Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition.
Global energy balance in mammals is controlled by the actions of circulating hormones that coordinate fuel production and utilization in metabolically active tissues. Bone-derived osteocalcin, in its undercarboxylated, hormonal form, regulates fat deposition and is a potent insulin secretagogue. Here, we show that insulin receptor (IR) signaling in osteoblasts controls osteoblast development and osteocalcin expression by suppressing the Runx2 inhibitor Twist2. Mice lacking IR in osteoblasts have low circulating undercarboxylated osteocalcin and reduced bone acquisition due to decreased bone formation and deficient numbers of osteoblasts. With age, these mice develop marked peripheral adiposity and hyperglycemia accompanied by severe glucose intolerance and insulin resistance. The metabolic abnormalities in these mice are improved by infusion of undercarboxylated osteocalcin. These results indicate the existence of a bone-pancreas endocrine loop through which insulin signaling in the osteoblast ensures osteoblast differentiation and stimulates osteocalcin production, which in turn regulates insulin sensitivity and pancreatic insulin secretion.
Fulzele
Keertik
K
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Riddle
Ryan C
RC
DiGirolamo
Douglas J
DJ
Cao
Xuemei
X
Wan
Chao
C
Chen
Dongquan
D
Faugere
Marie-Claude
MC
Aja
Susan
S
Hussain
Mehboob A
MA
Brüning
Jens C
JC
Clemens
Thomas L
TL
D050154:Adiposity; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis; D011972:Receptor, Insulin / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000378:metabolism
D012097:Repressor Proteins; D051879:Twist-Related Protein 1; C096852:Twist2 protein, mouse; D015675:Osteocalcin; D011972:Receptor, Insulin