leptin and Bone-Diseases

The metabolism and homeostasis of the skeletal system have historically been considered to be associated with the endocrine system. However, this view has been expanded with the recognition of several neural pathways playing important roles in the regulation of bone metabolism via central relays. In particular, bone metabolism and homeostasis have been reported to be precisely modulated by the central neural signaling. Initiated by the finding of leptin, the axis of neural regulation on bone expands rapidly. The semaphorin-plexin system plays an important role in the cross-talk between osteoclasts and osteoblasts; a complex system has also been identified and includes neuropeptide Y and cannabinoids. These findings facilitate our understanding of the central neuropeptides and neural factors in the modulation of bone metabolism and homeostasis, and these neuronal pathways also represent an area of research scenario that identifies the novel regulation between brain and bone. These regulatory mechanisms correlate with other homeostatic networks and demonstrate a more intricate and synergetic bone biology than previously envisioned. As such, this review summarizes the current knowledge of the neural regulation of bone metabolism and homeostasis, as well as its role in skeletal diseases and discusses the emerging challenges presented in this field.

Topics: Animals; Bone and Bones; Bone Diseases; Bone Remodeling; Brain; Homeostasis; Humans; Leptin; Neuropeptide Y; Semaphorins; Signal Transduction

Adipose tissue has been more accepted as an active contributor to whole body homeostasis, rather than just a fat depot, since leptin, a 16 kDa protein, was discovered as the product of the obese gene in 1994. With more and more studies conducted on this hormone, it has been shown that there is a close relationship between adipose tissue and bone, which have important effects on each other. Bone is the source of many hormones, such as osteocalcin, that can affect energy metabolism and then the anabolism or catabolism of fat tissue. In contrast, the adipose tissue synthesizes and releases a series of adipokines, which are involved in bone metabolism through direct or indirect effects on bone formation and resorption. Interestingly, leptin, one of the most important cytokines derived from fat tissue, seems to account for the largest part of effects on bone, through direct or indirect involvement in bone remodeling and by playing a significant role in many bone diseases, such as osteoporosis, osteoarthritis, rheumatic arthritis, bone tumors and even fractures. In this review, we will discuss the progress in leptin research, particularly focusing on the roles of leptin in bone diseases.

Topics: Adipokines; Adipose Tissue; Animals; Bone and Bones; Bone Diseases; Bone Remodeling; Energy Metabolism; Humans; Leptin; Obesity; Osteocalcin; Osteogenesis

Leptin is an adipokine with pleiotropic actions that regulates food intake, energy metabolism, inflammation and immunity, and also participates in the complex mechanism that regulates skeleton biology, both at bone and cartilage level. Leptin is increased in obesity and contributes to the "low-grade inflammatory state" of obese subjects causing a cluster of metabolic aberrations that affects joints and bone. In this review, we report the most recent research advances about the role of leptin in bone and cartilage function and its implication in inflammatory and degenerative joint diseases, such as osteoarthritis, rheumatoid arthritis and osteoporosis.

Topics: Adipose Tissue; Animals; Bone Diseases; Energy Metabolism; Humans; Joint Diseases; Leptin; Obesity; Signal Transduction

The mouse genetic revolution has shown repeatedly that most organs have more functions than expected. This has led to the realization that, in addition to a molecular and cellular approach, there is a need for a whole-organism study of physiology. The skeleton is an example of how a whole-organism approach to physiology can broaden the functions of a given organ, reveal connections of this organ with others such as the brain, pancreas and gut, and shed new light on the pathogenesis of degenerative diseases affecting multiple organs.

Topics: Animals; Appetite; Bone and Bones; Bone Diseases; Energy Metabolism; Humans; Leptin; Organ Specificity; Osteocalcin; Physiological Phenomena

Anorexia nervosa (AN) initiates an adaptive response at the level of the hypothalamus, which results in a complex interplay involving most elements of the neuroendocrine axis. Consequences of onset of disease in adolescence include amenorrhoea, pubertal arrest with potential loss of target height, and osteoporosis with reduced capacity for future attainment of peak bone mass. With recovery, delay in restoration of menses is common. Hormonal therapies for restoration of bone mineral density (BMD) in adolescents have shown limited efficacy. This review will discuss the reproductive endocrine effects of AN in adolescence, and discuss new investigative tools for monitoring restoration of reproductive function and BMD in this population.

Topics: Adolescent; Anorexia Nervosa; Bone Density; Bone Density Conservation Agents; Bone Diseases; Bone Resorption; Calcium; Dehydroepiandrosterone; Diphosphonates; Estrogen Replacement Therapy; Exercise Therapy; Female; Ghrelin; Humans; Hypothalamo-Hypophyseal System; Insulin-Like Growth Factor I; Leptin; Ovary; Peptide YY; Pituitary-Adrenal System; Reproductive Medicine; Vitamin D; Weight Gain

This review focuses on recent publications concerning medical complications in patients with eating disorders, including anorexia nervosa and bulimia nervosa.. Recent literature continues to reflect that multiple organ systems are frequently affected by eating disorders. The literature underscores the frequently cited risk of premature death in those with anorexia nervosa. A plethora of dermatologic changes have been described, some signaling serious underlying pathophysiology, such as purpura, which indicates a bleeding diathesis. Much of the literature continues to delineate the fact that diabetic patients with eating disorders are at high risk of developing diabetic complications. Gastrointestinal complications can be serious, including gastric dilatation and severe liver dysfunction. Acrocyanosis is common, and patients with anorexia nervosa are at risk of various arrhythmias. Low-weight patients are at high risk for osteopenia/osteoporosis. Nutritional abnormalities are also common, including sodium depletion and hypovolemia, hypophosphatemia and hypomagnesemia. Resting energy expenditure, although very low in low-weight patients, increases dramatically early in refeeding.. Medical complications are common and often serious in patients with eating disorders, particularly those with anorexia nervosa.

Topics: Anorexia Nervosa; Bone Diseases; Bulimia Nervosa; Cardiovascular Diseases; Endocrine System Diseases; Gastrointestinal Diseases; Humans; Leptin; Lung Diseases; Nutrition Disorders; Skin Diseases

Topics: Adolescent; Adrenergic beta-Antagonists; Animals; Bone and Bones; Bone Density; Bone Diseases; Child; Dietary Supplements; Diphosphonates; Humans; Leptin; Osteoblasts; Osteogenesis; Pamidronate; Sympathetic Nervous System; Vitamin D; Vitamin D Deficiency

Several systemic hormones and localized growth factors coordinate events of bone formation and resorption to support bone growth in the young and maintain bone mineral content in the adult. Some of the more important factors produced in the bone microenvironment that impact skeletal biology include prostaglandins, cytokines, and insulin-like growth factors. Dietary fat sources that exert potent biological effects on the skeletal tissues belong to the omega-6 and omega-3 families of essential fatty acids. Specific long-chain polyunsaturated fatty acids (PUFA) belonging to these families are substrates for prostanoids that influence the differentiation and activity of cells in bone and cartilage tissues. These PUFA appear to alter prostanoid formation, cell-to-cell signaling processes, and impact transcription factors in vivo. Hence, these biologically active PUFA can be called nutraceutical fatty acids. This review highlights the role of nutraceutical fatty acids on bone metabolism and joint disease. The recent discovery of transcription factors controlling osteoblast function, and soluble proteins directing osteoclastogenesis and osteoblastogenesis offer new research opportunities for studying nutraceutical fatty acids in skeletal biology.

Topics: Animals; Bone and Bones; Bone Density; Bone Diseases; Bone Remodeling; Cytokines; Dietary Fats, Unsaturated; Dinoprostone; Fatty Acids, Essential; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Health Status; Humans; Leptin; Somatomedins

Clinical and basic research continues to expand our understanding of the complex pathogenesis of inflammatory bowel diseases. The potential roles played by fatty acid intake, serum leptin, and nitric oxide in the promotion of intestinal inflammation in Crohn's disease and ulcerative colitis will be reviewed. In addition, important advances in the areas of bone disease, vitamin deficiency, growth failure, and home parenteral nutrition will be discussed.

Topics: Adult; Bone Diseases; Child; Humans; Inflammatory Bowel Diseases; Leptin; Nitric Oxide; Parenteral Nutrition, Home; Vitamin A; Vitamin E

Leptin is an adipokine that regulates various metabolism, but its association with secondary hyperparathyroidism (SHPT), a clinical manifestation of chronic kidney disease-mineral and bone disorder (CKD-MBD), remains obscure. Parathyroidectomy (PTX) is recommended for severe SHPT patients. Here, the associations between circulating leptin and clinical characteristics in CKD patients were investigated. Effects of PTX on leptin production were analyzed in vivo and in vitro. Controls and CKD patients had approximate serum leptin levels in that a larger proportion of CKD patients with body mass index (BMI) <23 kg/m(2). Serum leptin was related to anemia, albumin, and bone metabolism disorders in CKD patients. Lower intact parathyroid hormone (PTH) was related with higher leptin in PTX patients group. Severe SHPT inhibited uremia-enhanced leptin production in 3T3-L1 adipocytes, which was attenuated after PTX. High levels of PTH were found to reduce Akt phosphorylation and leptin production in vitro but high levels of calcium and phosphorus were not. Successful PTX was found to improve anemia and malnutrition in severe SHPT patients, and this was correlated with increased circulating leptin levels via up-regulated Akt signaling in adipocytes. These findings indicated the therapeutic potential of leptin and related target pathway for improving survival and quality of life in CKD.

Topics: Adolescent; Adult; Aged; Anemia; Bone Diseases; Female; Humans; Leptin; Male; Malnutrition; Middle Aged; Parathyroidectomy; Renal Insufficiency, Chronic

Mineral bone disorder (MBD) is an early complication of chronic kidney disease (CKD), with complex interactions in the bone-kidney-energy axis. These events lead to impaired bone remodelling, which in turn is associated with cardiovascular disease. Recently, we reported on a positive effect of phosphate binder treatment on bone remodelling markers and a reduction in serum FGF-23 levels in predialysis-CKD patients. The goal of the present study of this trial was to examine the effects of phosphate binders on energy-regulating hormones and Wnt pathway.. In this present post hoc analysis of the above randomized, open-label, 8-week trial, which compared the effects of increasing doses of sevelamer-HCl or calcium acetate on various CKD-MBD parameters in 40 normophosphatemic CKD Stage 3-4 patients, we measured serum sclerostin, Dickkopf-1, leptin, adiponectin and serotonin concentrations.. Serum sclerostin, Dickkopf-1 and leptin were elevated at baseline despite normal calcium, phosphorus levels and daily urinary phosphorus excretion. There were significant and positive correlations between sclerostin and FGF-23, as well between leptin and Dickkopf-1. Treatment with both phosphate binders led to a significant decrease in phosphate overload. However, sevelamer-HCl, but not with calcium acetate, led to a significant decrease in serum FGF-23, sclerostin and leptin, and to a significant increase in bone alkaline phosphatase levels.. Early stages of CKD are associated with an impairment of the Wnt pathway, as reflected by elevated sclerostin, and a dysregulation of energy-regulating hormones. Many of these disturbances can be ameliorated by phosphate binder treatment, more with sevelamer-HCl than with calcium acetate.

Topics: Acetates; Adaptor Proteins, Signal Transducing; Adiponectin; beta Catenin; Biomarkers; Bone Density; Bone Diseases; Bone Morphogenetic Proteins; Calcium Compounds; Chelating Agents; Energy Metabolism; Female; Fibroblast Growth Factor-23; Genetic Markers; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Polyamines; Renal Insufficiency, Chronic; Serotonin; Sevelamer; Wnt Proteins

Topics: Bone Density; Bone Diseases; Collagen; Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Fractures, Bone; Homeostasis; Humans; Hypoglycemic Agents; Leptin; Metformin; Osteoporosis; Pregnancy; Thiazolidinediones

Obesity is a risk factor for thoracic ossification of ligament flavum (TOLF) that is characterized by ectopic bone formation in the spinal ligaments. Hyperleptinemia is a common feature of obese people, and leptin, an adipocyte-derived cytokine with proliferative and osteogenic effects in several cell types, is believed to be an important factor in the pathogenesis of TOLF. However, how leptin might stimulate cell osteogenic differentiation in TOLF is not totally understood. We reported here that leptin-induced osteogenic effect in TOLF cells is associated with activation of signaling molecules STAT3, JNK, and ERK1/2 but not p38. Blocking STAT3 phosphorylation with a selective inhibitor, AG490, significantly abolished leptin-induced osteogenic differentiation of TOLF cells, whereas blocking ERK1/2 and JNK phosphorylation with their selective inhibitors PD98059 and SP600125, respectively, had only marginal effects. In addition, we showed that STAT3 interacted with Runt-related transcription factor 2 (Runx2) in the nucleus, and STAT3, Runx2, and steroid receptor coactivator steroid receptor coactivator-1 were components of the transcription complex recruited on Runx2 target gene promoters in response to leptin treatment. Our experiments identified STAT3, Runx2, and steroid receptor coactivator-1 as critical molecules in mediating leptin-stimulated cell osteogenesis in TOLF.

Topics: Aged; Anthracenes; Bone Diseases; Cell Differentiation; Core Binding Factor Alpha 1 Subunit; Female; Flavonoids; Histone Acetyltransferases; Humans; Leptin; Ligaments, Articular; Male; Middle Aged; Mitogen-Activated Protein Kinase 3; Models, Biological; Nuclear Receptor Coactivator 1; STAT3 Transcription Factor; Thoracic Diseases; Transcription Factors

Ob/ob and db/db mice have different aberrations in leptin signaling that both lead to abnormalities in bone mineral density (BMD), and bone histological and histomorphometric outcomes. A few studies have directly compared bone metabolism in ob/ob and db/db mice, and biomechanical strength properties that are surrogate measures of fracture risk, have not been extensively studied. This study compared bone mineral content (BMC), BMD and biomechanical strength properties of femurs and lumbar vertebrae among 10 week old male ob/ob, db/db and C57Bl/6 wildtype (WT) mice. Femurs and lumbar vertebrae were specifically studied to determine if trabecular and cortical bone are regulated by leptin in a similar manner in ob/ob and db/db mice. Femurs of ob/ob and db/db mice had lower BMC, BMD and biomechanical strength properties, including peak load, compared to WT mice. In contrast, lumbar vertebrae BMC and BMD did not differ among genotypes, nor did the peak load from compression testing of an individual lumbar vertebra differ among groups. These findings suggest that leptin deficiency in adolescent male mice first results in changes in femurs, a representative long bone, and alterations in lumbar vertebrae may occur later in life.

Topics: Animals; Biomechanical Phenomena; Body Weight; Bone and Bones; Bone Density; Bone Diseases; Dose-Response Relationship, Drug; Femur; Genotype; Leptin; Lumbar Vertebrae; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Time Factors