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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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Lee R, Won KJ, Kim JH, Lee BH, Hwang SH, Nah SY. Gintonin Stimulates Glucose Uptake in Myocytes: Involvement of Calcium and Extracellular Signal-Regulated Kinase Signaling. Biomolecules 2024; 14:1316. [PMID: 39456249 PMCID: PMC11505745 DOI: 10.3390/biom14101316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/14/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
Ginseng has anti-hyperglycemic effects. Gintonin, a glycolipoprotein derived from ginseng, also stimulates insulin release from pancreatic beta cells. However, the role of gintonin in glucose metabolism within skeletal muscle is unknown. Here, we showed the effect of gintonin on glucose uptake, glycogen content, glucose transporter (GLUT) 4 expression, and adenosine triphosphate (ATP) content in C2C12 myotubes. Gintonin (3-30 μg/mL) dose-dependently stimulated glucose uptake in myotubes. The expression of GLUT4 on the cell membrane was increased by gintonin treatment. Treatment with 1-3 μg/mL of gintonin increased glycogen content in myotubes, but the content was decreased at 30 μg/mL of gintonin. The ATP content in myotubes increased following treatment with 10-100 μg/mL gintonin. Gintonin transiently elevated intracellular calcium concentrations and increased the phosphorylation of extracellular signal-regulated kinase (ERK). Gintonin-induced transient calcium increases were inhibited by treatment with the lysophosphatidic acid receptor inhibitor Ki16425, the phospholipase C inhibitor U73122, and the inositol 1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenyl borate. Gintonin-stimulated glucose uptake was decreased by treatment with U73122, the intracellular calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester, and the ERK inhibitor PD98059. These results show that gintonin plays a role in glucose metabolism by increasing glucose uptake through transient calcium increases and ERK signaling pathways. Thus, gintonin may be beneficial for glucose metabolism control.
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Affiliation(s)
- Rami Lee
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; (R.L.); (J.-H.K.)
| | - Kyung-Jong Won
- Department of Physiology and Premedical Science, College of Medicine, Konkuk University, Chungju 27478, Republic of Korea;
| | - Ji-Hun Kim
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; (R.L.); (J.-H.K.)
| | - Byung-Hwan Lee
- Jeju Self-Governing Provincial Veterinary Research Institute, Jeju 63344, Republic of Korea;
| | - Sung-Hee Hwang
- Department of Pharmaceutical Engineering, College of Health Sciences, Sangji University, Wonju 26339, Republic of Korea
| | - Seung-Yeol Nah
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea; (R.L.); (J.-H.K.)
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Mizokami A, Otani T, Mukai S, Hirata M. Roles of Nutrition-Sensing Receptor GPRC6A in Energy Metabolism and Oral Inflammatory Diseases. CURRENT ORAL HEALTH REPORTS 2024; 11:306-311. [DOI: 10.1007/s40496-024-00386-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 01/03/2025]
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Otani T, Mizokami A, Takeuchi H, Inai T, Hirata M. The role of adhesion molecules in osteocalcin-induced effects on glucose and lipid metabolism in adipocytes. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119701. [PMID: 38417588 DOI: 10.1016/j.bbamcr.2024.119701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 02/08/2024] [Accepted: 02/21/2024] [Indexed: 03/01/2024]
Abstract
Recent findings suggest that uncarboxylated osteocalcin (GluOC) promotes glucose and lipid metabolism via its putative receptor GPRC6A; however, its direct effect on adipocytes remains elusive. In this study, we elucidated the effects of GluOC on adipocytes, with an emphasis on the role of cell adhesion molecules. We determined that GluOC promoted the expression of adipocyte adhesion molecule (ACAM) and its transcription factor Krüppel-like factor 4 and enhanced the cortical actin filament assembly, which ameliorated lipid droplet hypertrophy. Additionally, GluOC upregulated the expression of integrin αVβ3 and activation of focal adhesion kinase (FAK) and prevented insulin receptor substrate 1 (IRS1) degradation by inhibiting the ubiquitin-proteasome system via the FAK-PLC-PKC axis, which activated IRS1-Akt-mediated glucose transporter 4 (GLUT4) transport. Furthermore, we showed that GluOC elevated the expression of the insulin-independent glucose transporters GLUT1 and GLUT8, which facilitated insulin stimulation-independent glucose transport. The GluOC-induced activation of integrin αVβ3 signaling promoted microtubule assembly, which improved glucose and lipid metabolism via its involvement in intracellular vesicular transport. GluOC treatment also suppressed collagen type 1 formation, which might prevent adipose tissue fibrosis in obese individuals. Overall, our results imply that GluOC promotes glucose and lipid metabolism via ACAM, integrin αVβ3, and GLUT1 and 8 expression, directly affecting adipocytes.
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Affiliation(s)
- Takahito Otani
- Division of Functional Structure, Department of Morphological Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
| | - Akiko Mizokami
- Oral Health/Brain Health/Total Health Research Center, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Hiroshi Takeuchi
- Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu 803-8580, Japan
| | - Tetsuichiro Inai
- Division of Functional Structure, Department of Morphological Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan
| | - Masato Hirata
- Oral Medicine Research Center, Fukuoka Dental College, Fukuoka 814-0193, Japan.
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Li XY, Jiang CL, Zheng C, Hong CZ, Pan LH, Li QM, Luo JP, Zha XQ. Polygonatum cyrtonema Hua Polysaccharide Alleviates Fatigue by Modulating Osteocalcin-Mediated Crosstalk between Bones and Muscles. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:6468-6479. [PMID: 37043685 DOI: 10.1021/acs.jafc.2c08192] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Osteocalcin was reported to regulate muscle energy metabolism, thus fighting fatigue during exercise. The current work aimed to investigate the anti-fatigue effect and the underlying mechanism of a homogeneous polysaccharide (PCPY-1) from Polgonatum cyrtonema after structure characterization. In the exhaustive swimming mouse model and the co-culture system of BMSCs/C2C12 cells, PCPY-1 significantly stimulated BMSC differentiation into osteoblasts as determined by ALP activity, matrix mineralization, and the protein expressions of osteogenic markers BMP-2, phosphor-Smad1, RUNX2, and osteocalcin. Meanwhile, PCPY-1 remarkably enhanced myoblast energy metabolism by upregulating osteocalcin release and GPRC6A protein expression; the phosphorylation levels of CREB and HSL; the mRNA levels of GLUT4, CD36, FATP1, and CPT1B; and ATP production in vitro and in vivo. Accordingly, PCPY-1 exhibited good anti-fatigue capacity in mice as confirmed by fatigue-related indicators. Our findings indicated PCPY-1 could enhance osteocalcin-mediated communication between bones and muscles, which was conducive to muscle energy metabolism and ATP generation, thus alleviating fatigue in exhausted swimming mice.
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Affiliation(s)
- Xue-Ying Li
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Chao-Li Jiang
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Chao Zheng
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Cheng-Zhi Hong
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Li-Hua Pan
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Qiang-Ming Li
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Jian-Ping Luo
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
| | - Xue-Qiang Zha
- Engineering Research Centre of Bioprocess of Ministry of Education, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- School of Food and Biological Engineering, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
- Key Laboratory of Metabolism and Regulation for Major Disease of Anhui Higher Education Institutes, Hefei University of Technology, No. 193 Tunxi Road, Hefei 230009, People's Republic of China
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Kurgan N, Skelly LE, Ludwa IA, Klentrou P, Josse AR. Twelve weeks of a diet and exercise intervention alters the acute bone response to exercise in adolescent females with overweight/obesity. Front Physiol 2023; 13:1049604. [PMID: 36685198 PMCID: PMC9846109 DOI: 10.3389/fphys.2022.1049604] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 12/12/2022] [Indexed: 01/06/2023] Open
Abstract
Introduction: Exercise and consumption of dairy foods have been shown to improve bone mineralization. However, little is known about the magnitude and timing of their synergistic effects on markers and regulators of bone metabolism in response to acute exercise in adolescent females with obesity, a population susceptible to altered bone metabolism and mineral properties. This study examined the influence of twelve weeks of exercise training and nutritional counselling on the bone biochemical marker response to acute exercise and whether higher dairy consumption could further influence the response. Methods: Thirty adolescent females (14.3 ± 2.0 years) with overweight/obesity (OW/OB) completed a 12-week lifestyle modification intervention involving exercise training and nutritional counselling. Participants were randomized into two groups: higher dairy intake (RDa; 4 servings/day; n = 14) or low dairy intake (LDa; 0-2 servings/d; n = 16). Participants performed one bout of plyometric exercise (5 circuits; 120 jumps) both pre- and post-intervention. Blood samples were taken at rest, 5 min and 1 h post-exercise. Serum sclerostin, osteocalcin (OC), osteoprotegerin (OPG), receptor activator nuclear factor kappa B ligand (RANKL), and C-terminal telopeptide of type 1 collagen (βCTX) concentrations were measured. Results: While there was an overall increase in sclerostin pre-intervention from pre to 5 min post-exercise (+11% p = 0.04), this response was significantly decreased post-intervention (-25%, p = 0.03) independent of dairy intake. The OPG:RANKL ratio was unresponsive to acute exercise pre-intervention but increased 1 h post-exercise (+2.6 AU; p < 0.001) post-intervention. Dairy intake did not further influence these absolute responses. However, after the 12-week intervention, the RDa group showed a decrease in the relative RANKL post-exercise response (-21.9%; p < 0.01), leading to a consistent increase in the relative OPG:RANKL ratio response, which was not the case in the LDa group. There was no influence of the intervention or dairy product intake on OC, OPG, or βCTX responses to acute exercise (p > 0.05). Conclusion: A lifestyle modification intervention involving exercise training blunts the increase in sclerostin and can augment the increase in OPG:RANKL ratio to acute exercise in adolescent females with OW/OB, while dairy product consumption did not further influence these responses.
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Affiliation(s)
- Nigel Kurgan
- Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Lauren E. Skelly
- School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, ON, Canada
| | - Izabella A. Ludwa
- Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada
| | - Panagiota Klentrou
- Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Andrea R. Josse
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
- School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, ON, Canada
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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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Tumor necrosis factor alpha regulates myogenesis to inhibit differentiation and promote proliferation in satellite cells. Biochem Biophys Res Commun 2021; 580:35-40. [PMID: 34619550 DOI: 10.1016/j.bbrc.2021.09.067] [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: 08/19/2021] [Revised: 09/18/2021] [Accepted: 09/25/2021] [Indexed: 01/06/2023]
Abstract
TNF-α and NF-κB signaling is involved in the wasting of skeletal muscle in various conditions, in addition to cancer cachexia. TNF-α and NF-κB signaling promotes the expression level of muscle RING finger protein 1, a ubiquitin ligase, causing muscle degradation. Several studies have indicated that of TNF-α and NF-κB signaling suppresses muscle differentiation by reducing the levels of MyoD protein. On the other hand, TNF-α and NF-κB is required for myoblast proliferation. Thus, the role of TNF-α and NF-κB signaling in the process of myogenesis and regeneration of skeletal muscle is not completely elucidated. Here, we reported that TNF-α reduced the width of single fibers of skeletal muscle in an organ culture model. TNF-α and p65 repressed the transactivation of MyoD and suppressed myoblast differentiation. In addition, TNF-α increased the number of satellite cells, and NF-κB signaling was promoted at the proliferation stage during skeletal muscle regeneration in vivo. TNF-α and NF-κB signaling regulate myogenesis to inhibit differentiation and promote proliferation in satellite cells.
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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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Huang S, Wang J, Men H, Tan Y, Lin Q, Gozal E, Zheng Y, Cai L. Cardiac metallothionein overexpression rescues diabetic cardiomyopathy in Akt2-knockout mice. J Cell Mol Med 2021; 25:6828-6840. [PMID: 34053181 PMCID: PMC8278119 DOI: 10.1111/jcmm.16687] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 05/04/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
To efficiently prevent diabetic cardiomyopathy (DCM), we have explored and confirmed that metallothionein (MT) prevents DCM by attenuating oxidative stress, and increasing expression of proteins associated with glucose metabolism. To determine whether Akt2 expression is critical to MT prevention of DCM, mice with either global Akt2 gene deletion (Akt2-KO), or cardiomyocyte-specific overexpressing MT gene (MT-TG) or both combined (MT-TG/Akt2-KO) were used. Akt2-KO mice exhibited symptoms of DCM (cardiac remodelling and dysfunction), and reduced expression of glycogen and glucose metabolism-related proteins, despite an increase in total Akt (t-Akt) phosphorylation. Cardiac MT overexpression in MT-TG/Akt2-KO mice prevented DCM and restored glucose metabolism-related proteins expression and baseline t-Akt phosphorylation. Furthermore, phosphorylation of ERK1/2 increased in the heart of MT-TG/Akt2-KO mice, compared with Akt2-KO mice. As ERK1/2 has been implicated in the regulation of glucose transport and metabolism this increase could potentially underlie MT protective effect in MT-TG/Akt2-KO mice. Therefore, these results show that although our previous work has shown that MT preserving Akt2 activity is sufficient to prevent DCM, in the absence of Akt2 MT may stimulate alternative or downstream pathways protecting from DCM in a type 2 model of diabetes, and that this protection may be associated with the ERK activation pathway.
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Affiliation(s)
- Shan Huang
- Department of PediatricsPediatric Research InstituteUniversity of Louisville School of MedicineLouisvilleKYUSA
- Department of Cardiovascular DiseaseThe First Hospital of Jilin UniversityChangchunChina
| | - Jiqun Wang
- Department of PediatricsPediatric Research InstituteUniversity of Louisville School of MedicineLouisvilleKYUSA
- Department of Cardiovascular DiseaseThe First Hospital of Jilin UniversityChangchunChina
| | - Hongbo Men
- Department of PediatricsPediatric Research InstituteUniversity of Louisville School of MedicineLouisvilleKYUSA
- Department of Cardiovascular DiseaseThe First Hospital of Jilin UniversityChangchunChina
| | - Yi Tan
- Department of PediatricsPediatric Research InstituteUniversity of Louisville School of MedicineLouisvilleKYUSA
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKYUSA
| | - Qian Lin
- Department of PediatricsPediatric Research InstituteUniversity of Louisville School of MedicineLouisvilleKYUSA
| | - Evelyne Gozal
- Department of PediatricsPediatric Research InstituteUniversity of Louisville School of MedicineLouisvilleKYUSA
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKYUSA
| | - Yang Zheng
- Department of Cardiovascular DiseaseThe First Hospital of Jilin UniversityChangchunChina
| | - Lu Cai
- Department of PediatricsPediatric Research InstituteUniversity of Louisville School of MedicineLouisvilleKYUSA
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKYUSA
- Department of Radiation OncologyUniversity of Louisville School of MedicineLouisvilleKYUSA
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Blair HC, Schlesinger PH. Survival of the glycosylated. eLife 2021; 10:65719. [PMID: 33480844 PMCID: PMC7822590 DOI: 10.7554/elife.65719] [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: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 11/13/2022] Open
Abstract
Osteocalcin is a bone matrix protein that acts like a hormone when it reaches the blood, and has different effects in mice and humans.
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Affiliation(s)
- Harry C Blair
- Veterans Affairs Medical Center and the Department of Pathology, University of Pittsburgh, Pittsburgh, United States
| | - Paul H Schlesinger
- Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, United States
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Otani T, Mizokami A, Kawakubo-Yasukochi T, Takeuchi H, Inai T, Hirata M. The roles of osteocalcin in lipid metabolism in adipose tissue and liver. Adv Biol Regul 2020; 78:100752. [PMID: 32992234 DOI: 10.1016/j.jbior.2020.100752] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 09/08/2020] [Indexed: 06/11/2023]
Abstract
Bone provides skeletal support and functions as an endocrine organ by producing osteocalcin, whose uncarboxylated form (GluOC) increases the metabolism of glucose and lipid by activating its putative G protein-coupled receptor (family C group 6 subtype A). Low doses (≤10 ng/ml) of GluOC induce the expression of adiponectin, adipose triglyceride lipase and peroxisome proliferator-activated receptor γ, and promote active phosphorylation of lipolytic enzymes such as perilipin and hormone-sensitive lipase via the cAMP-PKA-Src-Rap1-ERK-CREB signaling axis in 3T3-L1 adipocytes. Administration of high-dose (≥20 ng/ml) GluOC induces programmed necrosis (necroptosis) through a juxtacrine mechanism triggered by the binding of Fas ligand, whose expression is induced by forkhead box O1, to Fas that is expressed in adjacent adipocytes. Furthermore, expression of adiponectin and adipose triglyceride lipase in adipocytes is triggered in the same manner as following low-dose GluOC stimulation; these effects protect mice from diet-induced accumulation of triglycerides in hepatocytes and consequent liver injury through the upregulation of nuclear translocation of nuclear factor-E2-related factor-2, expression of antioxidant enzymes, and inhibition of the c-Jun N-terminal kinase pathway. Evaluation of these molecular mechanisms leads us to consider that GluOC might have potential as a treatment for lipid metabolism disorders. Indeed, there have been many reports demonstrating the negative correlation between serum osteocalcin levels and obesity or non-alcoholic fatty liver disease, a common risk factor for which is dyslipidemia in humans. The present review summarizes the effects of GluOC on lipid metabolism as well as its possible therapeutic application for metabolic diseases including obesity and dyslipidemia.
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Affiliation(s)
- Takahito Otani
- Division of Functional Structure, Department of Morphological Biology, Fukuoka Dental College, Fukuoka, 814-0193, Japan
| | - Akiko Mizokami
- OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan
| | | | - Hiroshi Takeuchi
- Division of Applied Pharmacology, Kyushu Dental University, Kitakyushu, 803-8580, Japan
| | - Tetsuichiro Inai
- Division of Functional Structure, Department of Morphological Biology, Fukuoka Dental College, Fukuoka, 814-0193, Japan; Oral Medicine Research Center, Fukuoka Dental College, Fukuoka, 814-0193, Japan
| | - Masato Hirata
- Oral Medicine Research Center, Fukuoka Dental College, Fukuoka, 814-0193, Japan.
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Pandey A, Khan HR, Alex NS, Puttaraju M, Chandrasekaran TT, Rudraiah M. Under-carboxylated osteocalcin regulates glucose and lipid metabolism during pregnancy and lactation in rats. J Endocrinol Invest 2020; 43:1081-1095. [PMID: 32056149 DOI: 10.1007/s40618-020-01195-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 02/03/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE Under-carboxylated osteocalcin (UcOC), a bone-released hormone is suggested to regulate energy metabolism. Pregnancy and lactation physiological conditions that require high levels of energy. The current study attempts to examine whether UcOC is involved in regulating energy metabolism during these conditions using adult Wistar rats. METHODS AND RESULTS Insulin tolerance tests indicated insulin resistance during late pregnancy (day 19 of pregnancy; P19) and insulin sensitivity during early lactation (day 6 of lactation; L6). Gene expression analyses suggested that muscle glucose metabolism was downregulated during P19 and enhanced during L6. Concomitantly, circulatory UcOC levels were lower during pregnancy but higher during early lactation; the rise in UcOC levels was tightly linked to the lactation process. Altering endogenous UcOC levels pharmacologically with warfarin and alendronate in P19 and L6 rats changed whole-body insulin response and muscle glucose transporter (Glut4) expression. Glut4 expression can be increased by either UcOC or estrogen receptors (ERs), both of which act independent of each other. A high fat diet decreased UcOC levels and insulin sensitivity in lactating rats, suggesting that diet can compromise UcOC-established energy homeostasis. Gene expression of lipid metabolism markers and triglyceride levels suggested that UcOC suppression during early pregnancy is an essential step in maternal lipid storage. CONCLUSION Taken together, we found that UcOC plays an important role in energy homeostasis via regulation of glucose and lipid metabolism during pregnancy and lactation.
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Affiliation(s)
- A Pandey
- Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - H R Khan
- Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - N S Alex
- Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - M Puttaraju
- Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - T T Chandrasekaran
- Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - M Rudraiah
- Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India.
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Karsenty G. The facts of the matter: What is a hormone? PLoS Genet 2020; 16:e1008938. [PMID: 32589668 PMCID: PMC7319275 DOI: 10.1371/journal.pgen.1008938] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 06/17/2020] [Indexed: 12/17/2022] Open
Affiliation(s)
- Gerard Karsenty
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, New York, United States of America
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15
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Jørgensen CV, Bräuner‐Osborne H. Pharmacology and physiological function of the orphan GPRC6A receptor. Basic Clin Pharmacol Toxicol 2020; 126 Suppl 6:77-87. [DOI: 10.1111/bcpt.13397] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 02/11/2020] [Accepted: 02/11/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Christinna V. Jørgensen
- Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
| | - Hans Bräuner‐Osborne
- Department of Drug Design and Pharmacology Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark
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16
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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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17
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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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18
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Lin X, Parker L, McLennan E, Hayes A, McConell G, Brennan-Speranza TC, Levinger I. Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice. J Bone Miner Res 2019; 34:1517-1530. [PMID: 30908701 DOI: 10.1002/jbmr.3731] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Revised: 03/18/2019] [Accepted: 03/20/2019] [Indexed: 01/05/2023]
Abstract
Short-term administration of glucocorticoids (GCs) impairs muscle insulin sensitivity at least in part via the reduction of undercarboxylated osteocalcin (ucOC). However, whether ucOC treatment reverses the GC-induced muscle insulin resistance remains unclear. To test the hypothesis that ucOC directly ameliorates impaired insulin-stimulated glucose uptake (ISGU) induced by short-term GC administration in mice muscle and to identify the molecular mechanisms, mice were implanted with placebo or corticosterone (CS) slow-release pellets. Two days post-surgery, insulin-tolerance tests (ITTs) were performed. On day 3, serum was collected and extensor digitorum longus (EDL) and soleus muscles were isolated and treated ex vivo with vehicle, ucOC (30 ng/mL), insulin (60 µU/mL), or both. Circulating hormone levels, muscle glucose uptake, and muscle signaling proteins were assessed. CS administration reduced both serum osteocalcin and ucOC levels, whole-body insulin sensitivity, and muscle ISGU in EDL. Ex vivo ucOC treatment restored ISGU in CS-affected muscle, without increasing non-insulin-stimulated glucose uptake. In CS-affected EDL muscle, ucOC enhanced insulin action on phosphorylated (p-)protein kinase B (Akt)Ser473 and the p-extracellular signal-regulated kinase isoform 2 (ERK2)Thr202/Tyr204 /total (t)ERK2 ratio, which correlated with ISGU. In CS-affected soleus muscle, ucOC enhanced insulin action on p-mammalian target of rapamycin (mTOR)Ser2481 , the p-mTORSer2481 /tmTOR ratio, p-Akt substrate of 160kD (AS160)Thr642 , and p-protein kinase C (PKC) (pan)Thr410 , which correlated with ISGU. Furthermore, p-PKC (pan)Thr410 correlated with p-AktSer473 and p-AS160Thr642 . ucOC exerts direct insulin-sensitizing effects on CS-affected mouse muscle, likely through an enhancement in activity of key proteins involved in both insulin and ucOC signaling pathways. Furthermore, these effects are muscle type-dependent. © 2019 American Society for Bone and Mineral Research.
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Affiliation(s)
- Xuzhu Lin
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
| | - Lewan Parker
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia.,Institute for Physical Activity and Nutrition (IPAN), Deakin University, Geelong, VIC, Australia
| | - Emma McLennan
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
| | - Alan Hayes
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia.,College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.,Department of Medicine-Western Health, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia
| | - Glenn McConell
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
| | - Tara C Brennan-Speranza
- Department of Physiology and Bosch Institute for Medical Research, University of Sydney, Australia
| | - Itamar Levinger
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia.,Department of Medicine-Western Health, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne Medical School, The University of Melbourne, Melbourne, VIC, Australia
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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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20
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Kanazawa I, Takeno A, Tanaka KI, Notsu M, Sugimoto T. Osteoblast AMP-activated protein kinase regulates glucose metabolism and bone mass in adult mice. Biochem Biophys Res Commun 2018; 503:1955-1961. [DOI: 10.1016/j.bbrc.2018.07.141] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 07/27/2018] [Indexed: 01/07/2023]
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21
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Lin X, Parker L, Mclennan E, Zhang X, Hayes A, McConell G, Brennan-Speranza TC, Levinger I. Uncarboxylated Osteocalcin Enhances Glucose Uptake Ex Vivo in Insulin-Stimulated Mouse Oxidative But Not Glycolytic Muscle. Calcif Tissue Int 2018; 103:198-205. [PMID: 29427234 DOI: 10.1007/s00223-018-0400-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 01/31/2018] [Indexed: 01/14/2023]
Abstract
Uncarboxylated osteocalcin (ucOC) stimulates muscle glucose uptake in mice EDL and soleus muscles. However, whether ucOC also exerts a similar effect in insulin-stimulated muscles in a muscle type-specific manner is currently unclear. We aimed to test the hypothesis that, with insulin stimulation, ucOC per se has a greater effect on oxidative muscle compared with glycolytic muscle, and to explore the underlying mechanisms. Mouse (C57BL6, male 9-12 weeks) extensor digitorum longus (EDL) and soleus muscles were isolated and longitudinally split into halves. Muscle samples were treated with varying doses of recombinant ucOC (0, 0.3, 1, 3, 30 ng/ml), followed by insulin addition. Muscle glucose uptake, protein phosphorylation and total expression of protein kinase B (Akt), Akt substrate of 160 kDa (AS160), extracellular signal-regulated kinase isoform 2 (ERK2), and adenosine monophosphate-activated protein kinase subunit α (AMPKα) were assessed. ucOC treatment at 30 ng/ml enhanced muscle glucose uptake in insulin-stimulated soleus, a mainly oxidative muscle (17.5%, p < 0.05), but not in EDL-a mostly glycolytic muscle. In insulin-stimulated soleus only, ucOC treatment (3 and 30 ng/ml) increased phosphorylation of AS160 and ERK2, but not Akt or AMPKα. The ucOC-induced increase in ERK2 phosphorylation in soleus was not associated with the increase in glucose uptake or AS160 phosphorylation. ucOC enhances glucose uptake and AS160 phosphorylation in insulin-stimulated oxidative but not glycolytic muscle, via upstream mechanisms which appear to be independent of ERK or AMPK.
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Affiliation(s)
- Xuzhu Lin
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
| | - Lewan Parker
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Australia
| | - Emma Mclennan
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
| | - Xinmei Zhang
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia
| | - Alan Hayes
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
- College of Health and Biomedicine, Victoria University, Melbourne, Australia
- Australian Institute for Musculoskeletal Science, Victoria University, Melbourne, Australia
| | - Glenn McConell
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia
| | - Tara C Brennan-Speranza
- Department of Physiology and Bosch Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Itamar Levinger
- Institute of Health and Sport (IHES), Victoria University, Melbourne, Australia.
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia.
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Undercarboxylated Osteocalcin: Experimental and Human Evidence for a Role in Glucose Homeostasis and Muscle Regulation of Insulin Sensitivity. Nutrients 2018; 10:nu10070847. [PMID: 29966260 PMCID: PMC6073619 DOI: 10.3390/nu10070847] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 06/22/2018] [Accepted: 06/25/2018] [Indexed: 12/13/2022] Open
Abstract
Recent advances have indicated that osteocalcin, and in particular its undercarboxylated form (ucOC), is not only a nutritional biomarker reflective of vitamin K status and an indicator of bone health but also an active hormone that mediates glucose metabolism in experimental studies. This work has been supported by the putative identification of G protein-coupled receptor, class C, group 6, member A (GPRC6A) as a cell surface receptor for ucOC. Of note, ucOC has been associated with diabetes and with cardiovascular risk in epidemiological studies, consistent with a pathophysiological role for ucOC in vivo. Limitations of existing knowledge include uncertainty regarding the underlying mechanisms by which ucOC interacts with GPRC6A to modulate metabolic and cardiovascular outcomes, technical issues with commonly used assays for ucOC in serum, and a paucity of clinical trials to prove causation and illuminate the scope for novel health interventions. A key emerging area of research is the role of ucOC in relation to expression of GPRC6A in muscle, and whether exercise interventions may modulate metabolic outcomes favorably in part via ucOC. Further research is warranted to clarify potential direct and indirect roles for ucOC in human health and cardiometabolic diseases.
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Han Y, You X, Xing W, Zhang Z, Zou W. Paracrine and endocrine actions of bone-the functions of secretory proteins from osteoblasts, osteocytes, and osteoclasts. Bone Res 2018; 6:16. [PMID: 29844945 PMCID: PMC5967329 DOI: 10.1038/s41413-018-0019-6] [Citation(s) in RCA: 363] [Impact Index Per Article: 51.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 03/21/2018] [Accepted: 04/16/2018] [Indexed: 12/17/2022] Open
Abstract
The skeleton is a dynamic organ that is constantly remodeled. Proteins secreted from bone cells, namely osteoblasts, osteocytes, and osteoclasts exert regulation on osteoblastogenesis, osteclastogenesis, and angiogenesis in a paracrine manner. Osteoblasts secrete a range of different molecules including RANKL/OPG, M-CSF, SEMA3A, WNT5A, and WNT16 that regulate osteoclastogenesis. Osteoblasts also produce VEGFA that stimulates osteoblastogenesis and angiogenesis. Osteocytes produce sclerostin (SOST) that inhibits osteoblast differentiation and promotes osteoclast differentiation. Osteoclasts secrete factors including BMP6, CTHRC1, EFNB2, S1P, WNT10B, SEMA4D, and CT-1 that act on osteoblasts and osteocytes, and thereby influenceaA osteogenesis. Osteoclast precursors produce the angiogenic factor PDGF-BB to promote the formation of Type H vessels, which then stimulate osteoblastogenesis. Besides, the evidences over the past decades show that at least three hormones or "osteokines" from bone cells have endocrine functions. FGF23 is produced by osteoblasts and osteocytes and can regulate phosphate metabolism. Osteocalcin (OCN) secreted by osteoblasts regulates systemic glucose and energy metabolism, reproduction, and cognition. Lipocalin-2 (LCN2) is secreted by osteoblasts and can influence energy metabolism by suppressing appetite in the brain. We review the recent progresses in the paracrine and endocrine functions of the secretory proteins of osteoblasts, osteocytes, and osteoclasts, revealing connections of the skeleton with other tissues and providing added insights into the pathogenesis of degenerative diseases affecting multiple organs and the drug discovery process.
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Affiliation(s)
- Yujiao Han
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031 China
| | - Xiuling You
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031 China
| | - Wenhui Xing
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031 China
| | - Zhong Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031 China
| | - Weiguo Zou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Sciences, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031 China
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24
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Moser SC, van der Eerden BCJ. Osteocalcin-A Versatile Bone-Derived Hormone. Front Endocrinol (Lausanne) 2018; 9:794. [PMID: 30687236 PMCID: PMC6335246 DOI: 10.3389/fendo.2018.00794] [Citation(s) in RCA: 126] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 12/18/2018] [Indexed: 11/13/2022] Open
Abstract
Bone has long been regarded as a static organ, simply providing protection and support. However, this mindset has changed radically in recent years and bone is becoming increasingly recognized for its endocrine function of secreting several hormones, thereby controlling various physiological pathways. One of the factors released by the skeleton is osteocalcin. Importantly, osteocalcin is secreted solely by osteoblasts but only has minor effects on bone mineralization and density. Instead, it has been reported to control several physiological processes in an endocrine manner, such as glucose homeostasis and exercise capacity, brain development, cognition, and male fertility. The aim of this review is to provide an overview of the currently known roles of osteocalcin and their underlying mechanisms. At present, one of the major goals in this field is translating basic research into therapeutic applications, therefore ongoing efforts to bring these findings to the clinics will also be discussed.
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Tangseefa P, Martin SK, Fitter S, Baldock PA, Proud CG, Zannettino ACW. Osteocalcin-dependent regulation of glucose metabolism and fertility: Skeletal implications for the development of insulin resistance. J Cell Physiol 2017; 233:3769-3783. [PMID: 28834550 DOI: 10.1002/jcp.26163] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 08/22/2017] [Indexed: 01/22/2023]
Abstract
The skeleton has recently emerged as a critical insulin target tissue that regulates whole body glucose metabolism and male reproductive function. While our understanding of these new regulatory axes remains in its infancy, the bone-specific protein, osteocalcin, has been shown to be centrally involved. Undercarboxylated osteocalcin acts as a secretagogue in a feed-forward loop to stimulate pancreatic β-cell proliferation and insulin secretion, improve insulin sensitivity, and promote testosterone production. Importantly, dysregulation of insulin signaling in bone causes a reduction in serum osteocalcin levels that is associated with elevated blood glucose and reduced serum insulin levels, suggesting that the skeleton may play a significant role in the development of diet-induced insulin resistance. Insulin signaling is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) which becomes hyper-activated in response to nutrient overload. Loss- and gain-of function models suggest that mTORC1 function in bone is essential for normal skeletal development; however, the role of this complex in the regulation of glucose metabolism remains to be determined. This review highlights our current understanding of the role played by osteocalcin in the skeletal regulation of glucose metabolism and fertility. In particular, it examines data emerging from transgenic mouse models which have revealed a pancreas-bone-testis regulatory axis and discusses recent human studies which seek to corroborate findings from mouse models with clinical observations. Moreover, we review recent studies which suggest dysregulation of insulin signaling in bone leads to the development of insulin resistance and discuss the potential role of mTORC1 signaling in this process.
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Affiliation(s)
- Pawanrat Tangseefa
- Faculty of Health and Medical Science, Myeloma Research Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Sally K Martin
- Faculty of Health and Medical Science, Myeloma Research Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Stephen Fitter
- Faculty of Health and Medical Science, Myeloma Research Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
| | - Paul A Baldock
- Skeletal Metabolism Group, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Christopher G Proud
- Nutrition & Metabolism, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
- School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
- Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou, China
| | - Andrew C W Zannettino
- Faculty of Health and Medical Science, Myeloma Research Laboratory, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
- Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia
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26
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Chanon S, Durand C, Vieille-Marchiset A, Robert M, Dibner C, Simon C, Lefai E. Glucose Uptake Measurement and Response to Insulin Stimulation in In Vitro Cultured Human Primary Myotubes. J Vis Exp 2017. [PMID: 28671646 DOI: 10.3791/55743] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Skeletal muscle is the largest glucose deposit in mammals and largely contributes to glucose homeostasis. Assessment of insulin sensitivity of muscle cells is of major relevance for all studies dedicated to exploring muscle glucose metabolism and characterizing metabolic alterations. In muscle cells, glucose transporter type 4 (GLUT4) proteins translocate to the plasma membrane in response to insulin, thus allowing massive entry of glucose into the cell. The ability of muscle cells to respond to insulin by increasing the rate of glucose uptake is one of the standard readouts to quantify muscle cell sensitivity to insulin. Human primary myotubes are a suitable in vitro model, as the cells maintain many features of the donor phenotype, including insulin sensitivity. This in vitro model is also suitable for the test of any compounds that could impact insulin responsiveness. Measurements of the glucose uptake rate in differentiated myotubes reflect insulin sensitivity. In this method, human primary muscle cells are cultured in vitro to obtain differentiated myotubes, and glucose uptake rates with and without insulin stimulation are measured. We provide a detailed protocol to quantify passive and active glucose transport rates using radiolabeled [3H] 2-deoxy-D-Glucose ([3H]2dG). Calculation methods are provided to quantify active basal and insulin-stimulated rates, as well as stimulation fold.
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Affiliation(s)
| | | | | | - Maud Robert
- Department of digestive and bariatric surgery, Obesity Integrated Center, University Hospital of Edouard Herriot, Hospices Civils de Lyon, Lyon 1 University
| | - Charna Dibner
- Division of Endocrinology, Diabetes, Hypertension and Nutrition, Department of Clinical Medicine, Faculty of Medicine, University of Geneva
| | - Chantal Simon
- CarMeN Laboratory, INSERM U1060, INRA 1397, University of Lyon
| | - Etienne Lefai
- CarMeN Laboratory, INSERM U1060, INRA 1397, University of Lyon;
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27
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Kokabu S, Nakatomi C, Matsubara T, Ono Y, Addison WN, Lowery JW, Urata M, Hudnall AM, Hitomi S, Nakatomi M, Sato T, Osawa K, Yoda T, Rosen V, Jimi E. The transcriptional co-repressor TLE3 regulates myogenic differentiation by repressing the activity of the MyoD transcription factor. J Biol Chem 2017; 292:12885-12894. [PMID: 28607151 DOI: 10.1074/jbc.m116.774570] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 06/08/2017] [Indexed: 11/06/2022] Open
Abstract
Satellite cells are skeletal muscle stem cells that provide myonuclei for postnatal muscle growth, maintenance, and repair/regeneration in adults. Normally, satellite cells are mitotically quiescent, but they are activated in response to muscle injury, in which case they proliferate extensively and exhibit up-regulated expression of the transcription factor MyoD, a master regulator of myogenesis. MyoD forms a heterodimer with E proteins through their basic helix-loop-helix domain, binds to E boxes in the genome and thereby activates transcription at muscle-specific promoters. The central role of MyoD in muscle differentiation has increased interest in finding potential MyoD regulators. Here we identified transducin-like enhancer of split (TLE3), one of the Groucho/TLE family members, as a regulator of MyoD function during myogenesis. TLE3 was expressed in activated and proliferative satellite cells in which increased TLE3 levels suppressed myogenic differentiation, and, conversely, reduced TLE3 levels promoted myogenesis with a concomitant increase in proliferation. We found that, via its glutamine- and serine/proline-rich domains, TLE3 interferes with MyoD function by disrupting the association between the basic helix-loop-helix domain of MyoD and E proteins. Our findings indicate that TLE3 participates in skeletal muscle homeostasis by dampening satellite cell differentiation via repression of MyoD transcriptional activity.
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Affiliation(s)
- Shoichiro Kokabu
- Divisions of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu 803-8580, Japan; Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan; Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115.
| | - Chihiro Nakatomi
- Divisions of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu 803-8580, Japan
| | - Takuma Matsubara
- Divisions of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu 803-8580, Japan
| | - Yusuke Ono
- Musculoskeletal Molecular Biology Research Group, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8102, Japan
| | - William N Addison
- Research Unit, Department of Human Genetics, Shriners Hospitals for Children, McGill University, Montreal, Quebec H4A 0A9, Canada
| | - Jonathan W Lowery
- Division of Biomedical Science, College of Osteopathic Medicine, Marian University, Indianapolis, Indiana 46222
| | - Mariko Urata
- Divisions of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu 803-8580, Japan
| | - Aaron M Hudnall
- Division of Biomedical Science, College of Osteopathic Medicine, Marian University, Indianapolis, Indiana 46222
| | - Suzuro Hitomi
- Division of Physiology, Kyushu Dental University, Kitakyushu 803-8580, Japan
| | - Mitsushiro Nakatomi
- Division of Anatomy, Department of Health Promotion, Kyushu Dental University, Kitakyushu 803-8580, Japan
| | - Tsuyoshi Sato
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
| | - Kenji Osawa
- Division of Oral Medicine, Department of Science of Physical Functions, Kyushu Dental University, Kitakyushu 803-8580, Japan
| | - Tetsuya Yoda
- Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan
| | - Vicki Rosen
- Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115
| | - Eijiro Jimi
- Divisions of Molecular Signaling and Biochemistry, Kyushu Dental University, Kitakyushu 803-8580, Japan; Oral Health Brain Health Total Health, Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan
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28
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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: 95] [Impact Index Per Article: 11.9] [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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29
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De Toni L, Di Nisio A, Rocca MS, De Rocco Ponce M, Ferlin A, Foresta C. Osteocalcin, a bone-derived hormone with important andrological implications. Andrology 2017; 5:664-670. [PMID: 28395130 DOI: 10.1111/andr.12359] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 02/08/2017] [Accepted: 02/19/2017] [Indexed: 01/01/2023]
Abstract
Increasing evidence disclosed the existence of a novel multi-organ endocrine pathway, involving bone, pancreas and testis, of high penetrance in energy metabolism and male fertility. The main mediator of this axis is undercarboxylated osteocalcin (ucOC), a bone-derived protein-exerting systemic effects on tissues expressing the metabotropic receptor GPRC6A. The recognized effects of ucOC are the improvement of insulin secretion from the pancreas, the amelioration of systemic insulin sensitivity, in particular in skeletal muscle, and the stimulation of the global endocrine activity of the Leydig cell, including vitamin D 25-hydroxylation and testosterone production. The supporting evidence of this circuit in both animal and human models is here reviewed, with particular emphasis on the role of ucOC on testis function. The possible pharmacological modulation of this hormonal circuit for therapeutic aims is also discussed.
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Affiliation(s)
- L De Toni
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
| | - A Di Nisio
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
| | - M S Rocca
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
| | - M De Rocco Ponce
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
| | - A Ferlin
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
| | - C Foresta
- Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy
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30
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Bonnet N. Bone-Derived Factors: A New Gateway to Regulate Glycemia. Calcif Tissue Int 2017; 100:174-183. [PMID: 27832316 DOI: 10.1007/s00223-016-0210-y] [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: 02/11/2016] [Accepted: 11/02/2016] [Indexed: 01/26/2023]
Abstract
Type 2 diabetes mellitus (T2DM) and osteoporosis are two major disorders which prevalence increases with aging and is predicted to worsen in the coming years. Preclinical investigations suggest common mechanisms implicated in the pathogenesis of both disorders. Recent evidence has established that there is a clear link between glucose and bone metabolism. The emergence of bone as an endocrine regulator through FGF23 and osteocalcin has led to the re-evaluation of the role of bone cells and bone-derived factors in the development of metabolic diseases such as T2DM. The development of bone morphogenetic proteins, fibroblast growth factor 23, and osteoprotegerin-deficient mice has allowed to elucidate their role in bone homeostasis, as well as revealed their potential important function in glucose homeostasis. This review proposes emerging perspectives for several bone-derived factors that may regulate glycemia through the activation or inhibition of bone remodeling or directly by regulating function of key organs such as pancreatic beta cell proliferation, insulin expression and secretion, storage and release of glucose from the liver, skeletal muscle contraction, and browning of the adipose tissue. Connections between organs including bone-derived factors should further be explored to understand the pathophysiology of glucose metabolism and diabetes.
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Affiliation(s)
- Nicolas Bonnet
- Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospitals and Faculty of Medicine, 64 Av de la Roseraie, 1205, Geneva 14, Switzerland.
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31
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Chakraborty S, Bhattacharyya R, Banerjee D. Infections: A Possible Risk Factor for Type 2 Diabetes. Adv Clin Chem 2017; 80:227-251. [PMID: 28431641 DOI: 10.1016/bs.acc.2016.11.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Diabetes mellitus is one of the biggest challenges to human health globally, with an estimated 95% of the global diabetic population having type 2 diabetes. Classical causes for type 2 diabetes, such as genetics and obesity, do not account for the high incidence of the disease. Recent data suggest that infections may precipitate insulin resistance via multiple mechanisms, such as the proinflammatory cytokine response, the acute-phase response, and the alteration of the nutrient status. Even pathogen products, such as lipopolysaccharide and peptidoglycans, can be diabetogenic. Therefore, we argue that infections that are known to contribute to insulin resistance should be considered as risk factors for type 2 diabetes.
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Affiliation(s)
- Surajit Chakraborty
- Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | | | - Dibyajyoti Banerjee
- Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
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32
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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: 21] [Impact Index Per Article: 2.6] [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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33
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Lin X, Hanson E, Betik AC, Brennan-Speranza TC, Hayes A, Levinger I. Hindlimb Immobilization, But Not Castration, Induces Reduction of Undercarboxylated Osteocalcin Associated With Muscle Atrophy in Rats. J Bone Miner Res 2016; 31:1967-1978. [PMID: 27291707 DOI: 10.1002/jbmr.2884] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/01/2016] [Accepted: 06/04/2016] [Indexed: 11/10/2022]
Abstract
Undercarboxylated osteocalcin (ucOC) has been implicated in skeletal muscle insulin sensitivity and function. However, whether muscle mass and strength loss in atrophic conditions is related to a reduction in ucOC is not clear. We hypothesized that both immobilization and testosterone depletion would lead to reductions in ucOC, associated with not only the degree of muscle atrophy but also changes to atrophy signaling pathway(s) in male rats. We subjected 8-week-old male Fischer (F344) rats to 7 days of hindlimb immobilization 10 days after castration surgery. Hindlimb immobilization, but not castration, resulted in a significant reduction in ucOC (30%) and lower ucOC was correlated with the degree of muscle loss and muscle weakness. ucOC levels, the expression of ucOC-sensitive receptor G protein-coupled receptor, class C, group 6, member A (GPRC6A), as well as the activity of extracellular signal-regulated kinase (ERK) and 5' adenosine monophosphate-activated protein kinase (AMPK) were associated with the expression and activity of a number of proteins in the mammalian target of rapamycin complex 1 (mTORC1) and Forkhead Box O (FOXO) signaling pathways in a muscle type-specific manner. These data suggest that ucOC may have other effects on skeletal muscle in addition to its insulin sensitizing effect. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Xuzhu Lin
- Clinical Exercise Science Research Program, Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Australia
| | - Erik Hanson
- Clinical Exercise Science Research Program, Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Australia.,College of Health and Biomedicine, Victoria University, Melbourne, Australia
| | - Andrew C Betik
- Clinical Exercise Science Research Program, Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Australia.,College of Health and Biomedicine, Victoria University, Melbourne, Australia
| | - Tara C Brennan-Speranza
- Department of Physiology and Bosch Institute for Medical Research, University of Sydney, Australia
| | - Alan Hayes
- Clinical Exercise Science Research Program, Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Australia.,College of Health and Biomedicine, Victoria University, Melbourne, Australia.,Australian Institute for Musculoskeletal Science, Western Health, Melbourne, Australia
| | - Itamar Levinger
- Clinical Exercise Science Research Program, Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, Australia
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34
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Qi Z, Liu W, Lu J. The mechanisms underlying the beneficial effects of exercise on bone remodeling: Roles of bone-derived cytokines and microRNAs. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2016; 122:131-139. [PMID: 27179638 DOI: 10.1016/j.pbiomolbio.2016.05.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/02/2016] [Accepted: 05/07/2016] [Indexed: 12/31/2022]
Abstract
Bone remodeling is highly dynamic and complex in response to mechanical loading, such as exercise. In this review, we concluded that a number of individual factors are disturbing the clinical effects of exercise on bone remodeling. We updated the progress made on the differentiation of osteoblasts and osteoclasts in response to mechanical loading, hoping to provide a theoretical basis to improve bone metabolism with exercise. Increasing evidences indicate that bone is not only a structural scaffold but also an endocrine organ, which secretes osteocalcin and FGF23. Both of them have been known as a circulating hormone to promote insulin sensitivity and reduce body fat mass. The effects of exercise on these bone-derived cytokines provide a better understanding of how exercise-induced "osteokine" affects the whole-body homeostasis. Additionally, we discussed recent studies highlighting the post-transcriptional regulation of microRNAs in bone remodeling. We focus on the involvement of the microRNAs in osteoblastogenesis and osteoclastogenesis, and suggest that microRNAs may be critical for exercise-induced bone remodeling.
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Affiliation(s)
- Zhengtang Qi
- The Key Laboratory of Adolescent Health Assessment and Exercise Intervention (East China Normal University), Ministry of Education, Shanghai 200241, China; School of Physical Education and Health, East China Normal University, Shanghai 200241, China
| | - Weina Liu
- The Key Laboratory of Adolescent Health Assessment and Exercise Intervention (East China Normal University), Ministry of Education, Shanghai 200241, China; School of Physical Education and Health, East China Normal University, Shanghai 200241, China.
| | - Jianqiang Lu
- School of Kinesiology, Shanghai University of Sport, Shanghai 200438, China.
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35
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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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36
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Pi M, Kapoor K, Ye R, Nishimoto SK, Smith JC, Baudry J, Quarles LD. Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells. Endocrinology 2016; 157:1866-80. [PMID: 27007074 PMCID: PMC4870875 DOI: 10.1210/en.2015-2010] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic β-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. Computational models probe the structural basis of Ocn binding to GPRC6A and predict that the C-terminal hexapeptide docks to the extracellular side of the transmembrane domain of GPRC6A. Consistent with the modeling, mutations in the computationally identified binding pocket of GPRC6A reduced Ocn and C-terminal hexapeptide activation of this receptor. In addition, selective deletion of Gprc6a in β-cells (Gprc6a(β)(-cell-cko)) by crossing Gprc6a(flox/flox) mice with Ins2-Cre mice resulted in reduced pancreatic weight, islet number, insulin protein content, and insulin message expression. Both islet size and β-cell proliferation were reduced in Gprc6a(β)(-cell-cko) compared with control mice. Gprc6a(β)(-cell-cko) exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6a(β)(-cell-cko) mice showed reduced insulin simulation index in response to Ocn. These data establish the structural basis for Ocn direct activation of GPRC6A and confirm a role for GPRC6A in regulating β-cell proliferation and insulin secretion.
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Affiliation(s)
- Min Pi
- Departments of Medicine (M.P., R.Y., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S.), University of Tennessee, Knoxville, Tennessee 37996
| | - Karan Kapoor
- Departments of Medicine (M.P., R.Y., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S.), University of Tennessee, Knoxville, Tennessee 37996
| | - Ruisong Ye
- Departments of Medicine (M.P., R.Y., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S.), University of Tennessee, Knoxville, Tennessee 37996
| | - Satoru Kenneth Nishimoto
- Departments of Medicine (M.P., R.Y., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S.), University of Tennessee, Knoxville, Tennessee 37996
| | - Jeremy C Smith
- Departments of Medicine (M.P., R.Y., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S.), University of Tennessee, Knoxville, Tennessee 37996
| | - Jerome Baudry
- Departments of Medicine (M.P., R.Y., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S.), University of Tennessee, Knoxville, Tennessee 37996
| | - Leigh Darryl Quarles
- Departments of Medicine (M.P., R.Y., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.K.N.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S.), University of Tennessee, Knoxville, Tennessee 37996
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37
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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: 23] [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: 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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Kanazawa I. Osteocalcin as a hormone regulating glucose metabolism. World J Diabetes 2015; 6:1345-1354. [PMID: 26722618 PMCID: PMC4689779 DOI: 10.4239/wjd.v6.i18.1345] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 10/23/2015] [Accepted: 12/02/2015] [Indexed: 02/05/2023] Open
Abstract
The number of patients with osteoporosis and diabetes is rapidly increasing all over the world. Bone is recently recognized as an endocrine organ. Accumulating evidence has shown that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, regulates glucose homeostasis by stimulating insulin expression in pancreas and adiponectin expression in adipocytes, resulting in improving glucose intolerance. On the other hand, insulin and adiponectin stimulate osteocalcin expression in osteoblasts, suggesting that positive feedforward loops exist among bone, pancreas, and adipose tissue. In addition, recent studies have shown that osteocalcin enhances insulin sensitivity and the differentiation in muscle, while secreted factors from muscle, myokines, regulate bone metabolism. These findings suggest that bone metabolism and glucose metabolism are associated with each other through the action of osteocalcin. In this review, I describe the role of osteocalcin in the interaction among bone, pancreas, brain, adipose tissue, and muscle.
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Pi M, Kapoor K, Wu Y, Ye R, Senogles SE, Nishimoto SK, Hwang DJ, Miller DD, Narayanan R, Smith JC, Baudry J, Quarles LD. Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues. Mol Endocrinol 2015; 29:1759-73. [PMID: 26440882 DOI: 10.1210/me.2015-1161] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
G protein-coupled receptor (GPCR) family C group 6 member A (GPRC6A) is a multiligand GPCR that is activated by cations, L-amino acids, and osteocalcin. GPRC6A plays an important role in the regulation of testosterone (T) production and energy metabolism in mice. T has rapid, transcription-independent (nongenomic) effects that are mediated by a putative GPCR. We previously found that T can activate GPRC6A in vitro, but the possibility that T is a ligand for GPRC6A remains controversial. Here, we demonstrate direct T binding to GPRC6A and construct computational structural models of GPRC6A that are used to identify potential binding poses of T. Mutations of the predicted binding site residues were experimentally found to block T activation of GPRC6A, in agreement with the modeling. Using Gpr6ca(-/-) mice, we confirmed that loss of GPRC6A resulted in loss of T rapid signaling responses and elucidated several biological functions regulated by GPRC6A-dependent T rapid signaling, including T stimulation of insulin secretion in pancreatic islets and enzyme expression involved in the biosynthesis of T in Leydig cells. Finally, we identified a stereo-specific effect of an R-isomer of a selective androgen receptor modulator that is predicted to bind to and shown to activate GPRC6A but not androgen receptor. Together, our data show that GPRC6A directly mediates the rapid signaling response to T and uncovers previously unrecognized endocrine networks.
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Affiliation(s)
- Min Pi
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Karan Kapoor
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Yunpeng Wu
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Ruisong Ye
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Susan E Senogles
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Satoru K Nishimoto
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Dong-Jin Hwang
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Duane D Miller
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Ramesh Narayanan
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Jeremy C Smith
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - Jerome Baudry
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
| | - L Darryl Quarles
- Departments of Medicine (M.P., Y.W., R.Y., R.N., L.D.Q.) and Microbiology, Immunology and Biochemistry (S.E.S., S.K.N.), and Pharmaceutical Sciences (D.-J.H., D.D.M.), College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163; University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics (K.K., J.C.S., J.B.), Oak Ridge, Tennessee 37830; and Department of Biochemistry and Cellular and Molecular Biology (J.C.S., J.B.), University of Tennessee, Knoxville, Tennessee 37996
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