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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
Severance Institute for Vascular & Metabolic Research
Endocrine and Neuroendocrine Regulation of Glucose Homeostasis
Insulin Action in Glucose Homeostasis
Cell Metabolism
Nature 410,
11(1),
944-948,
23-34,2001
2010
Skeletal
Liver
Muscle
Nature Reviews Drug Discovery 8, 386-398, 2009
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Adipose Tissue
•
Adipose tissue secretes more than 600 bioactive molecules (adipokine)
•
Some may play important roles in the regulation of glucose homeostasis, these include
- leptin, adiponectin, resistin, vaspin, chemerin, visfatin, apelin….
Mol Metabolism 3, 230-240, 2014
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Skeletal Muscle
•
New Paradigm: Skeletal Muscle as an ‘Secretory Organ’ which exerts auto/paracrine and endocrine effects
•
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
Nature Reviews Endocrinology 8, 457-65, 2012
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Bone
Cell 130, 456-69, 2007
•
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
•
The metabolic functions of bone is mediated by osteocalcin (OC)

Mice lacking Esp gene (coding OST-PTP) were characterized by
I.
High serum ucOC levels without affecting bone formation
II. Better glycemic control & protection from obesity
Serendipity !!!
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Bone
Osteocalcin (OC)
•
A non-collagenous protein (49AA long, in mature) produced by osteoblasts
•
Build up within bones with hydroxyapatite (Ca10(PO4)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 (cOC) have a high affinity for Ca2+

Uncarboxylated OC (ucOC) are susceptible to be released
Secretion
•
Circulating OC appears in both cOC and ucOC form
Bone Resoption
•
OC in circulation (both cOC and ucOC) is reported to have hormonal functions in metabolism
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Bone
Osteocalcin (OC)
•
OC (ucOC) regulates glycemic control by enhancing insulin sensitivity, and insulin secretion
Cell (130), 456-69, 2007
PNAS (105), 5266-70, 2008
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Bone
Osteocalcin (OC)
•
OC (ucOC) reduced fat deposition and increased skeletal muscle mitochondria
28 Days of Deliver
Cell (130), 456-69, 2007
PNAS (105), 5266-70, 2008
Cell (130), 456-69, 2007
Severance Institute for Vascular & Metabolic Research
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
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Bone
•
Elevated total OC and cOC were associated with higher HOMA-IR in 384 elderly
 OC may function in glucose metabolism; ucOC does not appear to influence HOMA-IR in humans
Am J Clin Nutr 2009;90:1230–5
Severance Institute for Vascular & Metabolic Research
Endocrine Regulation of Glucose Homeostasis by Bone
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Both cOC and ucOC were associated with improved glucose tolerance (FPG, 2h-Glu) in 199 middle-aged males
 cOC was associated with enhanced β-cell function; ucOC was associated with HOMA-IR
 OC may function in glucose metabolism in humans
Diabetes Metab Res Rev 25, 768–772, 2009
Severance Institute for Vascular & Metabolic Research
Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control?
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Diet (500 Kcal/day) plus regular exercise (RT 2x / 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
Severance Institute for Vascular & Metabolic Research
Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control?
•
Acute aerobic exercise (75% VO2max), but power exercise (75% 1RM), significantly increased ucOC in obese middle
aged men
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% VO2max, 3x / week
•
Inverse correlations between serum OC levels and metabolic markers; regular physical activity was associated with
decrease in OC levels
Severance Institute for Vascular & Metabolic Research
Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control?
• What Regulates OC synthesis and OC secretion ???
• Can Exercise Regulate OC synthesis and OC secretion ???
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
Severance Institute for Vascular & Metabolic Research
Leptin Regulation on Bone Metabolism and Osteocalcin
Endocrinology 148(7), 3419-25, 2007
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High dose leptin administration (14 days) induced significant lower OC contents in Wistar rat
PNAS 101(9), 3256-63, 2004
•
Ann N Y Acad Sci 1192(1), 292-7, 2010
Chronic elevation of leptin attenuates bone formation and OC secretion
Severance Institute for Vascular & Metabolic Research
Leptin Regulations on Bone Metabolism and Osteocalcin
J Clin Endocrinol Metab 96(6), E884-90, 2011
Structural Equation Modeling (SEqM):
- Interrelationships among age, sex, BMI, leptin, osteocalcin, adiponectin, HOMA2-IR, and ISI
- A direct inverse association of leptin with osteocalcin
Severance Institute for Vascular & Metabolic Research
Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control?
Int J Endocrinol 23, 1-28, 2013
Int J Endocrinol 23, 1-28, 2013
Severance Institute for Vascular & Metabolic Research
How can Exercise Improve Glycemic Control by Osteocalcin?
Exercise
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 cOC and ucOC levels and the associations of these changes with
leptin and metabolic parameters among normoglycemic obese young males.
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
•
Normal lives
Ex
(n=10)
•
(n=29)
8-wk supervised A.E
 65-75% VO2max
 600 Kcal / 4x per wk / 8 wk
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Anthropometric Measures (BMI, % body fat, % trunk fat, WC)
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Glycemic Measures (FPG, Insulin, HOMA-IR, 2h OGTT)
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Bone Metabolism (cOC, ucOC, BMD, Bone-specific ALP, 1,25 D3)
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Adipokines (Leptin, Adiponectin, HMW Adiponectin)
Severance Institute for Vascular & Metabolic Research
The Effects of Aerobic Exercise on Serum OC and Glycemic Measures
Severance Institute for Vascular & Metabolic Research
The Effects of Aerobic Exercise on Serum OC and Glycemic Measures
Severance Institute for Vascular & Metabolic Research
The Effects of Aerobic Exercise on Serum OC and Glycemic Measures
Association_Δ Total OC_ Δ Anthropometric Measures
Severance Institute for Vascular & Metabolic Research
The Effects of Aerobic Exercise on Serum OC and Glycemic Measures
Association_ Δ ucOC_ Δ Anthropometric Measures
Severance Institute for Vascular & Metabolic Research
The Effects of Aerobic Exercise on Serum OC and Glycemic Measures
Association_ Δ OCs_ Δ Leptin
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
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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