Review

Nature Reviews Rheumatology 5, 365-372 (July 2009) | doi:10.1038/nrrheum.2009.102

Subject Category: Metabolic bone disease

Fat targets for skeletal health

Masanobu Kawai1, Maureen J. Devlin2 & Clifford J. Rosen1  About the authors

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Emerging evidence points to a critical role for the skeleton in several homeostatic processes, including energy balance. The connection between fuel utilization and skeletal remodeling begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Mature bone cells secrete factors that influence insulin sensitivity, and fat cells synthesize cytokines that regulate osteoblast differentiation; thus, these two pathways are closely linked. The emerging importance of the bone–fat interaction suggests that novel molecules could be used as targets to enhance bone formation and possibly prevent fractures. In this article, we discuss three pathways that could be pharmacologically targeted for the ultimate goal of enhancing bone mass and reducing osteoporotic fracture risk: the leptin, peroxisome proliferator-activated receptor gamma and osteocalcin pathways. Not surprisingly, because of the complex interactions across homeostatic networks, other pathways will probably be activated by this targeting, which could prove to be beneficial or detrimental for the organism. Hence, a more complete picture of energy utilization and skeletal remodeling will be required to bring any potential agents into the future clinical armamentarium.

Key points

  • Bone and fat arise from the same mesenchymal stem cells in the bone marrow
  • Osteoblasts secrete factors that regulate insulin production and adipocyte sensitivity to insulin
  • Leptin is an adipokine that acts through the hypothalamus to regulate appetite and bone remodeling
  • Peripheral fat stores are hormonally active and might regulate bone turnover

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Introduction

In the past decade there have been considerable advances in our understanding of skeletal acquisition and maintenance. There has also been a growing awareness that bone remodeling requires an energy source and is intimately linked to other homeostatic pathways. Several lines of evidence support this finding. First, osteoblasts and adipocytes both arise from mesenchymal stem cells (MSCs) in the bone marrow milieu. Research has further clarified the process of MSC lineage commitment, although more studies are needed to understand whether plasticity between these two cell types exists at various developmental stages (Figure 1). Second, changes in glucose and fat metabolism in a host of conditions, including diabetes mellitus, Cushing syndrome and anorexia nervosa, severely impact upon skeletal health. Similarly, bone-specific proteins secreted from osteoblasts have been shown to regulate glucose metabolism. Third, central nervous system processing in the hypothalamus from efferent fat depots regulates skeletal turnover via the sympathetic nervous system. Fourth, obesity in childhood has been associated with a greater fracture risk, even though BMI has been shown to directly correlate with bone mineral density (BMD). More comprehensive studies are required to understand the paradox between the positive effects of adipose 'insulation' on the cortical skeleton and the inherent capacity of adipose tissue to function as an endocrine organ secreting inflammatory cytokines and adipokines that are detrimental to the trabecular skeleton. This area, however, raises the provocative possibility that future therapeutics could directly target fat cells in order to positively affect the skeleton.

Figure 1 | PPARbold gamma regulates bone mass in the bone marrow milieu.
Figure 1 : PPAR|[gamma]| regulates bone mass in the bone marrow milieu. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comThe first step involves lineage commitment by MSCs. Several transcription factors, including PPARgamma and C/EBPs, govern adipogenesis, while transcription factors such as RUNX2 and SP7 (also known as OSX) are necessary for osteoblastogenesis. PPARgamma favors adipogenesis, and suppresses osteoblastogenesis partly through inhibiting the function of RUNX2, resulting in a reduced number of osteoblasts in the bone marrow. Second, PPARgamma stimulates osteoclastogenesis by enhancing c-fos expression in osteoclast precursor cells. Third, secretory inflammatory factors, including leptin, adipsin, adiponectin and resistin, are produced by bone marrow adipocytes. These cytokines possibly act in a paracrine manner on osteoblasts and suppress osteoblast function or differentiation, or both, in pathogenic conditions. Abbreviations: C/EBPs, CCAAT/enhancer binding proteins; HSC, hematopoietic stem cell; MSC, mesenchymal stem cell; OPG, osteoprotegerin; PPARgamma, peroxisome proliferator activated receptor gamma; RANKL, receptor activator of nuclear transcription factor kappaB ligand; RUNX2, runt-related transcription factor 2.

In this Review we discuss strategies focusing on three targets in the bone–fat network: leptin, peroxisome proliferator activated receptor gamma (PPARgamma), and osteocalcin. These molecules were chosen because the latest research in these areas has resulted in a growing understanding of their integration into the homeostatic processes of the skeleton.

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Leptin

Leptin is an adipokine produced by fat cells that mediates energy homeostasis, appetite levels and reproductive capacity.1 Since its discovery 15 years ago, there have been tremendous expectations about the possibility of targeting leptin as a therapeutic approach for obesity. Unfortunately, most of the clinical studies in obese patients, barring a few case reports in subjects with loss-of-function leptin or leptin receptor mutations, have failed to meet those expectations. There is emerging evidence, however, that leptin treatment might be an important adjunct to acquired lipodystrophic disorders, including chronic HIV infections and insulin-resistant diabetes mellitus. Similarly, although its role in skeletal physiology is complex, augmentation of leptin might have therapeutic applications for bone diseases, particularly in disordered states of fat metabolism associated with bone marrow adiposity.

Hypothalamic versus skeletal action

The major paradox concerning leptin relates to the extent to which it acts via the hypothalamus and skeletal innervation to regulate bone mass versus its putative direct actions on osteoblasts (Figure 2).2, 3, 4, 5, 6, 7, 8, 9, 10, 11 In humans, the relationship between leptin and bone mass varies with age, sex, energy status and skeletal site, limiting its clinical use as a marker of skeletal status. Leptin receptor (LEPR) polymorphisms affect circulating leptin levels or bone mass (or both), but the relationship between serum leptin and BMD is unclear, with studies reporting both positive and negative associations, particularly after body composition adjustment.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 Skeletal effects of leptin via a central hypothalamic pathway were first reported by Ducy et al.5 in 2000. Intracerebroventricular (ICV) leptin infusion in mice stimulates ventromedial hypothalamic expression of Lepr, triggering norepinephrine release by sympathetic nervous system fibers and activation of beta2-adrenergic receptors (ADRB2) in osteoblasts. ADRB2 upregulation decreases osteoblast activity and bone formation, and increases bone resorption via RANKL (also known as tumor necrosis factor ligand superfamily, member 11) production, leading to vertebral trabecular bone loss.3, 4, 5, 6, 7, 26, 27 Treatment with an ADRB agonist (isoprenaline) replicates the phenotype of low bone mass.6, 26, 27, 28 Parabiosis of mice treated with ICV leptin and untreated mice, however, demonstrates that the latter do not lose bone; as ICV leptin does not cross into the bloodstream, these data confirmed that leptin causes bone loss through increased sympathetic tone, rather than through the circulation.27

Figure 2 | Central and peripheral leptin signaling.
Figure 2 : Central and peripheral leptin signaling. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comCentral leptin signaling via hypothalamic LEPRs and the sympathetic nervous system to osteoblast ADRBs decreases trabecular bone volume. Peripheral leptin signaling reportedly increases cortical bone growth and BMSC differentiation to osteoblasts rather than to adipocytes. Abbreviations: BMSCs, bone marrow stromal cells; LEPR, leptin receptor; ADRB2, beta2-adrenergic receptor; SNS, sympathetic nervous system.

Genetic studies in mice

Gain-of-function and loss-of-function mouse models for this pathway provide additional insight, although they might complicate therapeutic considerations. For example, the skeletal phenotype of ob/ob (leptin-deficient) and db/db (Lepr null) mice includes high vertebral trabecular bone volume, but low femoral cortical and trabecular bone volume.4, 5, 11, 29, 30, 31, 32 Interestingly, hypoleptinemia secondary to caloric restriction produces a similar phenotype, with normal whole-body BMD and improved vertebral trabecular bone, but decreased femoral length, areal BMD and strength.33, 34, 35, 36, 37, 38, 39, 40, 41, 42 Similarly, the db/db mouse does not lose bone under caloric restriction, suggesting Lepr involvement in hypoleptinemia-induced bone loss.36 Finally, Adrb2-/- mice exhibit increased vertebral and distal femur trabecular bone mass, as well as increased cortical bone volume at the femoral midshaft, despite normal body mass and a normal endocrine profile.26, 6

The effects of changes in the beta1-adrenergic receptor (ADRB1) are also complex. Although ADRB1 is expressed at low levels (if at all) in bone, mice null for both Adrb1 and Adrb2 show decreased periosteal bone formation, cortical bone mass and BMD, but mice lacking all three beta-adrenergic receptors (beta-less mice) have increased body mass, leptin levels and cortical and trabecular bone mass compared with controls.26, 43 Thus, it has been suggested that the three beta-adrenergic receptors exert complementary effects in bone, although the role of leptin in such a mechanism is unclear.26 Moreover, although prevailing data from mice are compelling, the relationship between changes in adrenergic receptors and skeletal mass in humans remains unclear.

In addition, there is conflicting evidence regarding the direct anabolic actions of leptin in bone. In one study, Shi et al.44 compared mice with conditional Lepr deletion in neurons versus osteoblasts. Lepr(neuron)-/- mice exhibit increased vertebral trabecular bone mass, similar to the db/db global Lepr knockout. In stark contrast, Lepr deletion in osteoblasts (Lepr(osteoblast)-/-) produces no altered skeletal phenotype in vertebral or distal femoral trabecular bone. Leptin gain-of-function (l/l) mice, however, have decreased bone mass and trabecular bone volume.44 Although these results imply that leptin has no direct effect on osteoblasts, previous data suggest that leptin has an osteogenic function in cortical bone in some circumstances, either through inhibition of osteoclasts or stimulation of osteoblasts.11, 45 In addition, leptin treatment can increase periosteal bone formation and commitment of MSCs to bone rather than fat lineages, as well as inhibiting ovariectomy-induced bone loss,8, 10, 46, 47 and reversing both cortical and trabecular decrements in the limbs of ob/ob mice.9 In hind-limb unloading, in which there is profound suppression of bone formation and increases in bone resorption, treatment with either leptin or a nonselective beta-blocker (such as propranolol) reduced bone loss with equal efficacy.48, 49

There are several possible reasons for these contradictory results. First, antiosteogenic leptin effects are often seen in axial elements (for example, vertebral trabecular bone), but anabolic effects are observed in appendicular components (for example, limbs).11 One might speculate that decreased leptin levels enhance vertebral trabecular bone formation while inhibiting limb bone acquisition as an adaptation to starvation.50 Although the lack of an altered trabecular bone phenotype in the Lepr(osteoblast)-/- mice44 is persuasive, there are no data on bone density in a purely cortical bone site (for example, the midshaft femur). Second, it has been suggested that leptin has a biphasic effect in cortical bone, with bone formation enhanced at lower doses but suppressed at higher doses.51 This could translate into a unique clinical scenario in which pharmacologic 'replacement' of leptin deficiency would enhance bone formation, but supplementation with leptin in leptin-sufficient subjects would lead to bone loss due to sympathetic overactivity. Third, the effect of leptin resistance must be considered in any state of high leptin circulation. Finally, studies of leptin action vary in dosing, route of administration (ICV, intraperitoneal or subcutaneous), and duration, contributing to divergent outcomes.

Initial clinical data

Currently, the clinical potential of leptin supplementation, which might reverse bone loss in some scenarios and might be beneficial to trabecular bone, is at too preliminary a stage to draw any conclusions.51, 52 With respect to beta-blockers and osteoporosis, the epidemiologic studies of individuals treated with beta-blockers for hypertension or angina fail to show a convincing effect of these agents on bone density or fractures, in part because of the various types of beta-blockers being studied, and the heterogeneity within patient cohorts.53, 54, 55, 56 Furthermore, there are no long-term randomized, placebo-controlled studies of beta-blockers for fracture prevention.56

In studies of women with hypothalamic amenorrhea, modest dose escalation of daily recombinant leptin restores the gonadotropin reproductive axis and stimulates lipolysis.52 It is conceivable, although not proven, that recombinant leptin could, either alone or in combination with restoration of estrogen, reduce bone marrow adiposity, enhance osteoblast differentiation and strengthen bone mass. Once again, there are no large-scale studies to determine the efficacy of this approach. Similarly, the fat redistribution that characterizes chronic HIV infection has been associated with low bone mass. Unpublished studies using recombinant leptin have shown promise in reversing the lipodystrophy caused by HIV or the drugs used to combat this virus, or both. Whether these changes are accompanied by any beneficial effects on the skeleton remains to be established. The latest efforts are focusing on leptin mimetics that could recapitulate the positive benefits of leptin on body composition, while sparing the potential adverse skeletal effects.

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PPARbig gamma

PPARgamma is a member of the nuclear receptor super family, and is a critical transcription factor in adipogenesis. There are four isoforms of the PPARgamma protein, but only PPARgamma2 is specific for adipose tissue. In the adipogenic lineage scheme, PPARgamma heterodimerizes with retinoid X receptor alpha (RXRalpha). Activation of PPARgamma requires the binding of a ligand and recruitment of specific coactivators to allow the PPARgamma–RXRalpha heterodimer to induce gene transcription of insulin sensitizing targets, such as adiponectin and lipoprotein lipase.57 Ligands for PPARgamma include the naturally occurring prostaglandin J2 and 9(S)-HODE compounds, as well as the thiazolidinedione (TZD) class of synthetic compounds.58, 59 In 1999, two TZDs (rosiglitazone and pioglitazone) were approved by the US FDA for the treatment of type 2 diabetes mellitus based on their inherent property of enhancing insulin sensitivity. As will be discussed, however, there are differences within this class of agents not only with respect to their lipid lowering properties, but also in their propensity to increase the risk of cardiovascular disease and, most intriguingly, their capacity to cause bone loss and marrow adipogenesis.

During the process of adipogenesis, induction of PPARgamma is necessary to convert adipocyte precursors to fully differentiated adipose cells (Figure 1). CCAAT/enhancer-binding protein beta (CEBPbeta) strongly induces the expression of PPARgamma2 and, in turn, PPARgamma protein can stimulate the expression of CCAAT/enhancer-binding protein alpha (CEBPalpha). Early B-cell factor-1, a helix-loop-helix DNA-binding protein, has been shown to be critical for B-cell development.60 Interestingly, expression of this nuclear factor has been found in a variety of tissue sites, including white adipose tissue, and studies suggest that early B-cell factor-1 binds directly to the PPARG promoter and might act between CEBPbeta and CEBPalpha–PPARgamma in the adipocyte differentiation cascade.60, 61

Role in osteogenesis

Elbrecht et al.62 first showed that PPARgamma was expressed in bone marrow mesenchymal stromal cells. Subsequently, it was demonstrated that treatment of bone marrow stromal cells with TZDs resulted in the differentiation of these cells into adipocytes.63 When UAMS-33 cells (a pluripotent cell line) are transfected with PPARG2 and treated with rosiglitazone, adipocyte-like cells appear, and these cells cannot form a mineralized matrix.64 This has led some researchers to conclude that PPARgamma activation precludes osteogenesis. Certainly, this would seem to be the case when analyzing various microarray studies of gene expression; in vivo, however, these networks are counter-balanced by compensatory changes and other variables, such as age and sex. Thus, predictions of gene action based solely on expression can be misleading. For example, when UAMS-33 cells are transfected with PPARG2 and treated with rosiglitazone, reduced expression of RANKL and colony stimulating factor 1 mRNA is seen.65 In vivo, however, Cre–lox P inactivation of PPARG2 using the TEK tyrosine kinase promoter in hematopoietic stem cells results in inhibition of bone resorption and impaired osteoclastogenesis.66

Genetic studies in mice

Mouse models are critical for defining the effects of changes in Pparg2 levels in vivo. For example, homozygous Pparg knockout animals (strain Ppargtm1Tka) are not viable, but heterozygous Pparg+/- mice have a pronounced bone phenotype of increased bone density and decreased bone marrow adiposity.67 Similarly, Pparghyp/hyp mice with a partial loss of function mutation in the Pparg gene have high bone mass and little bone marrow fat.68 Also, deletion of Pparg in adipose tissue using the aP2 promoter results in a high bone mass phenotype before any reduction in fat mass is noted (C. J. Rosen, unpublished data).

Another approach is to treat various animal models directly with TZDs. Such studies have demonstrated that these agents can affect bone mass and bone marrow adiposity. Tornvig et al.69 first demonstrated that troglitazone increases bone marrow adiposity in the Apoe-/- strain, although no changes in bone mass were observed. Darglitazone, which is 20 times more potent than rosiglitazone and 100 times more potent than pioglitazone, caused a reduction in both trabecular and cortical bone and increased bone marrow fat in these mice.70, 71 In contrast, netoglitazone, a relatively weak TZD, increased bone marrow adiposity, but did not affect trabecular bone volume or whole body or areal BMD in C57BL/6 mice.72 Rosiglitazone treatment, particularly in older C57BL/6 mice, causes a significant decrease in trabecular bone density and a substantial increase in bone marrow adiposity, but these changes are genotype-specific and sex-specific.72, 73 Thus, ligand specificity and potency, coactivator and repressor recruitment, and background strain are all variables that predict the responsiveness of the mouse skeleton to TZDs.

Clinical data

In humans, variable skeletal responses to TZDs have also been reported. There are now several large randomized trials of rosiglitazone and pioglitazone for the treatment of type 2 diabetes mellitus demonstrating improved glycemic control, albeit with an associated increased risk of peripheral fractures, particularly in women.74, 75, 76, 77, 78, 79, 80, 81 Smaller studies have also shown a reduction in markers of bone formation and rapid bone loss from the axial skeleton in premenopausal and postmenopausal women.78, 79, 80, 81 Although there is considerable variability among patients in these trials, uncoupling of bone formation from resorption after treatment with the TZDs seems to be comparable with the early changes observed in glucocorticoid-induced osteoporosis. Interestingly, reversibility of TZD-induced bone loss has not been demonstrated.

Based on these studies, the PPARG gene could become a target for drugs aiming to enhance bone mass, as it can regulate lineage allocation within the bone marrow compartment. Attempts to design drugs that suppress PPARgamma expression in bone marrow stromal cells but preserve its capability to enhance insulin sensitivity have, however, met with severe difficulties. An alternative approach would be to manipulate a downstream target of PPARgamma in the bone marrow that would not affect glucose metabolism but, at the same time, would stimulate bone formation by redirecting bone marrow stromal cell lineage commitment. Currently, this strategy is being investigated by targeting one or more of the peripheral 'clock' genes that are expressed in bone as well as fat and that are immediately downstream of PPARgamma.46, 82

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Osteocalcin

Clinical findings have previously suggested a strong connection between energy status of the organism and skeletal turnover.82 For example, individuals with impaired glucose disposal (for example, patients with type I or type II diabetes mellitus) have an increased risk of osteoporotic fractures, even if they have normal bone mass.83, 84 Young women with anorexia nervosa exhibit low bone mass, increased adiponectin production and insulin sensitivity, and enhanced skeletal fragility.85, 86 In contrast, glucocorticoid excess, whether endogenous or exogenously induced, causes an adipose redistribution syndrome associated with low bone mass and insulin resistance.87, 88 Despite these observations, the network linking fat deposition to insulin sensitivity and skeletal remodeling was obscure for many years. The discovery that leptin worked indirectly via the hypothalamus to regulate osteoblastic activity set off a search for novel proteins that connected adipose tissue to bone.

Discovery and initial findings

Lee et al.89 provided the first concrete evidence that the skeleton could function as an endocrine organ, regulating glucose metabolism through the secretion of osteocalcin (OCN; also known as bone gamma-carboxyglutamate protein [BGLAP]). These investigators showed that OCN increased adiponectin and insulin expression in adipocytes and beta-cells, respectively, and that osteoblasts isolated from Ocn-/- (null) mice were incapable of producing this effect. Consistent with this finding, Ocn-/- mice were obese and had higher glucose and lower insulin levels than littermate controls, even though they had no demonstrable skeletal phenotype. To prove that OCN was involved in the interaction between bone and energy, these same authors identified a phosphatase, ESP (also known as PTPRV), which was expressed only in bone and testes. Interestingly, Esp-/- mice are born with profound hypoglycemia and increased insulin sensitivity. When one copy of Ocn was deleted in Esp-/- mice, the metabolic phenotypes were reversed, indicating that ESP and OCN were involved in the same regulatory pathway for glucose metabolism.

OCN is an osteoblast-specific protein and a major noncollagenous protein in the extracellular matrix. Glutamic acid residues in OCN undergo post-translational gamma-carboxylation into gamma-carboxyglutamic acid (Gla); this enhances the affinity of OCN for extracellular matrices, especially hydroxyapatite.90, 91 ESP is thought to be involved in gamma-carboxylation of OCN because mice lacking the Esp gene have increased serum levels of uncarboxylated OCN. Two studies demonstrated that uncarboxylated OCN, acting as a pro-hormone, can increase beta-cell proliferation, insulin secretion, insulin sensitivity, and adiponectin expression.89, 92 Thus, osteoblasts might be able to regulate glucose metabolism by modulating the bioactivity of OCN, possibly through ESP; however, several questions remain unanswered. First, the receptor for uncarboxylated or under-carboxylated OCN has not been described. Second, Esp is a mouse gene that is not expressed in humans; therefore, the significance of this pathway in humans will require more work. Finally, it is not clear how cells sense the varying ratios of uncarboxylated or under-carboxylated OCN to the fully carboxylated molecule.

Latest research

Notwithstanding these important issues, several studies have illustrated progress in this area. For example, Hinoi et al.93 noted that OCN bioactivity is modulated by enhanced sympathetic tone driven by leptin. Remarkably, leptin has been shown to suppress insulin secretion by beta-cells.94, 95 As leptin also negatively regulates osteoblast function, questions arose as to whether the inhibitory effect of leptin on insulin secretion was partially mediated by sympathetic tone. To answer that question, osteoblast-specific Adrb2 knockout mice were generated; these mice were hyperinsulinemic compared with controls, a finding similar to the phenotype in ob/ob mice. In addition, sympathetic tone increased Esp expression in osteoblasts, thereby enhancing gamma-carboxylation but reducing insulin secretion. To conclusively prove that leptin regulated insulin synthesis through OCN, Esp-/- mice were crossed with ob/ob mice. Ob/ob/Esp-/- mice had increased insulin levels compared with controls, and had improved glucose tolerance. Thus, a novel picture has emerged linking glucose metabolism, adipose stores and skeletal activity. This network is initiated by leptin, which, when secreted by adipocytes, stimulates sympathetic tone through the hypothalamus. In turn, sympathetic discharges might increase Esp expression in osteoblasts, resulting in decreased OCN bioactivity. Impaired OCN subsequently alters insulin secretion from beta-cells in the pancreatic islets.

This pathway is both challenging and fascinating in terms of potential clinical implications. First, the ESP-OCN network could be a suitable pharmacologic target for improving insulin sensitivity in adipocytes. Three studies have demonstrated an inverse correlation between serum OCN levels and plasma glucose levels, supporting a role for this pathway in humans.96, 97, 98 Conceivably, administration of an agent that increases levels of uncarboxylated osteocalcin, or recombinant osteocalcin itself, might increase insulin secretion. Several caveats must, however, be considered. First, as noted, Esp is not expressed in humans, so any studies targeting this pathway will first have to delineate the mechanisms of OCN-induced insulin sensitivity. In this context, warfarin, which blocks gamma-carboxylation of several molecules, including OCN, is widely used as an anticoagulant and has been reported to rarely cause hypoglycemia; surprisingly, analysis of glucose metabolism in patients using this drug is lacking. Second, increased uncarboxylated OCN seems to be beneficial for glucose metabolism, but the consequence of increased levels of this pro-hormone on the skeleton has not been firmly established. In vitro and in vivo, high OCN levels are positively correlated with increased bone turnover and formation, but neither OCN-deficient nor OCN transgenic mice have an altered skeletal phenotype.99, 100 Theoretically, inhibiting gamma-carboxylation of OCN could have an impact on bone formation and bone quality. Finally, we do not fully understand the evolutionary implications of this network. Pharmacologic manipulation of OCN synthesis or carboxylation might alter the homeostatic balance between the other two pathways that connect bone and fat.

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Conclusions

Novel studies targeting three distinct networks linking bone and fat provide us with new insight into energy metabolism and its relationship with skeletal turnover (Figure 3). Moreover, progress in this nascent field is accelerating at a rapid pace. For example, Yadav and colleagues101 have just reported that circulating serotonin, principally synthesized from enterochromaffin cells in the gut, inhibits bone formation. Moreover, this group showed that low density lipoprotein receptor-related protein 5 in the intestine tonically suppresses serotonin generation by regulating the enzyme tryptophan hydroxylase 1.102 These surprising findings provide another link between energy metabolism and the skeleton, this time through the gut. Similarly, our understanding of the bone–fat 'neighborhood' within the bone marrow has grown significantly.103 There is evidence to suggest that adipocytes are some of the earliest cells to appear during osteogenesis.104 Changes in oxygen tension and vascular recruitment are clearly important downstream events in this cascade after the appearance of adipocytes, although their precise role is not known.

Figure 3 | The three distinct networks that link bone and fat.
Figure 3 : The three distinct networks that link bone and fat. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.comLeptin signaling via the hypothalamus to the SNS and ADRB2 on osteoblasts triggers bone loss, but putative direct anabolic effects of leptin on osteoblasts remain unresolved. OCN produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, and increases numbers of pancreatic beta-cells and increases insulin secretion. Adipose-derived PPARgamma2 promotes bone marrow adiposity by inducing adiponectin production and decreases bone mass. Potential therapeutic targets include ADRB2 blockade to reduce leptin-induced bone loss, recombinant leptin or leptin mimetic to increase bone mass, PPARgamma agonism or antagonism to inhibit bone marrow adiposity and increase osteoblast differentiation, and recombinant OCN or gamma-carboxylation inhibitors to inhibit adipose deposition and improve bone mass. Leptin, OCN and PPARgamma2 signaling pathways are shown in green, blue and orange, respectively; therapeutic targets are shown in red boxes. Abbreviations: ADRB, beta-adrenergic receptor; OCN, osteocalcin; PPARgamma, peroxisome proliferator activated receptor gamma; SNS, sympathetic nervous system.

Thus, it is imperative to consider the array of cell–cell communications that regulate osteoblast differentiative function and MSC fate. Signals connecting peripheral adipocytes with beta-cells and bone cells imply that stem cells in various adipose depots might become a target for the treatment of osteoporosis. More work is necessary, however, for us to fully understand the consequences of pharmacologically manipulating these networks in order to enhance bone mass and prevent osteoporotic fractures.

Review criteria

We searched for original articles focusing on the bone–fat interaction in the MEDLINE and PubMed databases published between 1980 and 2009. The search terms we used were "bone", "fat", "adipose tissue", "osteocalcin", "PPARg", "leptin" and "bone remodelling". All papers identified were English-language, full-text papers. We also searched the reference lists of identified articles for further papers.

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Acknowledgments

This work was supported by NIH NIAMS grants AR 45433, 54604 to C. J. Rosen.

Competing interests statement

The authors declare no competing interests.

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Author affiliations

  1. Maine Medical Center Research Institute, Scarborough, ME, USA.
  2. Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.

Correspondence to: C. J. Rosen, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074-7205, USA
Email: rosenc@mmc.org

Published online 26 May 2009

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