Seminar 08-10-2008 - effects of bone on fat mass

Montreal 2008Montreal 2008

Effects of bone on fat Effects of bone on fat massmass

Highlights ASBMR, part Highlights ASBMR, part 22

Montreal 2008Montreal 2008

Effects of bone on fat Effects of bone on fat massmass

Highlights ASBMR, part Highlights ASBMR, part 22

Dr. E. van der VeerDr. E. van der Veer

University Medical Center GroningenUniversity Medical Center Groningen

Utrecht, Oct 8Utrecht, Oct 8TH TH 20082008

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Effects of Effects of fat massfat mass on on boneboneEffects of Effects of fat massfat mass on on bonebone Fat mass imposes mechanical stress on boneFat mass imposes mechanical stress on bone Adipocytes secretes biologically active moleculesAdipocytes secretes biologically active molecules

EstrogenEstrogen ResistinResistin LeptinLeptin Adiponectin Adiponectin Interleukin – 6 (IL-6)Interleukin – 6 (IL-6)

Pancreas secretes bone-active hormonesPancreas secretes bone-active hormones InsulinInsulin AmylinAmylin PreptinPreptin

Adipocytes and osteoblasts have common progenitor, Adipocytes and osteoblasts have common progenitor, the pluripotent mesenchymal stem cellthe pluripotent mesenchymal stem cell

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Osteoblasts and Osteoblasts and adipocytes adipocytes

originate from originate from common common

progenitor-progenitor-mesenchymal stem mesenchymal stem

cellscells

Osteoblasts and Osteoblasts and adipocytes adipocytes

originate from originate from common common

progenitor-progenitor-mesenchymal stem mesenchymal stem

cellscells

Rosen et al 2006

Zhao et al 2008

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Effects of Effects of bonebone on on fatfat massmassEffects of Effects of bonebone on on fatfat massmassHormones that regulate fat/glucose metabolism have

effects on the skeleton,

But does bone regulate the energy homeostasis?

Mice with increased levels of uncarboxylated osteocalcin (uOC) are protected from type 2 diabetes regulating adiponectin secretion,

Mice lacking osteocalcin display decreased B-cell proliferation, glucose intolerance and insulin resistance

(Lee NG et al, Cell 2007,130:458).

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Effects of Effects of bonebone on on fat massfat massEffects of Effects of bonebone on on fat massfat mass SA 444 SA 444 Osteocalcin and ObesityOsteocalcin and Obesity SpagnoliSpagnoli

Obese and Post Gastric By-pass patientsObese and Post Gastric By-pass patients

SU 461SU 461 Osteocalcin and type II DiabetesOsteocalcin and type II Diabetes NguyenNguyenMen aged 60+

SU 459SU 459 Osteocalcin and Fat Mass /Glucose KindblomElderly Swedish Men

SU 225SU 225 Osteocalcin gene and Osteocalcin gene and Body Fat MassBody Fat Mass McGuiganMcGuiganElderly Swedish WomenElderly Swedish Women

SA 198SA 198 Osteocalcin and Carotid Plaques / Metabolic Syndrome Waern

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OsteocalcinOsteocalcinOsteocalcinOsteocalcinProtein of 49 amino acidsProtein of 49 amino acids

3 glutamin residues3 glutamin residues

After carboxylation of the After carboxylation of the

GLU-residues binding to hydroxyapatiteGLU-residues binding to hydroxyapatite

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VITAMIN K CYCLEVITAMIN K CYCLE..VITAMIN K CYCLEVITAMIN K CYCLE..

ORAL ANTICOAGULANTS INHIBIT THE RECYCLING OF VITAMIN K

‘Inactive’ OSTEOCALCIN

OSTEOCALCIN

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Seeman et al. NEJM 2006

Bone turnoverBone turnover

PINPBALPOsteocalcine

CTxCrosslinks

TRAP

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Effects of Effects of bonebone on on fat massfat massEffects of Effects of bonebone on on fat massfat mass SA 444 SA 444 Osteocalcin and ObesityOsteocalcin and Obesity SpagnoliSpagnoli

Obese and Post Gastric By-pass patientsObese and Post Gastric By-pass patients

SU 461SU 461 Osteocalcin and type II DiabetesOsteocalcin and type II Diabetes NguyenNguyenMen aged 60+

SU 459SU 459 Osteocalcin and Fat Mass /Glucose KindblomElderly Swedish Men

SU 225SU 225 Osteocalcin gene and Osteocalcin gene and Body Fat MassBody Fat Mass McGuiganMcGuiganElderly Swedish WomenElderly Swedish Women

SA 198SA 198 Osteocalcin and Carotid Plaques / Metabolic Syndrome Waern

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Background:In obese patients with diabetes, gastric bypass surgery (GBS) through unknown mechanisms, leads to ~90% resolution of type 2 diabetes before any significant weight loss occurs.

SA 444 SA 444 Osteocalcin and ObesityOsteocalcin and ObesitySpagnoliSpagnoli


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Study is designed to determine: 1) uOC levels in obese patients with and without diabetes 2) the effect of Gastric By-pass Surgery on uOC

3) the relationship of uOC with adiponectin and in turn with insulin sensitivity.

SA 444 SA 444 Osteocalcin and ObesityOsteocalcin and Obesity

SpagnoliSpagnoli SA 444 SA 444 Osteocalcin and ObesityOsteocalcin and Obesity

SpagnoliSpagnoli

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40 obese patients (BMI: 48.5±9.7 kg/m2)

- 19 had type 2 diabetes,- 12 patients that had GBS 12-24 months prior to the study (post-GBS)

(BMI: 29±7 kg/m2); - 16 normal weight age-matched control subjects (BMI: 25±3.3 kg/m2).

Measured:glucose and insulin to determine HOMA, (Homeostatic model assessment

for quantifying insulin resistance) serum total and uncarboxylated osteocalcin, serum HMW-adiponectin by RIA or IRMA.



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SA 444 SA 444 Osteocalcin and Osteocalcin and ObesityObesity

SpagnoliSpagnoli

SA 444 SA 444 Osteocalcin and Osteocalcin and ObesityObesity

SpagnoliSpagnoli

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Inverse correlation was found between:uOC and HMW-adiponectin r = -0.28 p=0.02 uOC and HOMA r = -0.33 p=0.006 HMW-adiponectin and HOMA r = -0.32 p=0.008

ConclusionIn obese patients uOC levels are decreased, and normalize post-GBS.

These data support the hypothesis that uOC is a bone hormone that regulates insulin sensitivity by modulating adiponectin.

Spagnoli et al postulate that normalization of uOC is a mechanism for diabetes resolution post-GBS.



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Effects of Effects of bonebone on on fat massfat massEffects of Effects of bonebone on on fat massfat mass SA 444 Osteocalcin and Obesity Spagnoli

Obese and Post Gastric By-pass patients

SU 461 Osteocalcin and type II Diabetes Nguyen

Men aged 60+

SU 459 Osteocalcin and Fat Mass /Glucose Kindblom

Elderly Swedish Men

SA 198 Osteocalcin and Carotid Plaques / Metabolic Syndrome Waern

SU 225 Osteocalcin gene and Body Fat Mass McGuigan

Elderly Women

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SU 461 Osteocalcin and type II DiabetesNguyen


Background: Serum osteocalcin (OC), a 49-amino acid bone matrix protein, has

recently been shown to be associated with diabetes in mice. However, it is unknown whether the association is present in men.

Aim: Therefore, this study sought to examine the contribution of OC to the

susceptibility of type II diabetes in men

ASBMRSerum OC, sex hormone binding globulin (SHBG), 25(OH)D, and PTH were measured by radioimmunoassay in 443 men aged 60+ at baseline (1989) in the Dubbo Osteoporosis Epidemiology Study. The men’s health status, including fracture and diabetes, had been monitored between 1989 and 2007. Bone mineral density (BMD), clinical risk factors, and lifestyle factors had also been obtained at baseline and subsequent biannual visits.

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Conclusion Osteocalcin and serum testosteron were independent

risk factors for type II diabetes Thus, these data suggest that lower osteocalcin were

associated with an increased risk of type II diabetes in men.

The use of serum OC may help improve the prognostic accuracy of type II diabetes in men.

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Elderly Swedish Men



Elderly Women

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Background: Osteocalcin affect adiposity and glucose homeostasis in

mice, suggesting that the skeleton via an endocrine mechanism influences energy metabolism.

Aim: To investigate the relationship between plasma

osteocalcin and parameters reflecting fat mass and glucose homeostasis in humans.


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Methods:Methods:1010 elderly men (75.3± 3.2 years) of the MrOS Sweden study, 1010 elderly men (75.3± 3.2 years) of the MrOS Sweden study,

non-diabetic n= 857 non-diabetic n= 857 diabetic n= 153. diabetic n= 153.

Fasting levels were analysed of Fasting levels were analysed of plasma osteocalcin, plasma osteocalcin, plasma glucose, plasma glucose, serum insulin and serum insulin and lipidslipids

Fat mass and lean mass were analysed using dual energy X-ray Fat mass and lean mass were analysed using dual energy X-ray absorptiometry. absorptiometry.

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BMI

Total body fat

Glucose

(fasting)

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Pearson’s correlation coefficients for associations with Osteocalcin

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PINPPINP is strongly associated with is strongly associated with OsteocalcinOsteocalcin

Pearson’s r = 0.66Pearson’s r = 0.66

Both bone formation markers were included together as Both bone formation markers were included together as covariates in linear regression models:covariates in linear regression models:

OC was independently predicting glucose and fat mass,OC was independently predicting glucose and fat mass,

but PINP not.but PINP not.

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Conclusion:Conclusion: Osteocalcin is a negative predictor of fat mass and Osteocalcin is a negative predictor of fat mass and

plasma glucose in elderly menplasma glucose in elderly men In contrast, PINP is not an independent predictor In contrast, PINP is not an independent predictor

These human data support recently published These human data support recently published experimental studies, revealing endocrine functions of experimental studies, revealing endocrine functions of osteoblast-derived osteocalcin on glucose and fat osteoblast-derived osteocalcin on glucose and fat homeostasis.homeostasis.

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Elderly Swedish Men


Elderly Swedish Women


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SU 225 Osteocalcin gene and Body Fat MassMcGuigan


Aim: To determine the relationship between variation in the

osteocalcin gene with bone density, fracture and body fat parameters

Methods: 1044 elderly women all 75 years old at baseline

Follow-up 9 years

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4 SNPs around Osteocalcin locus on Chr 1,including rs1800247 located in the promoter rs 2842880 in intron 13

rs 933489 in intron 14

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• Osteocalcin SNP’s were associated with % total body fat at baseliners1800247 located in the promoter (p=0.045)rs 2842880 in intron 13 (p=0.009)

• No longer significant after correction for height

Changes in body fat between baseline and 5 years follow-up

The heterozygotes appeared to loose the most fat mass.

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Conclusion: The variation in the osteocalcin gene is linked both to

BMD and to fracture in elderly Caucasian women

Interestingly, we can not exclude an independent influence of the variation in the osteocalcin gene on changes in fat mass

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Elderly Swedish Men


Elderly Swedish Women


Elderly

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Aim:To investigate the relationship between

osteocalcin and indicators of the metabolic syndrome

Methods: 619 randomly selected 70 years old men and women longitudinal study with examinations at age 70, 76 och 86

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Results• Osteocalcin increased by 44 percent from 70 to 86 years of age.

This increase was related to, but independent of, declining kidney function (cystatin C) increasing PTH.

• Inverse correlation was found between:OC and BMDOC and BMIin both sexes at all ages investigated (P<0.05).

OC adjusted for BMI:OC and insulin r = -0.11 p<0.01OC and glucose r = -0.25 p<0.0001

A multiple regression model (diabetes excluded) with osteocalcin as dependent variable showed that glucose, (but not insulin), waist circumference and BMD were independent indirect predictors While PTH, cystatin C and ALP were independent direct predictors of osteocalcin (p <0.001).



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OC was inversely related to the risk of having bilateral carotoid plaques (OR per SD increase in osteocalcin 0.68 (95% CI 0.47 - 0.97)).

The risk for stroke within 15 years after the age of 70 was increased in men with low serum osteocalcin (p<0.01).

Low osteocalcin increased the risk of having high waist circumference (Men > 102 cm, women > 88 cm; OR per SD increase in osteocalcin 0.77 (0.67-0.89).

Low osteocalcin predicted the parameters of the metabolic syndrome high waist circumference, (p<0.01) BMI >30, high triglycerides, hypertension diabetes.



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Conclusion:

Low serum osteocalcin predicts high glucose and carotid plaques and indicators of the metabolic syndrome.



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bone regulates the energy

homeostasis

bone regulates the energy

homeostasis

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osteocalcin

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Central Regulation of Bone Central Regulation of Bone RemodelingRemodeling

interaction between bone and braininteraction between bone and brain

Central Regulation of Bone Central Regulation of Bone RemodelingRemodeling

interaction between bone and braininteraction between bone and brain

Rosen 2008

Cell Metab

Baldock et al 2007

Lundberg et al 2007

Sato et al 2007

Lee et al 2007

ASBMRMet dank aan de Nederlandse collegae voor de leerzame discussies tijdens de ASBMR

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Diabetic subjects had lower plasma osteocalcin (-21.7 %, p< 0.001) Diabetic subjects had lower plasma osteocalcin (-21.7 %, p< 0.001) than non-diabetic subjects. than non-diabetic subjects.

For both all subjects and non-diabetic subjects, plasma osteocalcin For both all subjects and non-diabetic subjects, plasma osteocalcin was clearly inversely related to BMI, fat mass and plasma glucose was clearly inversely related to BMI, fat mass and plasma glucose (p< 0.001), while it was not associated with height or lean mass. (p< 0.001), while it was not associated with height or lean mass.

Plasma osteocalcin explained a substantial part (6.3%) of the Plasma osteocalcin explained a substantial part (6.3%) of the variance in plasma glucose while it associated moderately with variance in plasma glucose while it associated moderately with serum insulin. serum insulin.

Multiple linear regression models adjusting for serum insulin and fat Multiple linear regression models adjusting for serum insulin and fat mass demonstrated that plasma osteocalcin was an independent mass demonstrated that plasma osteocalcin was an independent negative predictor of plasma glucose (p< 0.001).negative predictor of plasma glucose (p< 0.001).

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Methods and population619 randomly selected 70 years old men and women

longitudinal study with examinations at age 70, 76 och 86.

BMD was measured in calcaneus with dual photon absorptiometry and

osteocalcin was analysed by a double-antibody radioimmuno-assay.

Serum was sampled after 10 hours fasting and non-smoking in the morning.

Extra- and intracranial circulation was examined by means of duplex sonography and Transcranial Doppler techniques in 142 subjects at age 78.

Health & Medicine

Seminar 08-10-2008 - effects of bone on fat mass