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.
J Bone Miner Res. Bone as an endocrine organ. Increased bone formation in osteocalcin-deficient mice.
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Energy metabolism and the skeleton: Reciprocal interplay
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