severance institute for vascular & metabolic research serum osteocalcin is involved in the...

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


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


Endocrine Regulation of Glucose Homeostasis by Adipose Tissue

• 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….

Nature Reviews Endocrinology 8, 457-65, 2012


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


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 ucOC levels without affecting bone formation

II. Better glycemic control & protection from obesity Serendipity !!!



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

• OC in circulation (both cOC and ucOC) is reported to have hormonal functions in metabolism

• Circulating OC appears in both cOC and ucOC form

Bone Resoption

Secretion



Osteocalcin (OC)

• OC (ucOC) regulates glycemic control by enhancing insulin sensitivity, and insulin secretion

PNAS (105), 5266-70, 2008

Cell (130), 456-69, 2007



Osteocalcin (OC)

• OC (ucOC) 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



• Plasma OC is inversely related to plasma glucose in 1010 elderly men - JBMR 24(5), 785-91, 2009



• Elevated total OC and cOC were associated with higher HOMA-IR in 384 elderly

Am J Clin Nutr 2009;90:1230–5

OC may function in glucose metabolism; ucOC does not appear to influence HOMA-IR in humans



• 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

Diabetes Metab Res Rev 25, 768–772, 2009

OC may function in glucose metabolism in humans


Can Exercise Increase Serum Osteocalcin and Improve Glycemic Control?

• 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



• Acute aerobic exercise (75% VO2max), but power exercise (75% 1RM), significantly increased ucOC in obese middle

aged men



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



• What Regulates OC synthesis and OC secretion ???

• Can Exercise Regulate OC synthesis and OC secretion ???


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


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, 2010PNAS 101(9), 3256-63, 2004

• Chronic elevation of leptin attenuates bone formation and OC secretion

Leptin Regulations on Bone Metabolism and Osteocalcin


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, HOMA2-IR, and ISI



Int J Endocrinol 23, 1-28, 2013

Int J Endocrinol 23, 1-28, 2013

How can Exercise Improve Glycemic Control by Osteocalcin?


Exercise


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.



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% VO2max

600 Kcal / 4x per wk / 8 wk

• Normal lives

• Anthropometric Measures (BMI, % body fat, % trunk fat, WC)

• Glycemic Measures (FPG, Insulin, HOMA-IR, 2h OGTT)

• Bone Metabolism (cOC, ucOC, BMD, Bone-specific ALP, 1,25 D3)

• Adipokines (Leptin, Adiponectin, HMW Adiponectin)



Association_Δ Total OC_ Δ Anthropometric Measures



Association_ Δ ucOC_ Δ Anthropometric Measures



Association_ Δ OCs_ Δ Leptin



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



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 re-

duction and improved insulin sensitivity were accompanied by an increase in

serum osteocalcin

Thank You for Your Participation~!!!

severance institute for vascular & metabolic research serum osteocalcin is involved in the...

Documents

bone osteocalcin oc

uncarboxylated oc uc

glucose disposal

endocrine organ

severance institute

osteocalcin oc mice

metabolic functions

glucose homeostasis