerostin and Osteocalcin: Candidate Bone-Produced Hormones. Front Endocrinol (Lausanne) 2021; 12:584147. [PMID: 33776907 PMCID: PMC7988212 DOI: 10.3389/fendo.2021.584147] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 01/13/2021] [Indexed: 12/22/2022] Open
Abstract
In addition to its structural role, the skeleton serves as an endocrine organ that controls mineral metabolism and energy homeostasis. Three major cell types in bone - osteoblasts, osteoclasts, and osteocytes - dynamically form and maintain bone and secrete factors with systemic activity. Osteocalcin, an osteoblast-derived factor initially described as a matrix protein that regulates bone mineralization, has been suggested to be an osteoblast-derived endocrine hormone that regulates multiple target organs including pancreas, liver, muscle, adipose, testes, and the central and peripheral nervous system. Sclerostin is predominantly produced by osteocytes, and is best known as a paracrine-acting regulator of WNT signaling and activity of osteoblasts and osteoclasts on bone surfaces. In addition to this important paracrine role for sclerostin within bone, sclerostin protein has been noted to act at a distance to regulate adipocytes, energy homeostasis, and mineral metabolism in the kidney. In this article, we aim to bring together evidence supporting an endocrine function for sclerostin and osteocalcin, and discuss recent controversies regarding the proposed role of osteocalcin outside of bone. We summarize the current state of knowledge on animal models and human physiology related to the multiple functions of these bone-derived factors. Finally, we highlight areas in which future research is expected to yield additional insights into the biology of osteocalcin and sclerostin.
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Affiliation(s)
- Jialiang S. Wang
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Courtney M. Mazur
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Marc N. Wein
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Harvard Stem Cell Institute, Cambridge, MA, United States
- *Correspondence: Marc N. Wein,
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Rached A, Moriceau MA, Serfaty X, Lefebvre S, Lattard V. Biomarkers Potency to Monitor Non-target Fauna Poisoning by Anticoagulant Rodenticides. Front Vet Sci 2020; 7:616276. [PMID: 33426034 PMCID: PMC7785832 DOI: 10.3389/fvets.2020.616276] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022] Open
Abstract
The widespread use of pesticides to control agricultural pests is a hot topic on the public scene of environmental health. Selective pest control for minimum environmental impact is a major goal of the environmental toxicology field, notably to avoid unintended poisoning in different organisms. Anticoagulant rodenticides cause abnormal blood coagulation process; they have been widely used to control rodents, allowing inadvertent primary and secondary exposure in domestic animals and non-target predatory wildlife species through direct ingestion of rodenticide-containing bait or by consumption of poisoned prey. To report toxic effect, the most common approach is the measurement of liver or plasma residues of anticoagulant rodenticides in dead or intoxicated animals showing clinical symptoms. However, one major challenge is that literature currently lacks a hepatic or plasma concentration threshold value for the differentiation of exposure from toxicity. Regarding the variation in pharmacology properties of anticoagulant rodenticides inter- and intra-species, the dose-response relationship must be defined for each species to prejudge the relative risk of poisoning. Beyond that, biomarkers are a key solution widely used for ecological risk assessment of contaminants. Since anticoagulant rodenticides (AR) have toxic effects at the biochemical level, biomarkers can serve as indicators of toxic exposure. In this sense, toxicological knowledge of anticoagulant rodenticides within organisms is an important tool for defining sensitive, specific, and suitable biomarkers. In this review, we provide an overview of the toxicodynamic and toxicokinetic parameters of anticoagulant rodenticides in different animal species. We examine different types of biomarkers used to characterize and differentiate the exposure and toxic effects of anticoagulant rodenticide, showing the strengths and weaknesses of the assays. Finally, we describe possible new biomarkers and highlight their capabilities.
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Affiliation(s)
| | | | | | | | - Virginie Lattard
- USC 1233 RS2GP, VetAgro Sup, INRA, University of Lyon, Marcy l'Etoile, France
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25
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Desentis-Desentis MF, Rivas-Carrillo JD, Sánchez-Enríquez S. Protective role of osteocalcin in diabetes pathogenesis. J Bone Miner Metab 2020; 38:765-771. [PMID: 32725267 DOI: 10.1007/s00774-020-01130-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/08/2020] [Indexed: 12/18/2022]
Abstract
In diabetes, metabolic, inflammatory, and stress-associated alterations conduce to ß-cell failure and tissue damage. Osteocalcin is a bone protein with several endocrine functions in different tissues. In this review, we gathered scientific evidence of how osteocalcin could modulate functional disorders that are altered in diabetes in an integrative way. We include adipose tissue, pancreatic function, and oxidative stress aspects. In the first section, we focus on the role of inflammatory mediators and adiponectin in energy homeostasis and insulin sensitivity. In the following section, we discuss the effect of osteocalcin in metabolic and pancreatic function and its association in insulin signaling and in ß-cell proliferation. Finally, we focus on osteocalcin action in oxidative and endoplasmic reticulum stress, and in antioxidant regulation, since ß-cells are well known by its vulnerability to stress damage. These evidences support the notion that osteocalcin could have an important role in diabetes treatment.
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Affiliation(s)
- María Fernanda Desentis-Desentis
- Laboratory of Tissue Engineering and Transplant, Department of Physiology, University Center for Health Sciences, University de Guadalajara, 950 Sierra Mojada St., Col. Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico
- cGMP Cell Processing Facility, University Center for Health Sciences, University of Guadalajara, 950 Sierra Mojada St., Col. Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico
| | - Jorge David Rivas-Carrillo
- Laboratory of Tissue Engineering and Transplant, Department of Physiology, University Center for Health Sciences, University de Guadalajara, 950 Sierra Mojada St., Col. Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico
- cGMP Cell Processing Facility, University Center for Health Sciences, University of Guadalajara, 950 Sierra Mojada St., Col. Independencia, C.P. 44340, Guadalajara, Jalisco, Mexico
| | - Sergio Sánchez-Enríquez
- Department of Clinics, University Center of Los Altos, University of Guadalajara, 1200 Rafael Casillas Ave, ZC47620, Tepatitlán de Morelos, Jalisco, Mexico.
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26
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Ducy P. Bone Regulation of Insulin Secretion and Glucose Homeostasis. Endocrinology 2020; 161:5895464. [PMID: 32822470 DOI: 10.1210/endocr/bqaa149] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 08/18/2020] [Indexed: 12/31/2022]
Abstract
For centuries our image of the skeleton has been one of an inert structure playing a supporting role for muscles and a protective role for inner organs like the brain. Cell biology and physiology modified this view in the 20st century by defining the constant interplay between bone-forming and bone resorbing cells that take place during bone growth and remodeling, therefore demonstrating that bone is as alive as any other tissues in the body. During the past 40 years human and, most important, mouse genetics, have allowed not only the refinement of this notion by identifying the many genes and regulatory networks responsible for the crosstalk existing between bone cells, but have redefined the role of bone by showing that its influence goes way beyond its own physiology. Among its newly identified functions is the regulation of energy metabolism by 2 bone-derived hormones, osteocalcin and lipocalin-2. Their biology and respective roles in this process are the topic of this review.
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Affiliation(s)
- Patricia Ducy
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, College of Physicians and Surgeons, New York, New York
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27
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Liu X, Liu Y, Mathers J, Cameron M, Levinger I, Yeap BB, Lewis JR, Brock KE, Brennan-Speranza TC. Osteocalcin and measures of adiposity: a systematic review and meta-analysis of observational studies. Arch Osteoporos 2020; 15:145. [PMID: 32945990 DOI: 10.1007/s11657-020-00812-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 08/25/2020] [Indexed: 02/03/2023]
Abstract
UNLABELLED Osteocalcin, the osteoblast-derived protein, has been shown to be modulated in patients with problematic glucose metabolism. Our systematic review and meta-analysis found that in humans, higher blood osteocalcin level is associated with lower body indices of fat. PURPOSE/INTRODUCTION Osteocalcin (OC) was found to be inversely correlated with measures of glucose and energy metabolism, with some groups suggesting the undercarboxylated form (ucOC) to be metabolically active, although the link is not clear, especially in humans. Given obesity is a major risk factor for metabolic disorders, we aimed to assess the correlation between OC and two measures of body weight: body mass index (BMI) and percentage body fat (%BF). METHODS MEDLINE and EMBASE were searched to identify observational studies in adult populations that reported the crude correlation coefficients (r) between OC and BMI and %BF. Pool r were obtained using random-effects models. RESULTS Fifty-one publications were included in this analysis. Both total OC (TOC) (pooled r = - 0.151, 95% CI - 0.17, - 0.130; I2 = 52%) and ucOC (pooled r = - 0.060, 95% CI - 0.103, - 0.016; I2 = 54%) were inversely correlated with BMI. The pooled r between TOC and BMI in Caucasian-and-other-regions (r = - 0.187) were stronger than those in Asian populations (r = - 0.126; intra-group p = 0.002; R2 = 0.21). The mean/median BMI of the reported cohort was the major contributor to between-study heterogeneity in correlation between TOC/ucOC and BMI (R2 = 0.28 and 0.77, respectively). Both TOC and ucOC were also inversely correlated with %BF (TOC: pooled r = - 0.185, 95% CI - 0.257 to - 0.112; ucOC: pooled r = - 0.181, 95% CI - 0.258 to - 0.101). CONCLUSION Higher OC and ucOC were correlated with lower BMI and %BF. The inverse correlations between TOC/ucOC and BMI appear to be affected by ethnicity and obesity status.
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Affiliation(s)
- Xiaoying Liu
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Yihui Liu
- School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Julia Mathers
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Melissa Cameron
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Melbourne, Australia
- Australian Institute for Musculoskeletal Science (AIMSS), Department of Medicine-Western Health, Melbourne Medical School, The University of Melbourne, Melbourne, Australia
| | - Bu B Yeap
- Medical School, University of Western Australia, Perth, Australia
- Department of Endocrinology and Diabetes, Fiona Stanley Hospital, Perth, Australia
| | - Joshua R Lewis
- Medical School, University of Western Australia, Perth, Australia
- Centre for Kidney Research, Children's Hospital at Westmead, School of Public Health, Sydney Medical School, The University of Sydney, Sydney, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Kaye E Brock
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Tara C Brennan-Speranza
- Department of Physiology, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
- School of Public Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia.
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28
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Pham TT, Ivaska KK, Hannukainen JC, Virtanen KA, Lidell ME, Enerbäck S, Mäkelä K, Parkkola R, Piirola S, Oikonen V, Nuutila P, Kiviranta R. Human Bone Marrow Adipose Tissue is a Metabolically Active and Insulin-Sensitive Distinct Fat Depot. J Clin Endocrinol Metab 2020; 105:5822831. [PMID: 32311037 PMCID: PMC7247553 DOI: 10.1210/clinem/dgaa216] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/17/2020] [Indexed: 01/29/2023]
Abstract
CONTEXT Bone marrow (BM) in adult long bones is rich in adipose tissue, but the functions of BM adipocytes are largely unknown. We set out to elucidate the metabolic and molecular characteristics of BM adipose tissue (BMAT) in humans. OBJECTIVE Our aim was to determine if BMAT is an insulin-sensitive tissue, and whether the insulin sensitivity is altered in obesity or type 2 diabetes (T2DM). DESIGN This was a cross-sectional and longitudinal study. SETTING The study was conducted in a clinical research center. PATIENTS OR OTHER PARTICIPANTS Bone marrow adipose tissue glucose uptake (GU) was assessed in 23 morbidly obese subjects (9 with T2DM) and 9 healthy controls with normal body weight. In addition, GU was assessed in another 11 controls during cold exposure. Bone marrow adipose tissue samples for molecular analyses were collected from non-DM patients undergoing knee arthroplasty. INTERVENTION(S) Obese subjects were assessed before and 6 months after bariatric surgery and controls at 1 time point. MAIN OUTCOME MEASURE We used positron emission tomography imaging with 2-[18F]fluoro-2-deoxy-D-glucose tracer to characterize GU in femoral and vertebral BMAT. Bone marrow adipose tissue molecular profile was assessed using quantitative RT-PCR. RESULTS Insulin enhances GU in human BMAT. Femoral BMAT insulin sensitivity was impaired in obese patients with T2DM compared to controls, but it improved after bariatric surgery. Furthermore, gene expression analysis revealed that BMAT was distinct from brown and white adipose tissue. CONCLUSIONS Bone marrow adipose tissue is a metabolically active, insulin-sensitive and molecularly distinct fat depot that may play a role in whole body energy metabolism.
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Affiliation(s)
- Tam T Pham
- Turku PET Centre, University of Turku, Turku, Finland
| | - Kaisa K Ivaska
- Institute of Biomedicine, University of Turku, Turku, Finland
| | | | | | - Martin E Lidell
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Sven Enerbäck
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Keijo Mäkelä
- Department of Orthopaedics and Traumatology, Turku University Hospital, Turku, Finland
| | - Riitta Parkkola
- Department of Radiology, Turku University Hospital, Turku, Finland
| | - Sauli Piirola
- Turku PET Centre, University of Turku, Turku, Finland
| | - Vesa Oikonen
- Turku PET Centre, University of Turku, Turku, Finland
| | - Pirjo Nuutila
- Turku PET Centre, University of Turku, Turku, Finland
- Department of Endocrinology, Turku University Hospital, Turku, Finland
| | - Riku Kiviranta
- Institute of Biomedicine, University of Turku, Turku, Finland
- Department of Endocrinology, Turku University Hospital, Turku, Finland
- Correspondence and Reprint Requests: Riku Kiviranta, Institute of Biomedicine, University of Turku, 20520 Turku, Finland. E-mail:
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Gonzalez-Gil AM, Elizondo-Montemayor L. The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review. Nutrients 2020; 12:E1899. [PMID: 32604889 PMCID: PMC7353393 DOI: 10.3390/nu12061899] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/18/2020] [Accepted: 06/18/2020] [Indexed: 12/17/2022] Open
Abstract
Exercise is an effective strategy for preventing and treating obesity and its related cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning, redistribution of energy substrates, optimization of global energy expenditure, enhancement of hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines, hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an important role in the body's response to exercise. To our knowledge, no review has provided a comprehensive integrative overview of these novel molecular players and the mechanisms involved in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass, and reduced inflammation. In this review, we explain the potential role of these exercise-inducible factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines, in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin. We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways, and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation, and healthy weight induced by exercise.
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Affiliation(s)
- Adrian M. Gonzalez-Gil
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey N.L. 64710, Mexico;
- Tecnologico de Monterrey, Center for Research in Clinical Nutrition and Obesity, Ave. Morones Prieto 300, Monterrey N.L. 64710, Mexico
| | - Leticia Elizondo-Montemayor
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000, Monterrey N.L. 64710, Mexico;
- Tecnologico de Monterrey, Center for Research in Clinical Nutrition and Obesity, Ave. Morones Prieto 300, Monterrey N.L. 64710, Mexico
- Tecnologico de Monterrey, Cardiovascular and Metabolomics Research Group, Hospital Zambrano Hellion, San Pedro Garza Garcia P.C. 66278, Mexico
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30
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Lin X, Onda DA, Yang CH, Lewis JR, Levinger I, Loh K. Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology. Mol Metab 2020; 40:101040. [PMID: 32544571 PMCID: PMC7348059 DOI: 10.1016/j.molmet.2020.101040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/28/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023] Open
Abstract
Background Emerging evidence demonstrates that bone is an endocrine organ capable of influencing multiple physiological and pathological processes through the secretion of hormones. Recent research suggests complex crosstalk between the bone and other metabolic and cardiovascular tissues. It was uncovered that three of these bone-derived hormones—osteocalcin, lipocalin 2, and sclerostin—are involved in the endocrine regulations of cardiometabolic health and play vital roles in the pathophysiological process of developing cardiometabolic syndromes such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation is one of the hallmarks of cardiometabolic diseases and a major contributor to disease progression. Novel evidence also implicates important roles of bone-derived hormones in the regulation of chronic inflammation. Scope of review In this review, we provide a detailed overview of the physiological and pathological roles of osteocalcin, lipocalin 2, and sclerostin in cardiometabolic health regulation and disease development, with a focus on the modulation of chronic inflammation. Major conclusions Evidence supports that osteocalcin has a protective role in cardiometabolic health, and an increase of lipocalin 2 contributes to the development of cardiometabolic diseases partly via pro-inflammatory effects. The roles of sclerostin appear to be complicated: It exerts pro-adiposity and pro-insulin resistance effects in type 2 diabetes and has an anti-calcification effect during cardiovascular disease. A better understanding of the actions of these bone-derived hormones in the pathophysiology of cardiometabolic diseases will provide crucial insights to help further research develop new therapeutic strategies to treat these diseases.
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Affiliation(s)
- Xuzhu Lin
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
| | - Danise-Ann Onda
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | - Chieh-Hsin Yang
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| | - Joshua R Lewis
- School of Medical and Health Sciences, Edith Cowan University, Perth, Australia; Medical School, University of Western Australia, Perth, Australia
| | - Itamar Levinger
- Institute for Health and Sport (IHES), Victoria University, Footscray, VIC, Australia; Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, St Albans, VIC, Australia
| | - Kim Loh
- St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia; Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
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Uncarboxylated osteocalcin decreases insulin-stimulated glucose uptake without affecting insulin signaling and regulators of mitochondrial biogenesis in myotubes. J Physiol Biochem 2020; 76:169-178. [DOI: 10.1007/s13105-020-00732-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 02/07/2020] [Indexed: 01/28/2023]
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Russo V, Chen R, Armamento-Villareal R. Hypogonadism, Type-2 Diabetes Mellitus, and Bone Health: A Narrative Review. Front Endocrinol (Lausanne) 2020; 11:607240. [PMID: 33537005 PMCID: PMC7848021 DOI: 10.3389/fendo.2020.607240] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/30/2020] [Indexed: 12/26/2022] Open
Abstract
One of the complications from chronic hyperglycemia and insulin resistance due to type 2 diabetes mellitus (T2DM) on the hypothalamic-pituitary-gonadal axis in men is the high prevalence of hypogonadotropic hypogonadism (HH). Both T2DM and hypogonadism are associated with impaired bone health and increased fracture risk but whether the combination results in even worse bone disease than either one alone is not well-studied. It is possible that having both conditions predisposes men to an even greater risk for fracture than either one alone. Given the common occurrence of HH or hypogonadism in general in T2DM, a significant number of men could be at risk. To date, there is very little information on the bone health men with both hypogonadism and T2DM. Insulin resistance, which is the primary defect in T2DM, is associated with low testosterone (T) levels in men and may play a role in the bidirectional relationship between these two conditions, which together may portend a worse outcome for bone. The present manuscript aims to review the available evidences on the effect of the combination of hypogonadism and T2DM on bone health and metabolic profile, highlights the possible metabolic role of the skeleton, and examines the pathways involved in the interplay between bone, insulin resistance, and gonadal steroids.
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Affiliation(s)
- Vittoria Russo
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Michael E. DeBakey VA Medical Center, Houston, TX, United States
| | - Rui Chen
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Michael E. DeBakey VA Medical Center, Houston, TX, United States
| | - Reina Armamento-Villareal
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
- Department of Medicine, Michael E. DeBakey VA Medical Center, Houston, TX, United States
- *Correspondence: Reina Armamento-Villareal,
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Park D, Gu H, Baek JH, Baek K. Undercarboxylated osteocalcin downregulates pancreatic lipase expression in an ATF4-dependent manner in pancreatic acinar cells. Bone 2019; 127:220-227. [PMID: 31216497 DOI: 10.1016/j.bone.2019.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 04/17/2019] [Accepted: 06/13/2019] [Indexed: 10/26/2022]
Abstract
Osteocalcin is an osteoblast-specific secreted protein that has been associated with endocrine roles in multiple aspects of energy metabolism. We examined whether undercarboxylated osteocalcin (ucOC) downregulates pancreatic lipase (PNLIP) expression in pancreatic acinar cells and then identified the downstream signaling pathway involved. We previously demonstrated that β adrenergic blockade attenuates body weight/fat mass gain in high-fat diet-fed mice and that this effect is associated with decreased PNLIP expression in pancreatic acinar cells. In the present study, we first confirmed that the serum ucOC level is inversely correlated with PNLIP expression, i.e., mice exhibiting high serum levels of ucOC showed low PNLIP levels in the pancreas. In in vitro experiments using primary pancreatic acinar and 266-6 cells, ucOC downregulated PNLIP expression. cAMP/PKA signaling inhibitors significantly reversed ucOC-induced downregulation of PNLIP expression. ucOC promoted the phosphorylation of cAMP response element-binding protein 2 (ATF4). Overexpression of ATF4 significantly suppressed PNLIP expression. Knockdown of ATF4 by siRNA reversed the ucOC-induced downregulation of PNLIP expression. A luciferase reporter assay showed that ucOC suppressed PNLIP promoter transactivation. Chromatin immunoprecipitation and a luciferase reporter assay demonstrated that ATF4 directly bound to the CRE on the mouse PNLIP promoter and suppressed PNLIP transactivation. Knockdown of G-protein coupled receptor 6A (Gprc6a), a candidate receptor for mediating the response to ucOC in the bone-pancreas endocrine loop, by siRNA reversed the downregulating effect of ucOC on PNLIP expression. Taken together, ucOC downregulates pancreatic lipase expression in a cAMP/protein kinase A/ATF4-dependent manner. Gprc6a is a potential osteocalcin-sensing receptor that regulates PNLIP expression in pancreatic acinar cells.
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Affiliation(s)
- Danbi Park
- Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwondo 25457, Republic of Korea
| | - Hanna Gu
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea
| | - Jeong-Hwa Baek
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
| | - Kyunghwa Baek
- Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwondo 25457, Republic of Korea.
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Millar SA, Zala I, Anderson SI, O'Sullivan SE. Osteocalcin does not influence acute or chronic inflammation in human vascular cells. J Cell Physiol 2019; 235:3414-3424. [PMID: 31549398 PMCID: PMC6972510 DOI: 10.1002/jcp.29231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 09/04/2019] [Indexed: 12/19/2022]
Abstract
Some human observational studies have suggested an anti‐inflammatory role of osteocalcin (OCN). An inflammatory protocol using interferon‐γ and tumor necrosis factor‐α (10 ng/ml) was employed to examine the acute (24 hr) and chronic (144 hr) effects of uncarboxylated OCN (ucOCN) in commercial, primary, subcultured human aortic endothelial cells (HAEC), and human smooth muscle cells (HASMCs). The inflammatory protocol increased phosphorylation of intracellular signaling proteins (CREB, JNK, p38, ERK, AKT, STAT3, STAT5) and increased secretion of adhesion markers (vascular cell adhesion molecule‐1, intracellular adhesion molecule‐1, monocyte chemoattractant protein‐1) and proinflammatory cytokines (interleukin‐6 [IL‐6], IL‐8). After acute inflammation, there were no additive or reductive effects of ucOCN in either cell type. Following chronic inflammation, ucOCN did not affect cell responses, nor did it appear to have any pro‐ or anti‐inflammatory effects when administered acutely or chronically on its own in either cell type. Additionally, ucOCN did not affect lipopolysaccharide (LPS)‐induced acute inflammation in HAECs or HASMCs. The findings of this study do not support a causal role for OCN within the models of vascular inflammation chosen. Further confirmatory studies are warranted.
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Affiliation(s)
- Sophie A Millar
- Division of Graduate Entry Medicine and Medical Sciences, School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, UK
| | - Ieva Zala
- Division of Graduate Entry Medicine and Medical Sciences, School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, UK
| | - Susan I Anderson
- Division of Graduate Entry Medicine and Medical Sciences, School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, UK
| | - Saoirse E O'Sullivan
- Division of Graduate Entry Medicine and Medical Sciences, School of Medicine, Royal Derby Hospital, University of Nottingham, Derby, UK
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Guney G, Sener-Simsek B, Tokmak A, Yucel A, Buyukkagnici U, Yilmaz N, Engin-Ustun Y, Ozgu-Erdinc AS. Assessment of the Relationship between Serum Vitamin D and Osteocalcin Levels with Metabolic Syndrome in Non-Osteoporotic Postmenopausal Women. Geburtshilfe Frauenheilkd 2019; 79:293-299. [PMID: 30880828 PMCID: PMC6414302 DOI: 10.1055/a-0767-6572] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 07/27/2018] [Accepted: 10/19/2018] [Indexed: 12/29/2022] Open
Abstract
Introduction
The aim of this study was to compare serum vitamin D and osteocalcin levels in non-osteoporotic postmenopausal women with and without metabolic syndrome and to analyze the relationship between serum vitamin D and osteocalcin levels and the relationships between these two factors and other clinical/biochemical parameters.
Material and Method
This cross-sectional study was carried out in 191 postmenopausal non-osteoporotic (T-score > − 2.5) women. Patients were divided into two groups according to the presence or absence of metabolic syndrome. Blood samples were obtained and evaluated for 25-hydroxyvitamin D, osteocalcin, insulin resistance (using a homeostatic model assessment of insulin resistance), glycosylated hemoglobin (HbA
1c
), calcium, phosphorus, deoxypyridinoline, thyroid-stimulating hormone, lipid profile, fasting insulin, fasting glucose and HbA
1c
levels. Demographic and laboratory parameters were recorded for each woman.
Results
Vitamin D was found to be lower in women with metabolic syndrome compared to controls (16.1 ± 11.2 vs. 20.4 ± 13.1 mg/dL; p = 0.013). Similarly, osteocalcin was found to be significantly lower in the metabolic syndrome group compared to the control group (4.2 ± 2.1 vs. 5.5 ± 3.0; p < 0.001). A significant positive correlation was observed between vitamin D and osteocalcin levels (r = 0.198; p = 0.008). There was an inverse correlation between vitamin D and some of the lipid parameters. However, osteocalcin levels were negatively correlated with C-reactive protein, insulin resistance, and HbA
1c
in both groups (p = 0.003, p = 0.001 and p = 0.048, respectively).
Conclusion
Vitamin D deficiency is common in postmenopausal women, even in women who are non-osteoporotic. Serum levels of vitamin D are significantly decreased in cases with metabolic syndrome. Vitamin D may directly improve serum lipid profiles and may indirectly decrease insulin resistance and subclinical systemic inflammation through the impact on the metabolic functions of osteocalcin.
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Affiliation(s)
- Gurhan Guney
- Sakarya University Education and Research Hospital, Department of Obstetrics and Gynecology, Sakarya, Turkey
| | - Bilge Sener-Simsek
- University of Health Sciences, Zekai Tahir Burak Women's Health Research and Education Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey
| | - Aytekin Tokmak
- University of Health Sciences, Zekai Tahir Burak Women's Health Research and Education Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey
| | - Aykan Yucel
- University of Health Sciences, Zekai Tahir Burak Women's Health Research and Education Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey
| | - Umran Buyukkagnici
- University of Health Sciences, Zekai Tahir Burak Women's Health Research and Education Hospital, Department of Biochemistry, Ankara, Turkey
| | - Nafiye Yilmaz
- University of Health Sciences, Zekai Tahir Burak Women's Health Research and Education Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey
| | - Yaprak Engin-Ustun
- University of Health Sciences, Zekai Tahir Burak Women's Health Research and Education Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey
| | - A Seval Ozgu-Erdinc
- University of Health Sciences, Zekai Tahir Burak Women's Health Research and Education Hospital, Department of Obstetrics and Gynecology, Ankara, Turkey
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Raj JP, Venkatachalam S, Shekoba M, Norris JJ, Amaravati RS. Conventional antidiabetic agents and bone health: A pilot case-control study. Perspect Clin Res 2019; 10:177-182. [PMID: 31649868 PMCID: PMC6801990 DOI: 10.4103/picr.picr_125_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background and Objectives: The burden of noncommunicable diseases such as diabetes (type 2 diabetes mellitus [T2DM]) and osteoporosis is increasing with increasing longevity. Uncontrolled T2DM is an independent risk factor for osteoporosis explained by the insulin osteocalcin pathway. Due to limited information on the effect of various commonly used antidiabetic agents (ADA) on bone health, our study aims to analyze the association between the two. Methodology: This is a case–control study, with 100 cases of clinical osteoporosis and 100 age-, sex-, and dietary status-matched controls in whom osteoporosis was ruled out by dual-energy X-ray absorptiometry scan. Prescription details of T2DM, physical activity levels, and disease status were collected using a pretested questionnaire. Exposure to each ADA was compared using the Chi-squared test. Binary logistic regression was performed to adjust the two main confounders, namely glycemic control and physical activity levels, and adjusted risk estimates were calculated. Results: There were a total of 74 T2DM patients, of whom 45 (60.8%) were cases and 29 (39.2%) were controls. Sulfonylureas (adjusted odds ratio [aOR] = 0.164, P = 0.004) and insulin (aOR = 0.248, P = 0.042) showed a significant protective effect on bone health. Biguanides (OR = 1.994, P = 0.029) and thiazolidinediones (OR: 5.444, P = 0.033), which demonstrated that an increased risk of osteoporosis in univariate analysis became insignificant after multivariate analysis. Conclusion: Sulfonylureas and insulin through the insulin osteocalcin pathway show favorable effect on bone health, but the probability of increased fractures secondary to hypoglycemic falls should be borne in mind. We recommend larger prospective studies to confirm this association.
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Affiliation(s)
- Jeffrey Pradeep Raj
- Department of Pharmacology, St. John's Medical College, Bengaluru, Karnataka, India
| | | | - Mahesh Shekoba
- Department of Orthopaedics, St. John's Medical College, Bengaluru, Karnataka, India
| | | | - Rajkumar S Amaravati
- Department of Orthopaedics, St. John's Medical College, Bengaluru, Karnataka, India
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Kanazawa I, Tanaka S, Sugimoto T. The Association Between Osteocalcin and Chronic Inflammation in Patients with Type 2 Diabetes Mellitus. Calcif Tissue Int 2018; 103:599-605. [PMID: 30051143 DOI: 10.1007/s00223-018-0460-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 07/20/2018] [Indexed: 12/16/2022]
Abstract
Osteocalcin acts as an endocrine hormone to regulate energy homeostasis. Although several in vivo and in vitro studies suggest that osteocalcin is involved in chronic inflammation, the association between osteocalcin and chronic inflammation in humans is unknown. In this cross-sectional study, 246 patients with type 2 diabetes mellitus (T2DM) were recruited to investigate the association of bone turnover markers with chronic inflammation parameters such as high-sensitive C-reactive protein (hsCRP), ferritin, and leukocyte subtype counts. Bone-specific alkaline phosphatase (BAP), total osteocalcin (OC), undercarboxylated OC (ucOC), and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) were measured. Multiple regression analysis adjusted for age, duration of diabetes, body mass index, estimated glomerular filtration rate, and hemoglobin A1c showed that serum OC levels were significantly and negatively associated with hsCRP, ferritin, basophil count, and monocyte count (β = - 0.18, p = 0.013; β = - 0.22, p = 0.031; β = - 0.14, p = 0.038; and β = - 0.17, p = 0.012, respectively). Moreover, serum ucOC levels were significantly and negatively associated with hsCRP, ferritin, total leukocyte count, neutrophil count, and monocyte count (β = - 0.24, p = 0.007; β =- 0.37, p = 0.003; β = - 0.21, p = 0.007; β = - 0.24, p = 0.002; and β = - 0.20, p = 0.011, respectively). The ratio of ucOC to OC was significantly and negatively associated with ferritin (β = - 0.31, p = 0.014). However, neither BAP nor uNTX was associated with any chronic inflammation parameters. This is the first study to show that serum OC and ucOC levels were negatively associated with chronic inflammation parameters such as hsCRP, ferritin, and leukocyte subtypes in patients with T2DM. Therefore, OC could be a therapeutic target for protecting against chronic inflammation.
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Affiliation(s)
- Ippei Kanazawa
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.
| | - Sayuri Tanaka
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Toshitsugu Sugimoto
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
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Feng Y, Liao Y, Huang W, Lai X, Luo J, Du C, Lin J, Zhang Z, Qiu D, Liu Q, Shen H, Xiang AP, Zhang Q. Mesenchymal stromal cells-derived matrix Gla protein contribute to the alleviation of experimental colitis. Cell Death Dis 2018; 9:691. [PMID: 29880866 PMCID: PMC5992143 DOI: 10.1038/s41419-018-0734-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/17/2018] [Accepted: 05/21/2018] [Indexed: 12/16/2022]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease that is difficult to treat. However, previous preclinical and clinical studies have shown that mesenchymal stromal cells (MSCs) are a promising therapeutic approach, whereas the exact underlying molecular mechanisms of MSCs in treating CD remain unclear. Furthermore, the heterogeneity of MSCs, as well as the in vivo microenvironments may influence the therapeutic efficacy. In our previous study, we found that a subpopulation of mouse MSCs with a high expression of matrix Gla protein (MGP), one of the members of vitamin K-dependent protein family, possessed better immunoregulatory properties. Therefore, in this study we investigate whether the abundant MSCs-derived MGP participate in the therapeutic mechanisms for MSCs treating CD. Obvious suppression of cell proliferation and cytokine production in T cells were observed in vitro through MSCs-derived MGP. Moreover, MGP alleviated the clinical and histopathological severity of colonic inflammation in mouse experimental colitis models to a remarkable degree. Our results indicate that MGP might be a novel important mediator of MSCs-mediated immunomodulation in treating CD.
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Affiliation(s)
- Yuan Feng
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yan Liao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Weijun Huang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Xingqiang Lai
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Jing Luo
- Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Cong Du
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junyi Lin
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhongyuan Zhang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China
| | - Dongbo Qiu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiuli Liu
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huiyong Shen
- Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou, China.
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Qi Zhang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Mera P, Ferron M, Mosialou I. Regulation of Energy Metabolism by Bone-Derived Hormones. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a031666. [PMID: 28778968 DOI: 10.1101/cshperspect.a031666] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Like many other organs, bone can act as an endocrine organ through the secretion of bone-specific hormones or "osteokines." At least two osteokines are implicated in the control of glucose and energy metabolism: osteocalcin (OCN) and lipocalin-2 (LCN2). OCN stimulates the production and secretion of insulin by the pancreatic β-cells, but also favors adaptation to exercise by stimulating glucose and fatty acid (FA) utilization by the muscle. Both of these OCN functions are mediated by the G-protein-coupled receptor GPRC6A. In contrast, LCN2 influences energy metabolism by activating appetite-suppressing signaling in the brain. This action of LCN2 occurs through its binding to the melanocortin 4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVN) and ventromedial neurons of the hypothalamus.
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Affiliation(s)
- Paula Mera
- Columbia University Medical Center, New York, New York 10032
| | - Mathieu Ferron
- Institut de Recherches Cliniques de Montréal, Montréal, Quebec H2W 1R7, Canada
| | - Ioanna Mosialou
- Columbia University Medical Center, New York, New York 10032
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40
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Ye R, Pi M, Cox JV, Nishimoto SK, Quarles LD. CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:90. [PMID: 28659174 PMCID: PMC5490090 DOI: 10.1186/s13046-017-0561-x] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 06/20/2017] [Indexed: 12/17/2022]
Abstract
Background GPRC6A is implicated in the pathogenesis of prostate cancer, but its role remains uncertain because of a purported tolerant gene variant created by substitution of a K..Y polymorphism in the 3rd intracellular loop (IL) that evolved in the majority of humans and replaces the ancestral RKLP present in 40% of humans of African descent and all other species. Methods We determined whether the K..Y polymorphism is present in human-derived prostate cancer cell lines by sequencing the region of the 3rd IL and assessed the cellular localization of a “humanized” mouse GPRC6A containing the K..Y sequence by immunofluorescence. We assessed functions of GPRC6A in PC-3 cells expressing endogenous GPRC6A and in GPRC6A-deficient PC-3 cells created using CRISPR/Cas9 technology. The effect of GPRC6A on basal and ligand stimulated cell proliferation and migration was evaluated in vitro in wild-type and PC-3-deficient cell lines. The effect of editing GPRC6A on prostate cancer growth and progression in vivo was assessed in a Xenograft mouse model implanted with wild-type and PC-3 deficient cells and treated with the GPRC6A ligand osteocalcin. Results We found that all of the human prostate cancer cell lines tested endogenously express the “K..Y” polymorphism in the 3rd IL. Comparison of mouse wild-type GPRC6A with a “humanized” mouse GPRC6A construct created by replacing the “RKLP” with the “K..Y” sequence, found that both receptors were predominantly expressed on the cell surface. The transfected “humanized” GPRC6A receptor, however, preferentially activated mTOR compared to ERK signaling in HEK-293 cells. In contrast, in PC-3 cells expressing the endogenous GPRC6A with the “K..Y” polymorphism, the ligand osteocalcin stimulated ERK, AKT and mTOR phosphorylation, promoted cell proliferation and migration, and upregulated genes regulating testosterone biosynthesis. Targeting GPRC6A in PC-3 cells by CRISPR/Cas9 significantly blocked these responses in vitro. In addition, GPRC6A deficient PC-3 xenografts exhibited significantly less growth and were resistant to osteocalcin-induced prostate cancer progression compared to control PC-3 cells expressing GPRC6A. Conclusions Human GPRC6A is a functional osteocalcin and testosterone sensing receptor that promotes prostate cancer progression. GPRC6A may contribute to racial disparities in prostate cancer, and is a potential therapeutic target to develop antagonists to treat prostate cancer. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0561-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ruisong Ye
- Department of Medicine, University of Tennessee Health Science Center, 19 S Manassas St., Memphis, TN, 38163, USA
| | - Min Pi
- Department of Medicine, University of Tennessee Health Science Center, 19 S Manassas St., Memphis, TN, 38163, USA.
| | - John V Cox
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, 19 S Manassas St., Memphis, TN, 38163, USA
| | - Satoru K Nishimoto
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, 19 S Manassas St., Memphis, TN, 38163, USA
| | - L Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, 19 S Manassas St., Memphis, TN, 38163, USA.
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Lombardi G, Barbaro M, Locatelli M, Banfi G. Novel bone metabolism-associated hormones: the importance of the pre-analytical phase for understanding their physiological roles. Endocrine 2017; 56:460-484. [PMID: 28181144 DOI: 10.1007/s12020-017-1239-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Accepted: 01/17/2017] [Indexed: 02/08/2023]
Abstract
The endocrine function of bone is now a recognized feature of this tissue. Bone-derived hormones that modulate whole-body homeostasis, are being discovered as for the effects on bone of novel and classic hormones produced by other tissues become known. Often, however, the data regarding these last generation bone-derived or bone-targeting hormones do not give about a clear picture of their physiological roles or concentration ranges. A certain degree of uncertainty could stem from differences in the pre-analytical management of biological samples. The pre-analytical phase comprises a series of decisions and actions (i.e., choice of sample matrix, methods of collection, transportation, treatment and storage) preceding analysis. Errors arising in this phase will inevitably be carried over to the analytical phase where they can reduce the measurement accuracy, ultimately, leading discrepant results. While the pre-analytical phase is all important, in routine laboratory medicine, it is often not given due consideration in research and clinical trials. This is particularly true for novel molecules, such as the hormones regulating the endocrine function of bone. In this review we discuss the importance of the pre-analytical variables affecting the measurement of last generation bone-associated hormones and describe their, often debated and rarely clear physiological roles.
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Affiliation(s)
| | - Mosè Barbaro
- Laboratory Medicine Service, San Raffaele Hospital, Milano, Italy
| | | | - Giuseppe Banfi
- IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
- Vita-Salute San Raffaele University, Milano, Italy
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Le Doan V, Marcil V. [Osteocalcin and glucose metabolism: assessment of human studies]. Med Sci (Paris) 2017; 33:417-422. [PMID: 28497738 DOI: 10.1051/medsci/20173304012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Osteocalcin, a protein secreted by osteoblasts, is recognized as a biomarker of bone mineralization. Besides, animal experimental studies have shown that osteocalcin could play an important role in glucose metabolism. Over the course of the last decade, this theory has been investigated in several human studies. Most of the results obtained from these reports support a positive correlation between total and undercarboxylated osteocalcin and insulin secretion/sensitivity. Studies also corroborate a reverse association with glycemic parameters such as fasting glucose and glycated hemoglobin. Nevertheless, because most of the studies published are observational, it is not possible to yet confirm a direct cause-effect relationship. Research in the field will surely contribute to the development of new pharmacological strategies for the treatment of endocrine diseases.
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Affiliation(s)
- Valérie Le Doan
- Centre de recherche, CHU Sainte-Justine et Département de Nutrition, Université de Montréal, 3175 Côte Sainte-Catherine, Montréal, Québec, H3T 1C5 Canada
| | - Valérie Marcil
- Centre de recherche, CHU Sainte-Justine et Département de Nutrition, Université de Montréal, 3175 Côte Sainte-Catherine, Montréal, Québec, H3T 1C5 Canada
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43
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Osteocalcin and its endocrine functions. Biochem Pharmacol 2017; 132:1-8. [DOI: 10.1016/j.bcp.2017.02.001] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 02/02/2017] [Indexed: 12/31/2022]
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Abstract
The rising incidence of metabolic diseases worldwide has prompted renewed interest in the study of intermediary metabolism and cellular bioenergetics. The application of modern biochemical methods for quantitating fuel substrate metabolism with advanced mouse genetic approaches has greatly increased understanding of the mechanisms that integrate energy metabolism in the whole organism. Examination of the intermediary metabolism of skeletal cells has been sparked by a series of unanticipated observations in genetically modified mice that suggest the existence of novel endocrine pathways through which bone cells communicate their energy status to other centers of metabolic control. The recognition of this expanded role of the skeleton has in turn led to new lines of inquiry directed at defining the fuel requirements and bioenergetic properties of bone cells. This article provides a comprehensive review of historical and contemporary studies on the metabolic properties of bone cells and the mechanisms that control energy substrate utilization and bioenergetics. Special attention is devoted to identifying gaps in our current understanding of this new area of skeletal biology that will require additional research to better define the physiological significance of skeletal cell bioenergetics in human health and disease.
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Affiliation(s)
- Ryan C Riddle
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, Maryland; and The Baltimore Veterans Administration Medical Center, Baltimore, Maryland
| | - Thomas L Clemens
- Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, Maryland; and The Baltimore Veterans Administration Medical Center, Baltimore, Maryland
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Razny U, Fedak D, Kiec‐Wilk B, Goralska J, Gruca A, Zdzienicka A, Kiec‐Klimczak M, Solnica B, Hubalewska‐Dydejczyk A, Malczewska‐Malec M. Carboxylated and undercarboxylated osteocalcin in metabolic complications of human obesity and prediabetes. Diabetes Metab Res Rev 2017; 33:e2862. [PMID: 27667744 PMCID: PMC6681168 DOI: 10.1002/dmrr.2862] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 06/20/2016] [Accepted: 08/26/2016] [Indexed: 12/30/2022]
Abstract
BACKGROUND Carboxylated osteocalcin (Gla-OC) participates in bone remodeling, whereas the undercarboxylated form (Glu-OC) takes part in energy metabolism. This study was undertaken to compare the blood levels of Glu-OC and Gla-OC in nonobese, healthy obese, and prediabetic volunteers and correlate it with the metabolic markers of insulin resistance and early markers of inflammation. METHODS Nonobese (body mass index [BMI] <30 kg/m2 ; n = 34) and obese subjects (30 <BMI <40 kg/m2 ; n = 98), both sexes, aged 25 to 65 years, were divided into healthy control, normal weight subjects, healthy obese, and obese with biochemical markers of prediabetes. The subgroups with obesity and low or high Gla-OC or Glu-OC were also considered for statistical analysis. After 2 weeks of diet standardization, venous blood was sampled for the determination of Gla-OC, Glu-OC, lipid profile, parameters of inflammation (hsCRP, interleukin 6, sE-selectin, sPECAM-1, and monocyte chemoattractant protein 1), and adipokines (leptin, adiponectin, visfatin, and resistin). RESULTS Gla-OC in obese patients was significantly lower compared to nonobese ones (11.36 ± 0.39 vs 12.69 ± 0.90 ng/mL, P = .048) and weakly correlated with hsCRP (r = -0.18, P = .042), visfatin concentration (r = -0.19, P = .033), and BMI (r = -0.17, P = .047). Glu-OC was negatively associated with fasting insulin levels (r = -0.18, P = .049) and reduced in prediabetic individuals compared with healthy obese volunteers (3.04 ± 0.28 vs 4.48 ± 0.57, P = .025). CONCLUSIONS Decreased blood concentration of Glu-OC may be a selective early symptom of insulin resistance in obesity, whereas the decreased level of Gla-OC seems to be associated with the appearance of early markers of low grade inflammation accompanying obesity.
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Affiliation(s)
- Urszula Razny
- Department of Clinical BiochemistryJagiellonian University Medical CollegeKrakowPoland
| | - Danuta Fedak
- Department of Clinical BiochemistryJagiellonian University Medical CollegeKrakowPoland
| | - Beata Kiec‐Wilk
- Department of Metabolic DiseasesJagiellonian University Medical CollegeKrakowPoland
| | - Joanna Goralska
- Department of Clinical BiochemistryJagiellonian University Medical CollegeKrakowPoland
| | - Anna Gruca
- Department of Clinical BiochemistryJagiellonian University Medical CollegeKrakowPoland
| | - Anna Zdzienicka
- Department of Clinical BiochemistryJagiellonian University Medical CollegeKrakowPoland
| | | | - Bogdan Solnica
- Department of Clinical BiochemistryJagiellonian University Medical CollegeKrakowPoland
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Fernandes TAP, Gonçalves LML, Brito JAA. Relationships between Bone Turnover and Energy Metabolism. J Diabetes Res 2017; 2017:9021314. [PMID: 28695134 PMCID: PMC5485508 DOI: 10.1155/2017/9021314] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Revised: 05/12/2017] [Accepted: 05/22/2017] [Indexed: 12/31/2022] Open
Abstract
It is well established that diabetes can be detrimental to bone health, and its chronic complications have been associated with an increased risk of osteoporotic fracture. However, there is growing evidence that the skeleton plays a key role in a whole-organism approach to physiology. The hypothesis that bone may be involved in the regulation of physiological functions, such as insulin sensitivity and energy metabolism, has been suggested. Given the roles of insulin, adipokines, and osteocalcin in these pathways, the need for a more integrative conceptual approach to physiology is emphasized. Recent findings suggest that bone plays an important role in regulating intermediary metabolism, being possibly both a target of diabetic complications and a potential pathophysiologic factor in the disease itself. Understanding the relationships between bone turnover and glucose metabolism is important in order to develop treatments that might reestablish energy metabolism and bone health. This review describes new insights relating bone turnover and energy metabolism that have been reported in the literature.
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Affiliation(s)
- Tânia A. P. Fernandes
- Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- *Tânia A. P. Fernandes:
| | - Luísa M. L. Gonçalves
- Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
| | - José A. A. Brito
- Instituto Superior de Ciências da Saúde Egas Moniz (ISCSEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Campus Universitário-Quinta da Granja, 2829-511 Monte de Caparica, Portugal
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Lin X, Parker L, Mclennan E, Zhang X, Hayes A, McConell G, Brennan-Speranza TC, Levinger I. Recombinant Uncarboxylated Osteocalcin Per Se Enhances Mouse Skeletal Muscle Glucose Uptake in both Extensor Digitorum Longus and Soleus Muscles. Front Endocrinol (Lausanne) 2017; 8:330. [PMID: 29204135 PMCID: PMC5698688 DOI: 10.3389/fendo.2017.00330] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 11/06/2017] [Indexed: 11/20/2022] Open
Abstract
Emerging evidence suggests that undercarboxylated osteocalcin (ucOC) improves muscle glucose uptake in rodents. However, whether ucOC can directly increase glucose uptake in both glycolytic and oxidative muscles and the possible mechanisms of action still need further exploration. We tested the hypothesis that ucOC per se stimulates muscle glucose uptake via extracellular signal-regulated kinase (ERK), adenosine monophosphate-activated protein kinase (AMPK), and/or the mechanistic target of rapamycin complex 2 (mTORC2)-protein kinase B (AKT)-AKT substrate of 160 kDa (AS160) signaling cascade. Extensor digitorum longus (EDL) and soleus muscles from male C57BL/6 mice were isolated, divided into halves, and then incubated with ucOC with or without the pretreatment of ERK inhibitor U0126. ucOC increased muscle glucose uptake in both EDL and soleus. It also enhanced phosphorylation of ERK2 (Thr202/Tyr204) and AS160 (Thr642) in both muscle types and increased mTOR phosphorylation (Ser2481) in EDL only. ucOC had no significant effect on the phosphorylation of AMPKα (Thr172). The inhibition of ucOC-induced ERK phosphorylation had limited effect on ucOC-stimulated glucose uptake and AS160 phosphorylation in both muscle types, but appeared to inhibit the elevation in AKT phosphorylation only in EDL. Taken together, ucOC at the physiological range directly increased glucose uptake in both EDL and soleus muscles in mouse. The molecular mechanisms behind this ucOC effect on muscle glucose uptake seem to be muscle type-specific, involving enhanced phosphorylation of AS160 but limitedly modulated by ERK phosphorylation. Our study suggests that, since ucOC increases muscle glucose uptake without insulin, it could be considered as a potential agent to improve muscle glucose uptake in insulin resistant conditions.
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Affiliation(s)
- Xuzhu Lin
- Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia
| | - Lewan Parker
- Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia
- School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Melbourne, VIC, Australia
| | - Emma Mclennan
- Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia
| | - Xinmei Zhang
- Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia
| | - Alan Hayes
- Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia
- College of Health and Biomedicine, Victoria University, Geelong, VIC, Australia
- Australian Institute for Musculoskeletal Science, Western Health, Melbourne, VIC, Australia
| | - Glenn McConell
- Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia
| | - Tara C. Brennan-Speranza
- Department of Physiology, Bosch Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
| | - Itamar Levinger
- Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia
- Australian Institute for Musculoskeletal Science, Western Health, Melbourne, VIC, Australia
- *Correspondence: Itamar Levinger,
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Pi M, Nishimoto SK, Quarles LD. GPRC6A: Jack of all metabolism (or master of none). Mol Metab 2016; 6:185-193. [PMID: 28180060 PMCID: PMC5279936 DOI: 10.1016/j.molmet.2016.12.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 12/05/2016] [Accepted: 12/15/2016] [Indexed: 01/06/2023] Open
Abstract
Background GPRC6A, a widely expressed G-protein coupled receptor, is proposed to be a master regulator of complex endocrine networks and metabolic processes. GPRC6A is activated by multiple ligands, including osteocalcin (Ocn), testosterone (T), basic amino acids, and various cations. Scope of Review We review the controversy surrounding GPRC6A functions. In mice, GPRC6A is proposed to integrate metabolic functions through the coordinated secretion of hormones, including insulin, GLP-1, T, and IL-6, and direct effects of this receptor to control glucose and fat metabolism in the liver, skeletal muscle, and fat. Loss-of-GPRC6A results in metabolic syndrome (MetS), and activation of GPRC6A stimulates proliferation of β-cells, increases peripheral insulin sensitivity, and protects against high fat diet (HFD) induced metabolic abnormalities in most mouse models. Bone, cardiovascular, immune, and skin functions of GPRC6A have also been identified in mice. Expression of GPRC6A is increased in prostate cancer (PCa) cells, and inhibition of GPRC6A attenuates PCa progression in mouse models. The function of GPRC6A in humans, however, is not clear. During evolution, a unique polymorphism of GPRC6A emerged mainly in humans of Asian and European decent that has been proposed to alter membrane trafficking and function. In contrast, the ancestral allele found in all other species is retained in 1%, 15%, and 40% of people of Asian, European and African descent, respectively, suggesting GPRC6A gene variants may contribute to the racial disparities in the risk of developing MetS and PCa. Major Conclusions If the regulatory functions of GPRC6A identified in mice translate to humans, and polymorphisms in GPRC6A are found to predict racial disparities in human diseases, GPRC6A may be a new gene target to predict, prevent, and treat MetS, PCa, and other disorders impacted by GPRC6A.
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Affiliation(s)
- Min Pi
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Satoru Kenneth Nishimoto
- Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - L Darryl Quarles
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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Mizokami A, Wang D, Tanaka M, Gao J, Takeuchi H, Matsui T, Hirata M. An extract from pork bones containing osteocalcin improves glucose metabolism in mice by oral administration. Biosci Biotechnol Biochem 2016; 80:2176-2183. [DOI: 10.1080/09168451.2016.1214530] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Abstract
Osteocalcin (OC) is a bone-derived hormone that regulates energy metabolism. OC exists in two forms, carboxylated (GlaOC) and uncaboxylated (GluOC), but only the latter appears to have an endocrine function. In this study, we prepared an extract containing both Gla- and GluOC from boiled pork bone using 0.2 M carbonate buffer at pH 9.5, and tested whether the extract had beneficial effects on improving metabolic parameters in obese mice. The extract equivalent of 1.2 μg of GluOC/mouse was orally administrated to C57BL/6 female mice fed a high-fat, high-sucrose diet. Daily oral administration of the extract for four weeks decreased blood glucose levels and promoted glucose tolerance as well as insulin sensitivity. Our study shows for the first time that boiled pork bones are a source material for osteocalcin in the large-scale production of supplements designed to improve glucose metabolism.
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Affiliation(s)
- Akiko Mizokami
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
- OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - DaGuang Wang
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Mitsuru Tanaka
- Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, Japan
| | - Jing Gao
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Hiroshi Takeuchi
- Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu, Japan
| | - Toshiro Matsui
- Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, Japan
| | - Masato Hirata
- Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
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Yasutake Y, Mizokami A, Kawakubo-Yasukochi T, Chishaki S, Takahashi I, Takeuchi H, Hirata M. Long-term oral administration of osteocalcin induces insulin resistance in male mice fed a high-fat, high-sucrose diet. Am J Physiol Endocrinol Metab 2016; 310:E662-E675. [PMID: 26884384 DOI: 10.1152/ajpendo.00334.2015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 02/05/2016] [Indexed: 01/13/2023]
Abstract
Uncarboxylated osteocalcin (GluOC), a bone-derived hormone, regulates energy metabolism by stimulating insulin secretion, pancreatic β-cell proliferation, and adiponectin expression in adipocytes. Previously, we showed that long-term intermittent or daily oral administration of GluOC reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as pancreatic β-cell area in female mice fed a normal or high-fat, high-sucrose diet. We have now performed similar experiments with male mice and found that such GluOC administration induced glucose intolerance, insulin resistance, and adipocyte hypertrophy in those fed a high-fat, high-sucrose diet. In addition, GluOC increased the circulating concentration of testosterone and reduced that of adiponectin in such mice. These phenotypes were not observed in male mice fed a high-fat, high-sucrose diet after orchidectomy, but they were apparent in orchidectomized male mice or intact female mice that were fed such a diet and subjected to continuous testosterone supplementation. Our results thus reveal a sex difference in the effects of GluOC on glucose homeostasis. Given that oral administration of GluOC has been considered a potentially safe and convenient option for the treatment or prevention of metabolic disorders, this sex difference will need to be taken into account in further investigations.
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Affiliation(s)
- Yu Yasutake
- Laboratory of Molecular and Cellular Biochemistry
- Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Akiko Mizokami
- Laboratory of Molecular and Cellular Biochemistry
- OBT Research Center, and
| | - Tomoyo Kawakubo-Yasukochi
- Department of Immunological and Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan; and
| | | | - Ichiro Takahashi
- Division of Orthodontics, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Hiroshi Takeuchi
- Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu, Japan
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