Leptin is an adipocyte-derived hormone that regulates a broad spectrum of homeostatic functions following its binding to the signaling form of its receptor, ObRb, present on neurons of the central nervous system (Friedman and Halaas, 1998
; Spiegelman and Flier, 2001
). It is widely assumed that the hypothalamus, where ObRb
is expressed in several nuclei, is the main site where leptin acts in the brain (Elmquist, 2000
One homeostatic function regulated by leptin in rodents, sheep and humans is bone remodeling, the mechanism whereby vertebrates renew their bones during adulthood (Karsenty, 2006
; Pogoda et al., 2006
). Leptin regulates, only through a central relay, both phases of this process, resorption and formation (Ducy et al., 2000
; Shi et al., 2008
). One mediator linking leptin signaling in the brain to bone remodeling is the sympathetic tone which inhibits bone formation and favors bone resorption through the β2 adrenergic receptor (Adrβ2) expressed in osteoblasts (Elefteriou et al., 2005
; Takeda et al., 2002
). Hence, sympathetic activity can be used as a readout of leptin regulation of bone mass.
The leptin-dependent central control of bone mass raises the question of the identity of the neurons mediating it. Chemical lesioning experiments performed in both WT and leptin-deficient (ob/ob
) mice followed by leptin intracerebroventricular (ICV) infusion provided compelling evidence that, to regulate bone mass, leptin requires the integrity of neurons of the ventromedial hypothalamic (VMH) nuclei which in turn influence sympathetic activity (Takeda et al., 2002
). Surprisingly however, VMH-specific deletion of ObRb
does not affect bone mass (Balthasar et al., 2004
). At least two interpretations of these experiments can be proposed. The first one is that they are contradicting each other and that, since chemical lesioning is less precise than cell-specific gene deletion, results obtained using the former technique are not reliable (Waddington et al., 2007
). A second, more literal, interpretation views these two experiments as complementary and simply states that VMH neurons are necessary for leptin to regulate bone mass but signaling through ObRb on these neurons is not.
This latter interpretation gains further support if one looks at another function regulated centrally by leptin: appetite. Genetic inactivation of ObRb
in all neurons and chemical destruction of the arcuate nuclei of hypothalamus increases appetite (Cohen et al., 2001
), yet inactivation of ObRb
selectively in arcuate, VMH or in both nuclei does not when mice are fed a normal diet (Balthasar et al., 2004
). This inconsistency echoes the one noted above for the regulation of bone mass. Together they raise the prospect that leptin may first act elsewhere in the brain to affect synthesis of neuromediator(s) that in turn influences bone mass and energy metabolism by signaling to hypothalamic neurons.
Serotonin is an indoleamine produced in enterochromaffin cells of the duodenum and in serotonergic neurons of brainstem that does not cross the blood brain barrier (Mann et al., 1992
). Thus, it is de facto a molecule with two distinct functional identities depending on its site of synthesis: a hormone when made in the gut and a neurotransmitter when made in the brain (Walther et al., 2003
; Yadav et al., 2008
). Although brain-derived serotonin (BDS) has many known roles (Heath and Hen, 1995
) its potential function as a regulator of bone mass accrual or other homeostatic processes has not been thoroughly examined yet. This is an important question to address for several reasons. Firstly, the critical role exerted by gut-derived serotonin on bone formation (Yadav et al., 2008
) raises questions regarding the role BDS may have in this process. Additionally, in invertebrates where it has been tested genetically, serotonin strongly enhances appetite (Horvitz et al., 1982
; Srinivasan et al., 2008
Here we show that, unlike leptin, BDS favors bone mass accrual and appetite, and decreases energy expenditure following its binding to distinct receptors located on two different hypothalamic nuclei. Cell-specific gene deletion of the leptin receptor show that leptin regulation of these functions occurs by inhibiting serotonin synthesis in neurons of the brainstem. These results reveal a different map of leptin action in the brain, expand the importance of BDS in physiology, they also identify a molecular basis for the common central control of bone mass and appetite.