1 3 J Endocrinol Invest DOI 10.1007/s40618-016-0549-y OPINION Adipokines and bone metabolism: an interplay to untangle J. Pepe 1 · C. Cipriani 1 · M. Cilli 1 · L. Colangelo 1 · S. Minisola 1 Received: 4 September 2016 / Accepted: 6 September 2016 © Italian Society of Endocrinology (SIE) 2016 is probably mediated by the leptin receptor found on osteo- blasts and chondrocytes. The indirect effect is mediated by different pathways. Leptin also impacts and regulates osteocalcin, an osteoblast-derived hormone considered a marker of bone formation, which in turn regulates both bone metabolism and insulin sensitivity [4]. Serum leptin levels have been shown to have a strong positive correla- tion with bone mineral density (BMD) in women, and high levels of leptin were reported to be predictive of low risk of fractures in some but not all studies [4]. Leptin increases osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) alpha superfamily secreted by osteoblasts which acts as a soluble decoy receptor for the activator of nuclear factor kappa B (RANK), a transmembrane protein expressed by osteoclasts. By preventing the soluble recep- tor activator of nuclear factor kappa B ligand (RANKL) from binding to RANK, OPG protects bone from excessive resorption. Adiponectin levels have been shown to be inversely related to visceral fat and body mass index [5]; serum val- ues vary largely depending also on age, sex, menopausal status and comorbidities [6]. Secretion of adiponectin may be inhibited by cytokines, such as TNF alpha, interleu- kin 6 and hormones (cortisol and testosterone), which are also involved in bone metabolism. Adiponectin receptors have been demonstrated on osteoblasts, but also on mus- cle and liver, which are organs that interplay with adipose tissue and bone metabolism [7]. Osteoblasts and marrow adipocytes originate from a common mesenchymal pro- genitor, and adiponectin has been postulated as a poten- tial factor that may induce osteoblast proliferation and differentiation. Interestingly, osteocalcin may upregulate the expression of the adiponectin gene in adipocytes, thus improving insulin sensitivity. Adiponectin has been studied also in different clinical conditions such as non-alcoholic Recent evidence of increased fracture risk in obese patients has focused the attention on the relationship between adi- pose and skeletal tissue [1]. Adipocytes secrete a number of bioactive molecules, such as adipokines, which recently have been shown to have a role in bone metabolism. Adipokines are pleiotropic molecules, investigated in many physiological or patholog- ical processes, including inflammation, endothelial dam- age, atherosclerosis, impaired insulin signaling and hyper- tension. Adipokine dysregulation has been shown to be a strong determinant of the low-grade inflammatory state of obesity, which promotes a cascade of metabolic alterations leading to cardiovascular complications, insulin resistance or diabetes mellitus [2, 3]. So far, only a few adipokines (adiponectin, leptin, resistin, visfatin and the newly discov- ered omentin-1) have been studied in the context of bone metabolism. Leptin was the first adipokine discovered. Circulating levels seem to reflect the amount of energy stored in the adipose tissue; however, a wide variability in leptin levels has been reported in individuals with the same body mass index [4]. A number of factors regulate circulating leptin levels in healthy individuals. In addition, leptin also influ- ences several hypothalamic pituitary peripheral neuroen- docrine axes, including the thyroid, gonadal, cortisol and growth hormone axes. Leptin exerts its effect on bone metabolism by means of both direct and indirect mechanisms. The direct mechanism * J. Pepe jessica.pepe@uniroma1.it 1 Department of Internal Medicine and Medical Disciplines, “Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy