1) The document discusses several studies that examined the relationship between bone and fat mass. One study found lower levels of uncarboxylated osteocalcin in obese patients that normalized after gastric bypass surgery.
2) Another study found lower osteocalcin levels were associated with an increased risk of type 2 diabetes in men aged 60+.
3) A third study found osteocalcin was a negative predictor of fat mass and glucose levels in elderly men, but bone formation marker PINP was not an independent predictor.
4) Variation in the osteocalcin gene was also linked to body fat parameters in elderly women in one study discussed.
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Seminar 08-10-2008 - effects of bone on fat mass
1. Montreal 2008Montreal 2008
Effects of bone on fatEffects of bone on fat
massmass
Highlights ASBMR, part 2Highlights ASBMR, part 2
Dr. E. van der VeerDr. E. van der Veer
University Medical Center GroningenUniversity Medical Center Groningen
Utrecht, Oct 8Utrecht, Oct 8THTH
20082008
ASBMRASBMR
2. ASBMR
Effects ofEffects of fat massfat mass onon 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
AdiponectinAdiponectin
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
3. ASBMR
Osteoblasts andOsteoblasts and
adipocytes originateadipocytes originate
from commonfrom common
progenitor-progenitor-
mesenchymal stemmesenchymal stem
cellscells
Rosen et al 2006
Zhao et al 2008
4. ASBMR
Effects ofEffects of bonebone onon fatfat massmass
Hormones 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).
5. ASBMR
Effects ofEffects of bonebone onon fat massfat mass
SA 444SA 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
NguyenNguyen
Men aged 60+
SU 459SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
SU 225SU 225 Osteocalcin gene andOsteocalcin gene and Body Fat MassBody Fat Mass McGuiganMcGuigan
Elderly Swedish WomenElderly Swedish Women
SA 198SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
6. ASBMR
OsteocalcinOsteocalcin
Protein of 49 amino acidsProtein of 49 amino acids
3 glutamin residues3 glutamin residues
After carboxylation of theAfter carboxylation of the
GLU-residues binding to hydroxyapatiteGLU-residues binding to hydroxyapatite
7. ASBMR
VITAMIN K CYCLEVITAMIN K CYCLE..
ORAL ANTICOAGULANTS INHIBIT THE
RECYCLING OF VITAMIN K
‘Inactive’
OSTEOCALCIN
OSTEOCALCIN
8. ASBMR
Seeman et al. NEJM 2006
Bone turnoverBone turnover
PINP
BALP
Osteocalcine
CTx
Crosslinks
TRAP
9. ASBMR
Effects ofEffects of bonebone onon fat massfat mass
SA 444SA 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
NguyenNguyen
Men aged 60+
SU 459SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
SU 225SU 225 Osteocalcin gene andOsteocalcin gene and Body Fat MassBody Fat Mass McGuiganMcGuigan
Elderly Swedish WomenElderly Swedish Women
SA 198SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
10. ASBMR
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 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli
11. ASBMR
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 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli
12. ASBMR
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.
SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli
14. ASBMR
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
Conclusion
In 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.
SA 444SA 444 Osteocalcin and ObesityOsteocalcin and Obesity
SpagnoliSpagnoli
15. ASBMR
Effects ofEffects of bonebone onon 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
16. ASBMR
SU 461 Osteocalcin and type II Diabetes
Nguyen
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
17. ASBMR
Serum 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.
21. ASBMR
SU 461 Osteocalcin and type II Diabetes
Nguyen
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.
22. ASBMR
Effects ofEffects of bonebone onon fat massfat mass
SA 444 Osteocalcin and Obesity Spagnoli
Obese and Post Gastric By-pass patients
SU 461 Osteocalcin and type II Diabetes
Nguyen
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
23. ASBMR
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.
SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
24. ASBMR
SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
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= 857non-diabetic n= 857
diabetic n= 153.diabetic n= 153.
Fasting levels were analysed ofFasting levels were analysed of
plasma osteocalcin,plasma osteocalcin,
plasma glucose,plasma glucose,
serum insulin andserum insulin and
lipidslipids
Fat mass and lean mass were analysed using dual energy X-rayFat mass and lean mass were analysed using dual energy X-ray
absorptiometry.absorptiometry.
28. ASBMR
SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
PINPPINP is strongly associated withis strongly associated with OsteocalcinOsteocalcin
Pearson’s r = 0.66Pearson’s r = 0.66
Both bone formation markers were included together asBoth 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.
ASBMR
29. ASBMR
SU 459 Osteocalcin and Fat Mass /Glucose
Kindblom
Conclusion:Conclusion:
Osteocalcin is a negative predictor of fat mass andOsteocalcin is a negative predictor of fat mass and
plasma glucose in elderly menplasma glucose in elderly men
In contrast, PINP is not an independent predictorIn contrast, PINP is not an independent predictor
These human data support recently publishedThese human data support recently published
experimental studies, revealing endocrine functions ofexperimental studies, revealing endocrine functions of
osteoblast-derived osteocalcin on glucose and fatosteoblast-derived osteocalcin on glucose and fat
homeostasis.homeostasis.
30. ASBMR
Effects ofEffects of bonebone onon fat massfat mass
SA 444 Osteocalcin and Obesity Spagnoli
Obese and Post Gastric By-pass patients
SU 461 Osteocalcin and type II Diabetes
Nguyen
SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
SU 225 Osteocalcin gene and Body Fat Mass McGuigan
Elderly Swedish Women
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
31. ASBMR
SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
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
32. ASBMR
SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
4 SNPs around Osteocalcin locus on Chr 1,
including rs1800247 located in the promoter
rs 2842880 in intron 13
rs 933489 in intron 14
33. ASBMR
SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
• Osteocalcin SNP’s were associated with % total body fat at baseline
rs1800247 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.
34. ASBMR
SU 225 Osteocalcin gene and Body Fat Mass
McGuigan
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
35. ASBMR
Effects ofEffects of bonebone onon fat massfat mass
SA 444 Osteocalcin and Obesity Spagnoli
Obese and Post Gastric By-pass patients
SU 461 Osteocalcin and type II Diabetes
Nguyen
SU 459 Osteocalcin and Fat Mass /Glucose Kindblom
Elderly Swedish Men
SU 225 Osteocalcin gene and Body Fat Mass McGuigan
Elderly Swedish Women
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
Elderly
36. ASBMR
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
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
37. ASBMR
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 BMD
OC and BMI
in both sexes at all ages investigated (P<0.05).
OC adjusted for BMI:
OC and insulin r = -0.11 p<0.01
OC 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).
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
38. ASBMR
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.
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
39. ASBMR
Conclusion:
Low serum osteocalcin predicts high glucose and carotid
plaques and indicators of the metabolic syndrome.
SA 198 Osteocalcin and Carotid Plaques / Metabolic
Syndrome Waern
41. ASBMR
Central Regulation of BoneCentral 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
42. ASBMR
Met dank aan de Nederlandse collegae voor de leerzame discussies tijdens
de ASBMR
44. ASBMR
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 osteocalcinFor both all subjects and non-diabetic subjects, plasma osteocalcin
was clearly inversely related to BMI, fat mass and plasma glucosewas 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 thePlasma osteocalcin explained a substantial part (6.3%) of the
variance in plasma glucose while it associated moderately withvariance in plasma glucose while it associated moderately with
serum insulin.serum insulin.
Multiple linear regression models adjusting for serum insulin and fatMultiple linear regression models adjusting for serum insulin and fat
mass demonstrated that plasma osteocalcin was an independentmass demonstrated that plasma osteocalcin was an independent
negative predictor of plasma glucose (p< 0.001).negative predictor of plasma glucose (p< 0.001).
45. ASBMR
Methods and population
619 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.
Notes de l'éditeur
Common factors shared in osteoblast and adipocyte differentiation. Osteoblasts and adipocytes originate from common progenitor-mesenchymal stem cells. The balance of their differentiation is determined by several common factors, such as PPAR-γ, Wnt, TGF-β, leptin, and estrogen. Adipocytes express and secrete a variety of bioactive peptides, such as estrogen, resistin, leptin, adiponectin, and inflammatory cytokines. Some of these peptides affect human energy homeostasis and may be involved in bone metabolism. Adapted from Reference 15. It was previously believed that obesity and osteoporosis were two unrelated diseases, but recent studies have shown that both diseases share several common genetic and environmental factors. Body fat mass, a component of body weight, is one of the most important indices of obesity, and a substantial body of evidence indicates that fat mass may have beneficial effects on bone. Contrasting studies, however, suggest that excessive fat mass may not protect against osteoporosis or osteoporotic fracture. Differences in experimental design, sample structure, and even the selection of covariates may account for some of these inconsistent or contradictory results. Despite the lack of a clear consensus regarding the impact of effects of fat on bone, a number of mechanistic explanations have been proposed to support the observed epidemiologic and physiologic associations between fat and bone. The common precursor stem cell that leads to the differentiation of both adipocytes and osteoblasts, as well the secretion of adipocyte-derived hormones that affect bone development, may partially explain these associations. Based on our current state of knowledge, it is unclear whether fat has beneficial effects on bone. We anticipate that this will be an active and fruitful focus of research in the coming years.
Dr. E. van der Veer The Remodeling Cycle on a Trabecula. A microcrack severs canaliculi, which causes osteocytic apoptosis, with the location and extent of the damage defined by signals to lining cells. Lining cells and osteocytes release local factors that attract cells from blood and marrow into the remodeling compartment in which osteoclastogenesis occurs. Osteoclasts resorb matrix and the microcrack, then successive teams of osteoblasts deposit new lamellar bone. Osteoblasts that are trapped in the matrix become osteocytes; others die or form new, flattened osteoblast lining cells.
Cystatin C = kidney function
Common factors shared in osteoblast and adipocyte differentiation. Osteoblasts and adipocytes originate from common progenitor-mesenchymal stem cells. The balance of their differentiation is determined by several common factors, such as PPAR-γ, Wnt, TGF-β, leptin, and estrogen. Adipocytes express and secrete a variety of bioactive peptides, such as estrogen, resistin, leptin, adiponectin, and inflammatory cytokines. Some of these peptides affect human energy homeostasis and may be involved in bone metabolism. Adapted from Reference 15. It was previously believed that obesity and osteoporosis were two unrelated diseases, but recent studies have shown that both diseases share several common genetic and environmental factors. Body fat mass, a component of body weight, is one of the most important indices of obesity, and a substantial body of evidence indicates that fat mass may have beneficial effects on bone. Contrasting studies, however, suggest that excessive fat mass may not protect against osteoporosis or osteoporotic fracture. Differences in experimental design, sample structure, and even the selection of covariates may account for some of these inconsistent or contradictory results. Despite the lack of a clear consensus regarding the impact of effects of fat on bone, a number of mechanistic explanations have been proposed to support the observed epidemiologic and physiologic associations between fat and bone. The common precursor stem cell that leads to the differentiation of both adipocytes and osteoblasts, as well the secretion of adipocyte-derived hormones that affect bone development, may partially explain these associations. Based on our current state of knowledge, it is unclear whether fat has beneficial effects on bone. We anticipate that this will be an active and fruitful focus of research in the coming years.
Central regulation of bone remodeling occurs through the hypothalamus but is determined by both afferent and efferent signaling. Phase 1 is the afferent leptin signal that originates from peripheral adipocytes. Phase 2 involves the processing of this signal in the hypothalamus, which occurs in the ventromedial hypothalamus (VMH). The mediators of this phase likely include neuropeptide Y (NPY) and neuromedin U (NMU). Phase 3 represents the efferent (sympathetic) output from the hypothalamus to the β2-adrenergic receptor (β2-AR) on osteoblasts and the resultant change in transcription factors and clock genes that affect osteoblastogenesis. Suppression of osteoclastogenesis can occur indirectly through the suppression of receptor activator of NF-κB ligand (RANKL) in osteoblasts by cocaine- and amphetamine-regulated transcript (CART). NMU may mediate its effects downstream of β2-AR on the clock genes. Phase 4 represents skeletal regulation of adipocytes, most likely through the systemic release of osteocalcin. The dotted line in phase 4 represents the theoretical possibility that adipocytes could regulate osteoblast proliferation and differentiation. Other abbreviations: Y1, NPY receptor 1; Y2, NPY receptor 2; NMUR, neuromedin U receptor 2; OB, osteoblast; OC, osteoclast.