Fasting-induced lipolysis and hypothalamic insulin signaling are regulated by neuronal glucosylceramide synthase

Central nervous regulation of body weight and adipose tissue function is mainly conducted by hypothalamic neurons. Neuronal function depends on the integrity of the membrane lipid microenvironment. Lipid microdomainscontain large quantities of cholesterol and glycosphingolipids, including glucosylceramide synthase(GCS; gene: Ugcg )-derived gangliosides. The present study demonstrates that Ugcgf/f//CamKCreERT2 mice with genetic GCS deletion in forebrain neurons, dominantly targeting mediobasal hypothalamus (MBH), display impaired fasting-induced lipolysisaccompanied by a decreased norepinephrine content in white adipose tissue(WAT). MBH insulin receptor (IR) levels and signaling are increased in Ugcgf/f//CamKCreERT2 mice. These results are in concordance with reports stating that MBH insulin signaling restrains sympathetic nervous outflow to WAT in fasted mice. In line with the in vivo data, pharmacological GCS inhibition by Genz123346 also increases IR levels as well as IR phosphorylation in insulin-stimulated hypothalamic cells. In addition to studies suggesting that simple gangliosideslike GM3 regulate peripheral IR signaling, this work suggests that also complex neuronal gangliosidesmodulate hypothalamic IR signaling and protein levels. Exemplarily, the complex gangliosideGD1a interacts dynamically with the IR on adult hypothalamic neurons. In summary, our results suggest that neuronal GCS expression modulates MBH insulin signaling and WAT function in fasted mice.