Integrative Physiology: Defined Novel Metabolic Roles of Osteocalcin

Abstract

The prevailing model of osteology is that bones constantly undergo a remodeling process, and that the differentiation and functions of osteoblasts are partially regulated by leptin through different central hypothalamic pathways. The finding that bone remodeling is regulated by leptin suggested possible endocrinal effects of bones on energy metabolism. Recently, a reciprocal relationship between bones and energy metabolism was determined whereby leptin influences osteoblast functions and, in turn, the osteoblast-derived protein osteocalcin influences energy metabolism. The metabolic effects of bones are caused by the release of osteocalcin into the circulation in an uncarboxylated form due to incomplete γ-carboxylation. In this regard, the Esp gene encoding osteotesticular protein tyrosine phosphatase is particularly interesting because it may regulate γ-carboxylation of osteocalcin. Novel metabolic roles of osteocalcin have been identified, including increased insulin secretion and sensitivity, increased energy expenditure, fat mass reduction, and mitochondrial proliferation and functional enhancement. To date, only a positive correlation between osteocalcin and energy metabolism in humans has been detected, leaving causal effects unresolved. Further research topics include: identification of the osteocalcin receptor; the nature of osteocalcin regulation in other pathways regulating metabolism; crosstalk between nutrition, osteocalcin, and energy metabolism; and potential applications in the treatment of metabolic diseases.

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

“…Recent research now supports the concept that bone is also an endocrine organ similar to adipose tissue and plays an active role in energy homeostasis (Karsenty and Oury, 2012), specifically through a reciprocal hormonal relationship of osteocalcin and leptin regulating insulin and glucose homeostasis (Kanazawa, 2015;Schwetz et al, 2012: Ng, 2011Ferron et al, 2010;Kim et al, 2010;Hinoi et al, 2010;Lee and Karsenty, 2008;). Further study identifies the negative effect of leptin on osteocalcin, which is believed to inhibit insulin and reduce visceral fat (Ferron et al, 2013).…”

“…Further study identifies the negative effect of leptin on osteocalcin, which is believed to inhibit insulin and reduce visceral fat (Ferron et al, 2013). The precise relationship plasma leptin effects on bone remodeling may in fact be dose -dependent and bimodal, producing opposite effects of stimulation and suppression dependent upon its levels (Kim et al, 2010;Motyl and Rosen 2012). Effects are also suggested to be sex-specific (Dalskov et al, 2015) Much work is needed with…”

Bone resorption is suppressed immediately after the third and fourth days of multiday cycling but persistently increased following overnight recovery

“…Therefore, the exercise-induced cortisol response and hence metabolic stress has a significant part to play in influencing bone loss during multiday cycling. Bone responds to metabolic stress via the bone mineralising peptide, osteocalcin (OC), which has a secondary bioactive role in regulating energy metabolism (Kim et al 2010). Osteocalcin, although a marker of bone formation, is only active in bone mineralisation when in a carboxylated form and conversely is secreted as uncarboxylated OC (ucOC) during periods of energy shortage or high energy demand to promote cellular metabolic signalling (Kim et al 2010).…”

“…Bone responds to metabolic stress via the bone mineralising peptide, osteocalcin (OC), which has a secondary bioactive role in regulating energy metabolism (Kim et al 2010). Osteocalcin, although a marker of bone formation, is only active in bone mineralisation when in a carboxylated form and conversely is secreted as uncarboxylated OC (ucOC) during periods of energy shortage or high energy demand to promote cellular metabolic signalling (Kim et al 2010). Accordingly, serum leptin concentration decreased and the proportion of ucOC increased on the morning before racing on the twelfth and twenty-second days of the Giro d'Italia, which is a 3-week cycling tour (Lombardi et al 2012), thus indicating metabolic stress and not bone formation.…”

Pankreas-Kemik-Testis Ekseni

“…İnsülin ve osteokalsin arasındaki bu ilişkide geri besleme mekanizması bulunmamaktadır. Bu yüzden adipositlerden salınan leptin hormonu hipotalamus aracılığıyla osteokalsin ve insülin üretimini regüle eder [10][11][12] .…”