Osteocalcin in a rat model of metabolic syndrome

Abstract

Recently, a research group led by Gerard Karsenty at Columbia University in New York, USA has demonstrated that bone is an endocrine organ that secretes a multifunctional hormone, osteocalcin (OC), and proposed a regulatory circuitry involving bone, pancreas, adipose tissue and brain in maintaining energy homeostasis in mice (1). The principal hormonal role in this loop has been ascribed to OC. This osteoblast-derived (and vitamin K dependent) protein has been shown to induce insulin secretion and beta cell proliferation and to improve insulin sensitivity. It also increases adiponectin and decreases leptin release from the adipocytes. Osteocalcin has been postulated to be metabolically active in mice in its un(der)car-boxylated form. This groundbreaking research was immediately reflected by clinical studies that were undertaken to test the hypothesis in humans. Results are so far inconsistent and equivocal. Although in general many papers have reported various associations between OC and parameters of energy metabolism, serious discrepancies still exist in the literature as to which form of OC, the carboxylated or the un(der)car-boxylated one, is responsible for the metabolic activity in man. Whether OC serves a similar metabolic role in the rat is currently unknown. In this pilot study we looked at OC in rats fed Western type hyper-caloric diet to develop a condition similar to metabolic syndrome (MS) in humans. Two groups of rats were used. The control group received regular rat chow and plain water throughout the experiment. The experimental group was fed high fat (17 % lard) and high (17 %) fructose (HFHF) diet and had 10% fructose in their drinking water. The duration of the experiment was 10 weeks. Insulin tolerance test (ITT) was performed at the end of the experiment; serum lipids were measured; serum insulin, leptin and both forms of OC - carboxylated and ud-ercarboxylated, were determined by ELISA kits. HOMA-IR was calculated. Body weight of the animals did not differ after 10 weeks of dieting, but the diet manipulated rats had higher caloric intake. The metabolic syndrome induced by HFHF feeding was verified by increased visceral adipose tissue, elevated serum triglycerides (TGs) and blood glucose, positive ITT at the 90th minute, higher insulin and leptin levels. Undercarboxylated osteocalcin (ucOC) in the serum was reduced in the HFHF rats, whereas carboxylated osteocalcin (cOC) was slightly and insignificantly increased. The ratio ucOC/cOC was also lower in the experimental group. Undercarboxylated osteocalcin and ucOC/cOC were inversely associated with blood glucose in the HFHF group. No associations were found between ucOC and insulin, leptin, visceral adipose tissue or TGs. Carboxylated OC showed no correlation with any of the metabolic parameters examined. Our preliminary results support partly the hypothesis that ucOC might be implicated in energy regulation also in the rat. In this animal species the undercarboxylated form of OC is probably the metabolically active one. Nevertheless, compared to the reported effects in mice, OC in rats seems much less active. More evidence is necessary to conirm the hormonal role of OC in the rat.