METHODS AND RESULTS: Lean control, saline-treated obese and uncarboxylated
osteocalcin (uOC)-treated obese mice were subjected to
insulin tolerance test in vivo. Blood was collect for biochemical/metabolic profile analysis; and, skeletal muscle, white adipose tissue (WAT) and bone were collected for
protein (Western blotting) and
mRNA (RT-qPCR) analysis. uOC effects on
insulin resistance and
inflammation were also investigated in 3T3-L1 adipocytes challenged with
tumor necrosis factor.
Osteocalcin treatment improved in vivo
insulin resistance in obese mice. In WAT,
osteocalcin had positive effects such as (1) WAT
weight reduction; (2) upregulation of
glucose transporter (
GLUT) 4 protein and its
mRNA (Slc2a4); (3) improved
insulin-induced AKT phosphorylation; (4) downregulation of several genes involved in
inflammation and inflammassome transcriptional machinery, and (5) reduction of the density of macrophage in crown-like structures (histomorphometrical analysis). Notably, in 3T3-L1 adipocytes,
osteocalcin restored Slc2a4/GLUT4 content and reduced the expression of inflammatory genes after TNF-a challenge; moreover,
osteocalcin treatment increased AKT phosphorylation induced by
insulin. Finally, it was observed that in bone,
osteocalcin improves
insulin resistance by increasing
insulin-induced AKT phosphorylation and reducing the expression of genes involved in bone
insulin resistance, resulting in increased secretion of uncarboxylated
osteocalcin in circulation.
CONCLUSION: