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Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity.

ABSTRACT: Members of the family of bone morphogenetic proteins (BMPs) are important regulators of adipogenesis. We examined the role of the BMP receptor 1A gene (BMPR1A) in the pathophysiology of human obesity.We measured BMPR1A mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 297 subjects and sequenced the BMPR1A in 48 nonrelated white subjects. Twenty-one representative variants including HapMap tagging single nucleotide polymorphisms (SNPs) were then genotyped for association studies in German whites (n = 1,907). For replication analyses, we used a population of Sorbs from Germany (n = 900) and German childhood cohorts (n = 1,029 schoolchildren and 270 obese children).mRNA expression of the BMPR1A was significantly increased in both visceral and subcutaneous adipose tissue of overweight and obese subjects compared with lean subjects (P < 0.05). In a case-control study, four SNPs (rs7095025, rs11202222, rs10788528, and rs7922846) were nominally associated with obesity (adjusted P < 0.05). For three SNPs (rs7095025, rs11202222, and rs10788528), the association with obesity was confirmed in the independent cohort of Sorbs (adjusted P < 0.005). Consistent with this, BMPR1A SNPs were nominally associated with obesity-related quantitative traits in nondiabetic subjects in both adult cohorts. Furthermore, homozygous carriers of the obesity risk alleles had higher BMPR1A mRNA expression in fat than noncarriers.Our data suggest that genetic variation in the BMPR1A may play a role in the pathophysiology of human obesity, possibly mediated through effects on mRNA expression.

SUBMITTER: Bottcher Y

PROVIDER: S-EPMC2731538 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity.

Böttcher Yvonne Y Unbehauen Hanne H Klöting Nora N Ruschke Karen K Körner Antje A Schleinitz Dorit D Tönjes Anke A Enigk Beate B Wolf Sara S Dietrich Kerstin K Koriath Moritz M Scholz Gerhard Harry GH Tseng Yu-Hua YH Dietrich Arne A Schön Michael R MR Kiess Wieland W Stumvoll Michael M Blüher Matthias M Kovacs Peter P

Diabetes 20090605 9

<h4>Objective</h4>Members of the family of bone morphogenetic proteins (BMPs) are important regulators of adipogenesis. We examined the role of the BMP receptor 1A gene (BMPR1A) in the pathophysiology of human obesity.<h4>Research design and methods</h4>We measured BMPR1A mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 297 subjects and sequenced the BMPR1A in 48 nonrelated white subjects. Twenty-one representative variants including HapMap tagging single nucleo ...[more]

PMID: 19502417

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Project description:Previous work has shown that the soluble murine BMPR1A-fusion protein (mBMPR1A-mFc) binds to BMP2 and BMP4 with high affinity, preventing downstream signaling. Further, treatment of intact and ovariectomized mice with mBMPR1A-mFc leads to increased bone mass, and improved bone microarchitecture and strength, via increased bone formation and reduced resorption. In this study, we tested the effects of mBMPR1A-mFc on disuse-induced bone loss caused by 21 days of hindlimb unloading (HLU) via tail suspension versus cage controls (CONs). Adult female C57BL/6J mice (12 weeks old) were assigned to one of four groups (n?=?10 each): CON-VEH; CON-mBMPR1A-mFc; HLU-VEH; and HLU-mBMPR1A-mFc. Mice were injected subcutaneously with VEH or mBMPR1A-mFc (4.5?mg/kg, 2×/week). Leg BMD declined in the HLU-VEH group (-5.3%?±?1.3%), whereas it was unchanged in HLU-mBMPR1A-mFc (-0.3%?±?0.9%, p?<?0.05 versus HLU-VEH). Leg BMD increased significantly more in CON-mBMPR1A-mFc than CON-VEH (10.2%?±?0.6% versus 4.4%?±?0.8%). In the femur, trabecular, and cortical bone microarchitecture was worse in the HLU-VEH compared to CON-VEH mice, whereas mBMPR1A-mFc treatment for 3 weeks led to greater Tb.BV/TV, Tb.Th, and midshaft Ct.Th in both the HLU and CON groups compared to comparable VEH-treated counterparts (p?<?0.05). HLU-mBMPR1A-mFc mice also had 21% greater failure load (p?<?0.05) compared to their VEH-treated counterparts. Dynamic histomorphometry indicated that treatment with mBMPR1A-mFc led to significantly greater mineralizing surface and mineral apposition rate, resulting in a 3.5-fold and fivefold higher bone formation rate in the mBMPR1A-mFc-treated CON and HLU animals versus VEH groups, respectively. mBMPR1A-mFc-treated mice had a similar osteoblast surface but significantly lower osteoclast surface than VEH-treated animals in both the CON and HLU groups. Altogether, these findings suggest that treatment with the soluble BMPR1A fusion protein may be useful for maintenance of skeletal integrity in the setting of disuse-induced bone loss.

Dataset Information

Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity.

Publications

Adipose tissue expression and genetic variants of the bone morphogenetic protein receptor 1A gene (BMPR1A) are associated with human obesity.

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