The cross‐talk between the skeleton and energy metabolism (骨与能量代谢的相互作用)

In the current issue of the Journal, Zhao et al. report the relationship between metabolic syndrome (MS) and bone mineral density (BMD) measured by calcaneus ultrasonography in a large Chinese cohort. The authors found that men with MS had higher BMD, associated with lower high-density lipoprotein–cholesterol and higher fasting glucose levels, and hence, presumably, with insulin resistance and hyperinsulinemia in these patients. The associations between MS and BMD are not always in the same direction. The causes for these mixed results lie in the discrepancies of the criteria used to define MS, the sites and the instruments used for bone density measurements, the gender and ethnicity of the study populations, the confounding factors adjusted, and a variety of other variables. The relationship between bone and energy metabolism is becoming an exciting topic for ongoing research. With the use of state-of-the-art genetic engineering techniques, a novel role of skeletal physiology has been unveiled. Bone was traditionally regarded as an organ protecting and stabilizing the body, as well as for locomotion. It is also a pivotal target for hormones influencing calcium and phosphorus homeostasis and bone structure. Now, accumulating evidence from both basic and clinical research suggests that bone should be considered an endocrine organ regulating glucose homeostasis and energy metabolism. The endocrine nature of bone was first revealed in studies of mice lacking embryonic stem cell phosphatase (Esp), a gene encoding protein tyrosine phosphatase (PTP). Esp is exclusively expressed in osteoblasts and in the Sertoli cells of the testis. Although without bone phenotype changes, mice with global (Esp / ) or osteoblast-specific (Esposb / ) knockout of Esp usually die shortly after birth due to severe hypoglycemia. Investigations of the surviving mice demonstrate increased pancreatic islet size, b-cell number, and high circulating adiponectin levels. In addition, Esp / mice exhibit increased insulin sensitivity in muscle and white and brown adipose tissue. These mice also have less visceral fat, increased muscle mitochondrial area, and increased levels of proteins associated with mitochondrial biogenesis, indicating enhanced energy expenditure. These surprising findings suggest that the osteoblast is an endocrine cell modulating insulin secretion and sensitivity. However, the protein encoded by Esp is not secreted. Efforts were then made to search for bonespecific hormone(s) with the capacity to regulate energy metabolism. Osteocalcin shows some features of such a protein. Osteocalcin is secreted by osteoblasts and is released into the bloodstream in carboxylated and undercarboxylated forms. In contrast with the metabolic phenotypes observed in Esp-deficient mice, osteocalcin-deficient mice show early development of obesity, hyperglycemia, and a reduction in pancreatic b-cell mass. These results indicate that Esp / mice are a gain-of-function model for osteocalcin. Further experiments established that Esp acts upstream of osteocalcin, influencing osteocalcin function by regulating its degree of carboxylation. Only the undercarboxylated form of osteocalcin (ucOC) is responsible for promoting insulin secretion, improving glucose tolerance, and reducing fat mass, mediated, in part, through adiponectin. Osteoblasts also receive endocrine signals. The insulin receptor (InsR) is expressed in osteoblasts and mice lacking InsR in the osteoblasts develop hyperglycemia, hypoinsulinemia, and impaired glucose tolerance. A function of insulin signaling in osteoblasts is to inhibit the expression of osteoprotegererin (OPG), a gene implicated in suppressing bone resorption. It was found that with increased bone resorption activity by insulin signaling in osteoblasts, osteocalcin is decarboxylated into active ucOC in the acidic microenvironment of the resorption lacunae and then released into the circulation to affect energy metabolism by enhancing the expression of insulin and adiponectin genes in b-cells and adipocytes, respectively. The anti-diabetic effect of ucOC in rodents is intriguing and has led to numerous human studies evaluating whether osteocalcin can affect glucose and lipid metabolism in either non-diabetic individuals or patients with diabetes, MS, and polycystic ovarian syndrome. It is generally accepted that serum osteocalcin and/or ucOC concentrations are a marker of glucose tolerance. Higher serum osteocalcin levels are generally associated with improved glucose tolerance, insulin secretion and sensitivity, and less body fat. One longitudinal study indicates that osteocalcin may predict incident diabetes, but this was not replicated in another retrospective follow-up investigation.