1. Severance Institute for Vascular & Metabolic Research Serum Osteocalcin is Involved in the Pathogenesis of Exercise-Induced Improvements in Adiposity and Glucose Homeostasis Yu-Sik Kim 2014.10.25

2. Severance Institute for Vascular & Metabolic Research Nature Reviews Drug Discovery 8, 386-398, 2009 Endocrine and Neuroendocrine Regulation of Glucose Homeostasis Insulin Action in Glucose Homeostasis Cell Metabolism 11(1), 23-34, 2010 Liver Nature 410, 944-948, 2001 Skeletal Muscle

3. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Adipose Tissue adipokine Adipose tissue secretes more than 600 bioactive molecules (adipokine) Mol Metabolism 3, 230-240, 2014 Some may play important roles in the regulation of glucose homeostasis, these include - leptin, adiponectin, resistin, vaspin, chemerin, visfatin, apelin….

4. Nature Reviews Endocrinology 8, 457-65, 2012 Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Skeletal Muscle New Paradigm: Skeletal Muscle as an ‘Secretory Organ’ which exerts auto/paracrine and endocrine effects Myokines Myokine Concept: The beneficial effects of exercise is, to some extent, ascribed to exercise-hormones, Myokines Some myokines may play roles in the prevention of insulin resistance and associated metabolic status - BDNF, IL-6, IL-13, IL-15, FGF-21, fractalkine…and irisin

5. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Bone New Paradigm: Bone as an ‘Endocrine Organ’ which exerts metabolic effects on various targets Multiple metabolic effects involving glucose disposal, insulin secretion, and lipid metabolism Cell 130, 456-69, 2007 The metabolic functions of bone is mediated by osteocalcin (OC) Mice lacking Esp gene (coding OST-PTP) were characterized by I.High serum uc OC levels without affecting bone formation II.Better glycemic control & protection from obesity Serendipity !!!

6. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Bone Osteocalcin (OC) A non-collagenous protein ( 49 AA long, in mature ) produced by osteoblasts Build up within bones with hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ) A classic biomarker for bone health (serum OC levels are well correlated with BMD) Contains 3 glutamate (Glu) residues at 17, 21, 24 for γ carboxylation Carboxylated OC ( c OC) have a high affinity for Ca 2 + Uncarboxylated OC ( uc OC) are susceptible to be released OC in circulation (both c OC and uc OC) is reported to have hormonal functions in metabolism Circulating OC appears in both c OC and uc OC form Bone Resoption Secretion

7. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Bone Osteocalcin (OC) OC ( uc OC) regulates glycemic control by enhancing insulin sensitivity, and insulin secretion PNAS (105), 5266-70, 2008 Cell (130), 456-69, 2007

8. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Bone Osteocalcin (OC) OC ( uc OC) reduced fat deposition and increased skeletal muscle mitochondria Cell (130), 456-69, 2007 28 Days of Deliver PNAS (105), 5266-70, 2008 Cell (130), 456-69, 2007

9. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Bone Plasma OC is inversely related to plasma glucose in 1010 elderly men - JBMR 24(5), 785-91, 2009

10. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Bone Elevated total OC and c OC were associated with higher HOMA-IR in 384 elderly Am J Clin Nutr 2009;90:1230–5 OC may function in glucose metabolism; uc OC does not appear to influence HOMA-IR in humans

11. Severance Institute for Vascular & Metabolic Research Endocrine Regulation of Glucose Homeostasis by Endocrine Regulation of Glucose Homeostasis by Bone Both c OC and uc OC were associated with improved glucose tolerance (FPG, 2h-Glu) in 199 middle-aged males c OC was associated with enhanced β-cell function; uc OC was associated with HOMA-IR Diabetes Metab Res Rev 25, 768–772, 2009 OC may function in glucose metabolism in humans

12. Severance Institute for Vascular & Metabolic Research Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control? Diet (500 Kcal/day) plus regular exercise (RT 2 x / wk for 16 wk) induced significant increase in serum OC, which increased in parallel to reduced visceral fat mass, and increased leg strength and force in 149 middle aged men

13. Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control? Severance Institute for Vascular & Metabolic Research Acute aerobic exercise (75% VO 2max ), but power exercise (75% 1RM), significantly increased uc OC in obese middle aged men

14. Severance Institute for Vascular & Metabolic Research Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control? Osteocalcin and Glucose Metabolism in Postmenopausal Women Subjected to Aerobic Training Program for 8 Weeks Participants matched for age, body mass, and BMI 40 min at 70% to 80% VO 2max, 3 x / week Inverse correlations between serum OC levels and metabolic markers; regular physical activity was associated with decrease in OC levels

15. Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control? Severance Institute for Vascular & Metabolic Research What Regulates OC synthesis and OC secretion ??? Can Exercise Regulate OC synthesis and OC secretion ???

16. Severance Institute for Vascular & Metabolic Research Leptin Regulation on Bone Metabolism and Osteocalcin Cell 138, 976-89, 2009 Peptide 30, 967-73, 2009 Beneficial effects of leptin on bone growth involve hypothalamic relay that increases osteogenic activity

17. Severance Institute for Vascular & Metabolic Research Leptin Regulation on Bone Metabolism and Osteocalcin Endocrinology 148(7), 3419-25, 2007 High dose leptin administration (14 days) induced significant lower OC contents in Wistar rat Ann N Y Acad Sci 1192(1), 292-7, 2010 PNAS 101(9), 3256-63, 2004 Chronic elevation of leptin attenuates bone formation and OC secretion

18. Leptin Regulations on Bone Metabolism and Osteocalcin Severance Institute for Vascular & Metabolic Research J Clin Endocrinol Metab 96(6), E884-90, 2011 Structural Equation Modeling (SEqM): - A direct inverse association of leptin with osteocalcin - Interrelationships among age, sex, BMI, leptin, osteocalcin, adiponectin, HOMA 2 -IR, and ISI

19. Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control? Severance Institute for Vascular & Metabolic Research Int J Endocrinol 23, 1-28, 2013

20. How can Exercise Improve Glycemic Control by Osteocalcin? Severance Institute for Vascular & Metabolic Research Exercise

21. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures The effects of reduced body fat following 8-week aerobic exercise training on serum c OC and uc OC levels and the associations of these changes with leptin and metabolic parameters among normoglycemic obese young males.

22. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures 39 Obese Young Normoglycemic Males (Age: 25.31 ± 2.83 yr; BMI: 28.41 ± 2.36; % body fat: 27.18 ± 2.52; WC: 100.1 ± 4.60 cm) C (n=10) Ex (n=29) 8-wk supervised A.E 65-75% VO 2max 600 Kcal / 4 x per wk / 8 wk Normal lives Anthropometric Measures (BMI, % body fat, % trunk fat, WC) Glycemic Measures (FPG, Insulin, HOMA-IR, 2h OGTT) Bone Metabolism ( c OC, uc OC, BMD, Bone-specific ALP, 1,25 D 3 ) Adipokines (Leptin, Adiponectin, HMW Adiponectin)

23. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures

24. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures

25. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures Association_Δ Total OC_ Δ Anthropometric Measures

26. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures Association_ Δ ucOC_ Δ Anthropometric Measures

27. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures Association_ Δ OCs_ Δ Leptin

28. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures Association_ Δ OCs_ Δ HOMA-IR In multiple linear regression with Δ in total adiponectin, HMW%, and/or anthropometric measures, OC was not an independent predictor for HOMA-IR

29. Severance Institute for Vascular & Metabolic Research The Effects of Aerobic Exercise on Serum OC and Glycemic Measures Summary Body fat reduction following aerobic exercise significantly increased serum levels of total and uncarboxylated osteocalcin The increase in osteocalcin was in negative correlations with changes in obesity measures as well as leptin and HOMA-IR In a physiologic axis of bone-fat-energy metabolism, exercise-induced body fat reduction and improved insulin sensitivity were accompanied by an increase in serum osteocalcin

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