Associated Data

Based on these two experiments and a series of appropriate controls, we concluded that VMH neurons were leptin-sensitive antiosteogenic neurons. As it turns out now, this conclusion was both wrong and right. There was obviously an apparent contradiction between these results and ours. A first interpretation of these two experiments could be based on favoring one technical tool over the other.

Because a genetic approach is by far more accurate, sensitive, and specific than chemical lesioning, such an approach would thus tend to ignore the chemical lesioning results and embrace only the genetic results. Such an interpretation therefore rules out VMH neurons as the location where leptin signals in the brain to control bone mass. It does not provide any alternative mechanism to explain this well-documented function of leptin. Another interpretation of these two observations does not discard the validity of the chemical-lesioning experiments that are, after all, the founding experiments in the field of the central control of appetite.

If we consider that, at least technically, both genetic and lesioning experiments are valid, then what do they teach us and how do we reconcile them? A conservative view of these two experiments states, and in fact states only, that leptin needs the integrity of VMH and arcuate neurons of the hypothalamus to regulate bone mass accrual and appetite but needs not to signal itself in these neurons to fulfill these two functions. In other words, it may be that leptin needs the integrity of VMH and arcuate neurons to regulate bone mass and energy metabolism but that it needs not to signal itself in these neurons to do so.

Before explaining how we set out to test this hypothesis, it is critical to underscore how fortunate it was that both types of experiments, the chemical lesioning and the cell-specific gene inactivation, were performed. Indeed, if only the gene inactivation experiments had been done, one would not have been in a position to question their results. Indirectly, this illustrates that no technique in biology is above any other and that the conjunction of assays is always the most powerful approach. To test the aforementioned hypothesis, we relied heavily on clinical information.

In particular, we were intrigued by the fact that patients chronically taking serotonin reuptake inhibitors, a class of drugs supposed to increase the concentration of serotonin in the extracellular milieu, were prone to developing low bone mass, hyperphagia, and weight gain 41 — This clinical information indicates that brain serotonin regulates, directly or indirectly, bone remodeling and appetite.

Serotonin is a bioamine that is synthesized in the brain by neurons of the dorsal and ventral raphe in the brainstem. A remarkable feature of serotonin is that, although it can by synthesized in the brain or in the duodenum, it does not cross the blood-brain barrier. Hence, an ablation of brain serotonin does not affect the function of serotonin in the periphery and vice versa. The biosynthesis of serotonin is initiated by two different enzymes in brainstem neurons and duodenal cells: Therefore, inactivating Tph2 should generate a mouse model lacking serotonin only in the brain.

This is the strategy we used to study the role of serotonin in the regulation of bone mass accrual and energy metabolism. Notwithstanding behavior and mood abnormalities, Tph2 -null, i. They were osteopenic, anorectic, and had an increase in energy expenditure The existence of these phenotypic abnormalities established that brain serotonin is a regulator of bone remodeling and energy metabolism.


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To determine how serotonin controls these functions, we first focused on the regulation of bone mass by brain serotonin. Brain-derived serotonin is a neurotransmitter synthesized in Raphe nuclei neurons of the brainstem. The serotonergic neurons project to the ventromedial hypothalamus VMH and arcuate Arc neurons of the hypothalamus. Brain-derived serotonin regulates bone mass accrual positively after its binding to Htr2c receptors in neurons of VMH, whereas after its binding to the Htr1a and Htr2b receptors on neurons of the arcuate nuclei, serotonin favors appetite. How could the positive regulation of bone mass accrual exerted by brain serotonin be related to the negative regulation exerted by leptin signaling in the brain?

Coregulation of Bone Remodeling and Energy Metabolism

In agreement with this notion, we were able to show through double immunohistochemistry that the long form of the leptin receptor is expressed in Tph2 -expressing, i. Obviously, the formal proof, however, had to come from in vivo manipulations. This is exactly what was observed. Conversely, and with all the limitations that everybody using this technology accepts, cell-specific deletion of the leptin receptor should affect bone mass only when it takes place in brainstem neurons.

Again, this is exactly what was observed Leptin, an adipocyte-derived hormone, regulates bone mass accrual and appetite by inhibiting serotonin synthesis and release by the raphe nuclei neurons of the brainstem. Leptin acts through its binding to its receptor ObRb in the serotonergic neurons of the raphe nuclei. Given the fact that hypothalamic deletion of the leptin receptor does not affect these two functions, the problem was the same as for the regulation of bone mass by leptin Then, if the problem was the same, the hypothesis could be the same.

And the first suspect was already the same because patients chronically taking serotonin reuptake inhibitors often develop hyperphagia and obesity This hypothesis was tested using the brain-derived serotonin-deficient mice we had generated. These mutant mice demonstrated a severe anorexia and an early increase in energy expenditure. Hence, brain serotonin is in vertebrates, as it is in invertebrates, a positive and powerful regulator of appetite 50 , Axon guidance experiments showed the existence of connections between serotonergic neurons and arcuate neurons of the hypothalamus that are widely seen as the main hypothalamic site of the regulation of appetite.

From these experiments one can draw a model that fits the discrepancies highlighted earlier as well as the evolutionary pattern of expression of leptin. In this model, serotonin is an ancestral molecule favoring appetite from worms to humans; when bone appeared, serotonin acquired another function that is to favor bone mass accrual. Leptin is an add-on of evolution appearing with bone cells and inhibiting serotonin synthesis so that it inhibits both bone mass accrual and appetite Fig.

This work started with a rather modest goal, namely to demonstrate the existence of a hormonal link between the control of bone mass and energy metabolism. As the project developed, it became broader, uncovered the existence of a central control of bone mass, and provided a molecular link in the brain for the coregulation of bone mass and energy metabolism. Energy expenditure and serotonin. Biological action of leptin as an angiogenic factor. Potential role of leptin in endochondral ossification.

How to Prevent Loss of Bone Mineral Density - Osteopenia

J Bone Miner Res. Bone as an endocrine organ. Increased bone formation in osteocalcin-deficient mice.


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Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Evolution of leptin structure and function. Identification and expression cloning of a leptin receptor, OB-R. Positional cloning of the mouse obese gene and its human homologue. Molecular evolution of leptin. Detection and quantification of the leptin receptor splice variants Ob-Ra, b, and, e in different mouse tissues. Biochem Biophys Res Commun.

Relation of Serum Serotonin Levels to Bone Density and Structural Parameters in Women

Phenotypes of mouse diabetes and rat fatty due to mutations in the OB leptin receptor. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Anatomic localization of alternatively spliced leptin receptors Ob-R in mouse brain and other tissues. Leptin secretion and leptin receptor in the human stomach.

The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Selective deletion of leptin receptor in neurons leads to obesity. Leptin receptor signaling and the regulation of mammalian physiology. Int J Obes Lond. Evolution of Class I cytokine receptors. Nonadipose tissue production of leptin: Leptin acts as a growth factor on the chondrocytes of skeletal growth centers.

Effects of leptin to cultured growth plate chondrocytes. Leptin induces growth hormone secretion from peripheral blood mononuclear cells via a protein kinase C- and nitric oxide-dependent mechanism. Leptin inhibits bone formation through a hypothalamic relay: Leptin regulates bone formation via the sympathetic nervous system. The complex effects of leptin on bone metabolism through multiple pathways.

Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo. Leptin receptor isoform expression in rat osteoblasts and their functional analysis.

Energy metabolism and the skeleton: Reciprocal interplay

Role of central leptin signaling in the starvation-induced alteration of B-cell development. Bone mineral density directly correlates with elevated serum leptin in haemodialysis patients. Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Reflex sympathetic dystrophy of the lower extremity: Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Effects of beta-adrenergic agonists on bone-resorbing activity in human osteoclast-like cells.

Beta-blockers increase bone mineral density. Clin Orthop Relat Res. Use of beta-blockers and risk of fractures. Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: Impact on differentiation markers, apoptosis, and osteoclastic signaling. Leptin reduces ovariectomy-induced bone loss in rats.

Leptin, body composition and bone mineral density in premenopausal women. Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women. Fat and bone in children: The two faces of serotonin in bone biology. The serotonin signaling system: High bone density due to a mutation in LDL-receptor-related protein 5.

N Engl J Med. Leptin-dependent co-regulation of bone and energy metabolism. Effect of selective serotonin reuptake inhibitors on the risk of fracture. Genetic mouse models for bone studies--strengths and limitations. Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues. Extraction of DNA from microdissected archival tissues. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation.

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How Are Bone Remodeling and Energy Metabolism Coregulated?

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