Neural regulation of energy and bone homeostasis by the synaptic adhesion molecule Calsyntenin-3

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. Bone metabolism: Regulation by brain protein A protein that is highly expressed in brain cells plays a vital role in maintaining balanced energy expenditure and bone health. Recent research indicates that protein activity within brain cells can directly influence energy and bone metabolism. Disruption to these proteins may therefore be associated with obesity and osteoporosis. In experiments on mice, Seok Jun Moon at Yonsei University College of Dentistry in Seoul, South Korea and co-workers found that the protein calsyntenin-3 is expressed at high levels in brain cells. Mice lacking the protein had reduced body mass and growth rate, increased energy expenditure, and lower overall bone mass. This was true regardless of their diet, suggesting they were resistant to diet-induced obesity. The team believe calsyntenin-3 is one of several key brain-based regulators of energy and bone metabolism.