Effects of Leptin on the Skeleton Reid, Ian R; Baldock, Paul A; Cornish, Jillian
Endocrine reviews,
2018-December, Letnik:
39, Številka:
6
Journal Article
Recenzirano
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Abstract
Leptin originates in adipocytes, including those in bone marrow, and circulates in concentrations 20 to 90 times higher than those in the cerebrospinal fluid. It has direct anabolic effects ...on osteoblasts and chondrocytes, but it also influences bone indirectly, via the hypothalamus and sympathetic nervous system, via changes in body weight, and via effects on the production of other hormones (e.g., pituitary). Leptin's role in bone physiology is determined by the balance of these conflicting effects. Reflecting this inconsistency, the leptin-deficient mouse has reduced length and bone mineral content of long bones but increased vertebral trabecular bone. A consistent bone phenotype in human leptin deficiency has not been established. Systemic leptin administration in animals and humans usually exerts a positive effect on bone mass, and leptin administration into the cerebral ventricles usually normalizes the bone phenotype in leptin-deficient mice. Reflecting the role of the sympathetic nervous system in mediating the central catabolic effects of leptin on the skeleton, β-adrenergic agonists and antagonists have major effects on bone in mice, but this is not consistently seen in humans. The balance of the central and peripheral effects of leptin on bone remains an area of substantial controversy and might vary between species and according to other factors such as body weight, baseline circulating leptin levels, and the presence of specific pathologies. In humans, leptin is likely to contribute to the positive relationship observed between adiposity and bone density, which allows the skeleton to respond appropriately to changes in soft tissue mass.
Neuropeptide Y (NPY) acting in the hypothalamus is one of the most powerful orexigenic agents known. Of the five known Y receptors, hypothalamic Y1 and Y5 have been most strongly implicated in ...mediating hyperphagic effects. However, knockout of individual Y1 or Y5 receptors induces late-onset obesity--and Y5 receptor knockout also induces hyperphagia, possibly due to redundancy in functions of these genes. Here we show that food intake in mice requires the combined actions of both Y1 and Y5 receptors. Germline Y1Y5 ablation in Y1Y5(-/-) mice results in hypophagia, an effect that is at least partially mediated by the hypothalamus, since mice with adult-onset Y1Y5 receptor dual ablation targeted to the paraventricular nucleus (PVN) of the hypothalamus (Y1Y5(Hyp/Hyp)) also exhibit reduced spontaneous or fasting-induced food intake when fed a high fat diet. Interestingly, despite hypophagia, mice with germline or hypothalamus-specific Y1Y5 deficiency exhibited increased body weight and/or increased adiposity, possibly due to compensatory responses to gene deletion, such as the decreased energy expenditure observed in male Y1Y5(-/-) animals relative to wildtype values. While Y1 and Y5 receptors expressed in other hypothalamic areas besides the PVN--such as the dorsomedial nucleus and the ventromedial hypothalamus--cannot be excluded from having a role in the regulation of food intake, these studies demonstrate the pivotal, combined role of both Y1 and Y5 receptors in the mediation of food intake.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Excess caloric intake results in increased fat accumulation and an increase in energy expenditure via diet-induced adaptive thermogenesis; however, the underlying mechanisms controlling these ...processes are unclear. Here we identify the neuropeptide FF receptor-2 (NPFFR2) as a critical regulator of diet-induced thermogenesis and bone homoeostasis. Npffr2
mice exhibit a stronger bone phenotype and when fed a HFD display exacerbated obesity associated with a failure in activating brown adipose tissue (BAT) thermogenic response to energy excess, whereas the activation of cold-induced BAT thermogenesis is unaffected. NPFFR2 signalling is required to maintain basal arcuate nucleus NPY mRNA expression. Lack of NPFFR2 signalling leads to a decrease in BAT thermogenesis under HFD conditions with significantly lower UCP-1 and PGC-1α levels in the BAT. Together, these data demonstrate that NPFFR2 signalling promotes diet-induced thermogenesis via a novel hypothalamic NPY-dependent circuitry thereby coupling energy homoeostasis with energy partitioning to adipose and bone tissue.
Neuropepetide Y (NPY) is best known for its powerful stimulation of food intake and its effects on reducing energy expenditure. However, the pathways involved and the regulatory mechanisms behind ...this are not well understood. Here we demonstrate that NPY derived from the arcuate nucleus (Arc) is critical for the control of sympathetic outflow and brown adipose tissue (BAT) function. Mechanistically, a key change induced by Arc NPY signaling is a marked Y1 receptor-mediated reduction in tyrosine hydroxylase (TH) expression in the hypothalamic paraventricular nucleus (PVN), which is also associated with a reduction in TH expression in the locus coeruleus (LC) and other regions in the brainstem. Consistent with this, Arc NPY signaling decreased sympathetically innervated BAT thermogenesis, involving the downregulation of uncoupling protein 1 (UCP1) expression in BAT. Taken together, these data reveal a powerful Arc-NPY-regulated neuronal circuit that controls BAT thermogenesis and sympathetic output via TH neurons.
► Arc NPY reduces TH neuron activity in the PVN via direct Y1 receptor signaling ► Arc NPY signaling leads to reduced TH neuron activity in LC and A1/C1 cell groups ► Arc NPY signaling is associated with decreased UCP1 mRNA and thermogenesis in BAT
Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by ...intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.
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•Osteoclasts fission into daughter cells called osteomorphs•Osteomorphs fuse and recycle back into osteoclasts•Osteomorph upregulated genes control bone structure and function in mice•Osteomorph upregulated genes are implicated in rare and common bone diseases in humans
Tracking osteoclasts during cycles of fission and fusion reveals a transcriptionally distinct “osteomorph” population that are fusion competent, motile, and capable of forming osteoclasts that resorb bone.
Abstract Skeletal research is currently undergoing a period of marked expansion. The boundaries of “bone” research are being re-evaluated and with this, a growing recognition of a more complex and ...interconnected biology than previously considered. One aspect that has become the focus of particular attention is the relationship between bone and fat homeostasis. Evidence from a number of avenues indicates that bone and adipose regulation are both related and interdependent. This review examines the neuropeptide Y (NPY) system, known to exert powerful control over both bone and fat tissue. The actions of this system are characterized by signaling both within specific nuclei of the hypothalamus and also the target tissues, mediated predominantly through two G-protein coupled receptors (Y1 and Y2). In bone tissue, elevated NPY levels act consistently to repress osteoblast activity. Moreover, both central Y2 receptor and osteoblastic Y1 receptor signaling act similarly to repress bone formation. Conversely, loss of NPY expression or receptor signaling induces increased osteoblast activity and bone mass in both cortical and cancellous envelopes. In fat tissue, NPY action is more complex. Energy homeostasis is powerfully altered by elevations in hypothalamic NPY, resulting in increases in fat accretion and body-wide energy conservation, through the action of locally expressed Y1 receptors, while local Y2 receptors act to inhibit NPY-ergic tone. Loss of central NPY expression has a markedly reduced effect, consistent with a physiological drive to promote fat accretion. In fat tissue, NPY and Y1 receptors act to promote lipogenesis, consistent with their roles in the brain. Y2 receptors expressed in adipocytes also act in this manner, showing an opposing action to their role in the hypothalamus. While direct investigation of these processes has yet to be completed, these responses appear to be interrelated to some degree. The starvation-based signal of elevated central NPY inducing marked inhibition of osteoblast activity, whilst promoting fat accretion, indicating skeletal tissue is a component of the energy conservation system. Moreover, when NPY expression is reduced, consistent with high calorie intake and weight gain, bone formation is stimulated, strengthening the skeleton. In conclusion, NPY acts to regulate both bone and fat tissue in a coordinated manner, and remains a strong candidate for mediating interactions between these two tissues. This article is part of a Special Issue entitled: Interactions Between Bone, Adipose Tissue and Metabolism.
To examine an impact of three types of bariatric surgery compared with dietary intervention (DIET), on concurrent changes in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and appetite ...hormones over 3 years. Fifty-five adults were studied during phase of weight loss (0-12 months) and during weight stability (12-36 months) post intervention. Measurements of HOMA-IR, fasting and postprandial PYY and GLP1, adiponectin, CRP, RBP4, FGF21 hormones and dual-Xray absorptiometry were performed throughout the study. All surgical groups achieved significant reductions in HOMA-IR with greatest difference between Roux-en-Y gastric bypass and DIET (- 3.7; 95% CI - 5.4, - 2.1; p = 0.001) at 12-36 months. Initial (0-12 months) HOMA-IR values were no different to DIET after adjustment for the lost weight. During 12-36 months, after controlling for treatment procedure and weight, for every twofold increase in postprandial PYY and adiponectin, HOMA-IR decreased by 0.91 (95% CI - 1.71, - 0.11; p = 0.030) and by 0.59 (95% CI - 1.10, - 0.10; p = 0.023) respectively. Initial, non-sustained changes in RBP4 and FGF21 were not associated with HOMA-IR values. While initial rapid weight loss reduces insulin resistance, the enhanced secretions of PYY and adiponectin may contribute to weight-independent improvements in HOMA-IR during weight stability.Clinical trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000188730.
•Vitamin D exerts integrated effects in musculoskeletal development, aging and injury.•Vitamin D regulates bone and muscle-derived hormones, thereby potentially facilitating cross-talk.•Effects of ...vitamin D in muscle and bone are predominantly indirect via calcium and phosphate levels.•Vitamin D also exerts direct effects in muscle and bone by the local activity of the vitamin D receptor.•Vitamin D signaling presents a potential therapeutic target in the approach to musculoskeletal disease.
Beyond the established effects of muscle loading on bone, a complex network of hormones and growth factors integrates these adjacent tissues. One such hormone, vitamin D, exerts broad-ranging effects in muscle and bone calcium handling, differentiation and development. Vitamin D also modulates muscle and bone-derived hormones, potentially facilitating cross-talk between these tissues. In the clinical setting, vitamin D deficiency or mutations of the vitamin D receptor result in generalized atrophy of muscle and bone, suggesting coordinated effects of vitamin D at these sites. In this review, we discuss emerging evidence that vitamin D exerts specific effects throughout the life of the musculoskeletal system – in development, aging and injury. From this holistic viewpoint, we offer new insights into an old debate: whether vitamin D's effects in the musculoskeletal system are direct via local VDR signals or indirect via its systemic effects in calcium and phosphate homeostasis.
Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and ...suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.
•Anti-sclerostin treatment increases bone mass and fracture resistance in MM•Anti-sclerostin in combination with zoledronic acid is superior to zoledronic acid alone in increasing fracture resistance.
Neural pathways are now a well-appreciated factor in the regulatory milieu controlling the maintenance of bone mass. A number of neural pathways from the brain to bone have been identified. These ...pathways often involve elements of the energy homeostatic apparatus, indicating links between the regulation of bone metabolism and energy balance. Neuropeptide Y is one such factor that co-regulates these two processes. Initial studies outlined the skeletal actions of NPY from within the brain and the interactions with energy homeostatic processes. However, in recent years, an appreciation for the actions of NPY within bone cells has expanded. Cells of the osteoblastic lineage express both NPY ligand and a cognate receptor NPY, Y1R. Murine studies have demonstrated that both ligand and receptor actively control bone mass and osteoblast activity and interact with mechanical signals to integrate with the local loading environment. Local NPY signalling regulates osteoprogenitor production and differentiation, to cover the entire osteoblastic lineage. In addition, several recent studies have demonstrated extra-skeletal actions of osteoblastic NPY signalling, to regulate energy expenditure and with it adiposity, and in a separate study, to control release of a factor-controlling beta cell mass and insulin production/release and with it glucose tolerance. Thus, osteoblastic neuropeptide production and signalling illustrates the rapidly widening sphere of influence of skeletal tissue, and suggests a far more complex and interconnected physiology then is currently appreciated.
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