Leptin Inhibits Bone Formation through a Hypothalamic Relay

Ducy, Patricia; Amling, Michael; Takeda, Satoshi; Priemel, Matthias; Schilling, Arndt F.; Beil, Frank Timo; Shen, Jianhe; Vinson, Charles; Rueger, Johannes M.; Karsenty, Gérard

doi:10.1016/s0092-8674(00)81558-5

Cited by 1,947 publications

(1,658 citation statements)

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“…7 Although leptin's major role seems to be in the regulation of body weight and energy metabolism, several evidences suggest that this hormone could be involved in other pathophysiological mechanisms, such as immune function, angiogenesis, bone formation and fertility, and the expression of leptin receptor has been demonstrated in a variety of tissues. [8][9][10][11][12][13] The long form of leptin receptor (ObRb) has been found on platelet membrane, 14 and it has been demonstrated that leptin-deficient ob/ob mice, 15,16 and wild-type mice treated with a leptin-neutralizing antibody, 17 develop unstable thrombi and an attenuated thrombotic response to arterial injury, and they exhibit a defective platelet aggregation. Leptin also promotes thrombosis in the mouse, and it potentiates the aggregation of murine platelets in vitro in a leptin receptor-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

et al. 2006

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Objective: To verify whether platelet responsiveness to leptin is associated with metabolic syndrome risk factors. Design: Cross-sectional study. Subjects: We studied 169 consecutive patients, mean age ¼ 43.679.9 years, with overweight (N ¼ 57) or obesity (N ¼ 112). Measurements: Cluster analysis was used to generate three clusters based on platelet responsiveness to increasing doses of leptin. Profiles of metabolic syndrome risk factors of the three clusters were compared by discriminant analysis. Results: Platelet responsiveness to leptin was absent in cluster 1, whereas cluster 3 had the greatest platelet aggregation response to leptin pre-incubation. Plasma leptin levels significantly decreased from cluster 1 to cluster 3 in both gender. Patients in cluster 2 had an intermediate profile of leptin responsiveness. Highest body mass index (BMI) values were more frequent in non-responders, whereas the prevalence of high waist circumference, as well as hypertriglyceridemia and hypertension, increased with increasing responsiveness to leptin from cluster 1 to cluster 3. Pattern of metabolic syndrome risk factors qualified as group specific in 69.0% of the cluster 1, 54.9% of the cluster 2 and 55.8% of the cluster 3. Circulating leptin, waist circumference, plasma triglycerides and BMI defined distinctive patterns of metabolic syndrome risk factors in the clusters. Conclusions: In overweight and obese outpatients, metabolic syndrome risk factors parallel to some extent platelet responsiveness to leptin. Such a correlation involves plasma leptin levels, waist circumference, plasma triglycerides and BMI, and may contribute to the excess risk of cardiovascular events in overweight and obese patients.

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Section: Introductionmentioning

confidence: 99%

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

et al. 2006

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“…In this model, leptin not only regulates body mass, but also -and at much lower serum concentrations -has an inhibitory effect on bone mass. This effect is apparently not mediated via a direct effect on bone cells and is also independent of endocrine organs such as the pituitary gland, the parathyroid, or adrenal glands, but rather suggests an additional control of bone mass solely by the central nervous system [17].…”

Section: Systemic Regulation Of Bone Remodelingmentioning

confidence: 94%

Biology of bone and how it orchestrates the form and function of the skeleton

Sommerfeldt

Rubin

2001

European Spine Journal

168

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IntroductionThe skeleton's principal role as a structure has predisposed bone to the unfortunate reputation of being an inert and static material. Given bone tissue's ability to adapt its mass and morphology to functional demands, its ability to repair itself without leaving a scar, and its capacity to rapidly mobilize mineral stores on metabolic demand, it is in fact the ultimate "smart" material [43] and a dynamic example of "form follows function" in biological systems [45]. Considering the ever-growing number of patients who suffer from devastating disorders of the skeleton and the ever-increasing opportunities inherent in the post-genomics era to treat diseases and injuries to bone [44], it is critical for both the physician and the scientist to more fully understand the biology of bone and how its ability to form and resorb tissue ultimately orchestrates the structural and metabolic successes of the skeleton. CellsThree distinctly different cell types can be found within bone: the matrix-producing osteoblast, the tissue-resorbing osteoclast, and the osteocyte, which accounts for 90% of all cells in the adult skeleton. Osteocytes can be viewed as highly specialized and fully differentiated osteoblasts; Abstract The principal role of the skeleton is to provide structural support for the body. While the skeleton also serves as the body's mineral reservoir, the mineralized structure is the very basis of posture, opposes muscular contraction resulting in motion, withstands functional load bearing, and protects internal organs. Although the mass and morphology of the skeleton is defined, to some extent, by genetic determinants, it is the tissue's ability to remodel -the local resorption and formation of bone -which is responsible for achieving this intricate balance between competing responsibilities. The aim of this review is to address bone's form-function relationship, beginning with extensive research in the musculoskeletal disciplines, and focusing on several recent cellular and molecular discoveries which help understand the complex interdependence of bone cells, growth factors, physical stimuli, metabolic demands, and structural responsibilities. With a clinical and spine-oriented audience in mind, the principles of bone cell and molecular biology and physiology are presented, and an attempt has been made to incorporate epidemiologic data and therapeutic implications. Bone research remains interdisciplinary by nature, and a deeper understanding of bone biology will ultimately lead to advances in the treatment of diseases and injuries to bone itself.

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“…Activation of this receptor suppresses the key transcription factor, ATF4, while it enhances RANKL production. (43)(44)(45) In contrast, genetically manipulated mice with adipocytespecific expression of FoxC2 transcription factor, which increases sensitivity to the beta-adrenergic-cAMP-protein kinase (PKA) signaling pathway, (46) are characterized by high bone mass and conversion of epididymal WAT to beige fat, and beiging of marrow adipocytes. A secretome of beige adipocytes overexpressing FoxC2 includes bone anabolic Wnt10b, IGFBP2, and IGF-1 proteins.…”

Section: Preclinical Insightsmentioning

confidence: 99%

“…Activation of this receptor suppresses the key transcription factor, ATF4, while it enhances RANKL production. (43)(44)(45) …”

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confidence: 99%

Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights

Lecka‐Czernik

Rosen

2015

Journal of Bone and Mineral Research

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Skeletal complications have recently been recognized as another of the several comorbidities associated with diabetes. Clinical studies suggest that disordered glucose and lipid metabolism have a profound effect on bone. Diabetes-related changes in skeletal homeostasis result in a significant increased risk of fractures, although the pathophysiology may differ from postmenopausal osteoporosis. Efforts to understand the underlying mechanisms of diabetic bone disease have focused on the direct interaction of adipose tissue with skeletal remodeling and the potential influence of glucose utilization and energy uptake on these processes. One aspect that has emerged recently is the major role of the central nervous system in whole-body metabolism, bone turnover, adipose tissue remodeling, and beta cell secretion of insulin. Importantly, the skeleton contributes to the metabolic balance inherent in physiologic states. New animal models have provided the insights necessary to begin to dissect the effects of obesity and insulin resistance on the acquisition and maintenance of bone mass. In this Perspective, we focus on potential mechanisms that underlie the complex interactions between adipose tissue and skeletal turnover by focusing on the clinical evidence and on preclinical studies indicating that glucose intolerance may have a significant impact on the skeleton. In addition, we raise fundamental questions that need to be addressed in future studies to resolve the conundrum associated with glucose intolerance, obesity, and osteoporosis. © 2015 American Society for Bone and Mineral Research. KEY WORDS: BONE-FAT INTERACTIONS; SYSTEMS BIOLOGY; BONE INTERACTORS; CELL/TISSUE SIGNALING; TRANSCRIPTION FACTORS; DISEASES AND DISORDERS OF/RELATED TO BONE Clinical Insight Into the Effect of Disordered Glucose and Lipids Homeostasis on BoneD iabetes mellitus (DM) can be considered a disease of intracellular glucose starvation in muscle and fat, due to either lack of insulin (Type 1 [T1D]) or impaired insulin action (Type 2 [T2D]). Both types of DM are associated with an increase in fractures; however, the skeletal phenotype is very different. T1D patients have reduced bone mineral density (BMD), due to insulin and amylin deficiency, whereas T2D patients have either normal or high BMD. T2D is a disease of disordered energy storage as well as glucose intolerance and altered bone strength. Its prevalence is high and not abating. In the United States, 29.1 million people-9.3% of the population-have diabetes; among them, nearly 60% are characterized as obese (http://www.cdc.gov). Insulin resistance is a characteristic feature of T2D in liver, muscle, and fat, leading to glucose intolerance, elevated cardiometabolic risk factors (eg, low-density lipoprotein [LDL] cholesterol), and excess hepatic glucose output. Visceral adipocytes, in particular, are large and surrounded by fibrous and inflammatory elements.In clinical medicine a major paradox is the relationship of obesity to the skeleton. Obese individuals tend to have higher...

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Leptin Inhibits Bone Formation through a Hypothalamic Relay

Cited by 1,947 publications

References 44 publications

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

Relationship between metabolic syndrome and platelet responsiveness to leptin in overweight and obese patients

Biology of bone and how it orchestrates the form and function of the skeleton

Energy Excess, Glucose Utilization, and Skeletal Remodeling: New Insights

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