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.
