Osteocalcin, acts as a hormone and is able to increase testosterone, increase insulin and its sensitivity, as well as decrease fat mass by increasing energy expenditure.
Osteocalcin, (a.k.a. bone gamma-carboxyglutamic acid-containing protein (BGLAP)), is a noncollagenous protein hormone found in bone and dentin. Osteocalcin is secreted mainly by osteoblasts and a few other tissues, such as adipose tissue, and it was mainly thought to only aid in bone-building,
When the osteoblast releases osteocalcin, it’s either in it’s carboxylated or undercarboxylated form. The carboxylated form is when vitamin K “activates” it so that it can aid in bone mineralization in the bone matrix. The undercarboxylated osteocalcin is released into the bloodstream. Undercarboxylated is the hormonally active form of osteocalcin.
High levels (too high) of undercarboxylated osteocalcin is associated with:
- high levels of adiponectin (better insulin sensitivity)
- more insulin secretion (it stimulates the beta cells of the pancreas)
- increased energy expenditure
- lower fat mass
- higher testosterone
- impaired glucose metabolism (hyperinsulinemia and hypoglycemia) (R)
Whereas too low levels of undercarboxylated osteocalcin are associated with:
- insulin resistance
- reduced energy expenditure
- reduced testosterone levels
In the following study, both lower and higher total osteocalcin levels predicted increased all-cause mortality rates, with comparable associations for cardiovascular and noncardiovascular deaths. (R)
Undercarboxylated osteocalcin acts on the Leydig cells of the testis to stimulate testosterone biosynthesis via the bone-testis axis. The undercarboxylated osteocalcin binds to a G protein-coupled receptor (GPCR6A), which is expressed in the testis, and regulates StAR, Cyp11a, Cyp17 and 3β-HSD, cAMP and Cyp2r1 expression, through CREB as the transcriptional mediator which activates these enzymes. (R, R, R)
- StAR is the rate limited enzyme that transports cholesterol from the outer mitochondria into the inner mitochondria of the Leydig cells to synthesize the precursor to all steroids, pregnenolone.
- Cyp11a is the enzyme that converts cholesterol into pregnenolone.
- Cyp17 (17,20lyase) is the enzyme that converts pregnenolone to dehydroepiandrosterone (DHEA).
- 3β-HSD is the enzyme that converts pregnenolone to progesterone and androstenedione to DHEA in the adrenal gland.
- cAMP acts as a second messenger in cells and also increases testosterone synthesis and further increases StAR activity.
- Cyp2r1 is the enzyme that converts vitamin D into its active form. The active form of vitamin D also acts as a hormone, a steroid hormone, and has a significant positive effect on steroidogenesis. More on vitamin D here…
Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), however, this is not enough to raise testosterone to adequate levels in the absence of undercarboxylated osteocalcin. (R) LH signals testosterone synthesis as well as estrogen synthesis, hence high LH is associated with elevated estrogen.
Circulating undercarboxylated osteocalcin is also positively correlated with free testosterone. (R)
Osteocalcin also acts on muscle cells to promote energy availability and utilization, and in this manner favors exercise capacity. Osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids. It’s also mostly responsible for the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise. (R)
How to increase osteocalcin:
Vitamin D, and mainly the active form of vitamin D, stimulates the synthesis of osteocalcin (1,25-(OH)2D3) in a dose-dependent manner. (R, R) Vitamin D also decreases cortisol, estrogen, inhibits the aromatase, increases total and free testosterone, as well as increases androgen receptor sensitivity.
High intake of vitamin K results in a low proportion of undercarboxylated osteocalcin. Osteoblast releases inactive (undercarboxylated) osteocalcin, which is then activated (carboxylated) by vitamin K, which then undergoes decarboxylation in the resorption lacunae (osteoclast). This means the osteoclast also releases undercarboxylated osteocalcin, which is hormonally active. Vitamin K has been associated with enhanced bone mineral density, increased testosterone, enhanced insulin sensitivity and better glucose tolerance. The exact same benefits as undercarboxylated osteocalcin, meaning higher intake of vitamin K might not lead to lower undercarboxylated osteocalcin, as both the osteoblast and the osteoclast releases it into the circulation. It’s also possible that vitamin K increases total osteocalcin, and therefore the amount of undercarboxylated osteocalcin increases, despite that the ratio of undercarboxylated osteocalcin to carboxylated osteocalcin stay the same or decrease a bit.
Insulin & leptin
The osteoblast in bone contains insulin receptors, and requires insulin to activate the receptors and result in an increase in osteocalcin. (R) A high-fat diet results in a decrease in undercarboxylated osteocalcin and thus a decrease in insulin sensitivity. This could lead to insulin resistance, low/impaired bone turnover and increased fat mass. (R)
Osteocalcin mRNA is reduced in a magnesium deficiency, and therefore osteocalcin synthesis is reduced. (R) Also, magnesium ions induce a significant increase in osteocalcin levels in human osteoblasts. (R)
Acute exercise (especially aerobic exercise) appears to increase undercarboxylated osteocalcin levels. (R)
Chronically elevated cortisol leads to weight gain, insulin resistance, and diabetes, increased aromatase, degraded androgen receptors and increase the risk of autoimmune disease, etc, and it also suppresses osteoblast function, including osteocalcin synthesis. (R)
Zinc is known to aid in the bone formation and zinc intake is positively associated with osteocalcin levels, as zinc stimulates the osteoblast. (R) Just be sure to consume enough zinc rich foods and maybe take a supplement. 50mg a day would be a good starting dose.
Osteoblasts have receptors for GH and these cells produce large amounts of IGF-I. IGF-I has positive effects on bone formation; firstly, it is known to stimulate the formation of osteocalcin, collagen, and noncollagenous matrix proteins by differentiated osteoblasts and secondly, it increases the number of functional osteoblasts by promoting osteoprogenitor cell replication. (R)