Abstract
Neuronal regulation of energy and bone metabolism is important for body homeostasis. Many studies have emphasized the importance of synaptic adhesion molecules in the formation of synapses, but their roles in physiology still await further characterization. Here, we found that the synaptic adhesion molecule Calsyntenin-3 (CLSTN3) regulates energy and bone homeostasis. Clstn3 global knockout mice show reduced body mass with improved leptin sensitivity and increased energy expenditure compared to their wild-type littermates. In addition, Clstn3 knockout mice show reduced marrow volume and cortical bone mass without alteration of trabecular bone microarchitecture. This reduced bone mass is not bone cell-autonomous because neither osteoblast- nor osteoclast-specific Clstn3 knockout mice show bone defects; similarly, in vitro cultures of both Clstn3 knockout osteoblasts and osteoclasts do not show any defects. These reduced body and bone mass phenotypes can be attributed instead to neuronal CLSTN3 because they are recapitulated by pan-neuronal but not sympathetic neuron-specific deletion of Clstn3. This study reveals novel physiological functions of neuronal Clstn3 as a key regulator of energy and bone homeostasis.
Highlights
As common chronic diseases, respectively, associated with dysregulation of energy and skeletal homeostasis, obesity and osteoporosis are associated with significant morbidity and mortality
Given that increased expression of several skeletal homeostasisSynaptic adhesion molecules (SAMs) is associated with body mass index (BMI), we asked whether Clstn[3] expression is associated with BMI in a rodent animal model
Discussion it is widely accepted that the brain provides central regulation of energy and bone metabolism, the precise mechanisms remain largely unknown
Summary
As common chronic diseases associated with dysregulation of energy and skeletal homeostasis, obesity and osteoporosis are associated with significant morbidity and mortality. In an effort to ease the burden of these diseases, we need to prioritize improving our understanding of the mechanisms underlying energy and skeletal homeostasis. Evidence has accumulated that the brain regulates bone homeostasis[3,4]. Several molecules and pathways involved in the central regulation of energy and skeletal homeostasis. Recent evidence suggests that SAMs may be key players in the coregulation of bone and energy homeostasis. Subsequent molecular studies demonstrated that Cadm[1] knockout results in reduced body and bone mass with improved leptin sensitivity and increased
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