Context: Bone has recently been described as exhibiting properties of an endocrine organ by producing osteocalcin that increases insulin sensitivity and secretion in animal models.

Objective and Design: We aimed to evaluate circulating osteocalcin in association with insulin sensitivity and insulin secretion in three different studies in nondiabetic subjects: one cross-sectional study in 149 men (using minimal model), and two longitudinal studies in two independent groups (one formed by 26 women, and the other by 9 men and 11 women), after a mean of 7.3 and 16.8% weight loss, and after a mean of 8.7% weight loss plus regular exercise.

Results: In the cross-sectional study, circulating osteocalcin was associated with insulin sensitivity, mainly in lean subjects, and with insulin secretion (only in lean subjects). A mean of 16.8%, but not 7.3% weight loss, led to significant increases in circulating osteocalcin. However, a mean of 8.7% weight loss plus regular exercise led to the more pronounced effects on the serum osteocalcin concentration, which increased in parallel to reduced visceral fat mass, unchanged thigh muscle mass, and increased leg strength and force. The postintervention serum levels of osteocalcin were associated with both insulin sensitivity (r = 0.49; P = 0.03) and fasting triglycerides (r = −0.54; P = 0.01). The change in visceral fat was the parameter that best predicted the change in serum osteocalcin, once age, body mass index, and insulin sensitivity changes were controlled for (P = 0.002).

Conclusion: Circulating osteocalcin could mediate the role of bone as an endocrine organ in humans.