CNS gangliosides regulate ObR signaling

Neurons of the hypothalamic arcuate nucleus (Arc) are main regulators of energy homeostasis. Neuronal function depends on plasma membrane-located gangliosides. Our studies highlight a novel mechanism for central nervous system regulation of body weight. We demonstrate that leptin signaling is regulated by GCS-derived gangliosides that form complexes with leptin receptors on the plasma membrane of hypothalamic neurons and initiate leptin-dependent formation of intracellular signaling metabolites in vitro.

In line with well-renowned findings of leptin receptor-deficient mice (db/db mice) our mouse model featuring an inducible neuron-specific deletion of GCS (Ugcgf/f//CamKCreERT2 mice) displays obesity and lower sympathetic outflow to peripheral tissues. In these mice, we identified the Arc as an important mediator of deficient body weight regulation as Ugcg gene delivery to the Arc significantly ameliorates obesity development. In line with the in vitro data from cultured hypothalamic neurons, Ugcgf/f//CamKCreERT2 mice show impaired hypothalamic leptin receptor signaling. As a consequence of lower sympathetic activity, Ugcgf/f//CamKCreERT2 mice display decreased thermogenesis and lipid mobilization from peripheral fat stores, leading to a progressive increase in weight despite normal feeding behavior.

In summary, our studies highlight GCS-derived gangliosides as essential components for hypothalamic regulation of energy homeostasis and impaired leptin receptor signaling in ganglioside-depleted neurons as a new mechanism for the development of obesity.