Neurotensin-Neurotensin Receptor 2 signaling in adipocytes regulates food intake through ceramide metabolism

Neurotensin (NTS) is a secretory peptide produced by the lymphatic endothelial cells (LEC). Our previous study revealed that NTS suppressed the activity of brown adipose tissue via the interactions with NTSR2. In the current study, we found that the depletion of Ntsr2 in the white adipocytes upregulated food intake, while the local treatment of NTS suppressed the food intake. Mechanistic study revealed that the suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2 (CerS2), increased the abundance of its products ceramide C20-C24 and downregulated the production of GDF15 in the white adipose tissues, which was responsible for the elevation of food intake. With four populations of different age and ethnic background, we discovered a potential causal and positive correlation between ceramide C20-24 and food intake in human. Our study identified that NTS-NTSR2 signaling can perform the neurological regulation via controlling the production of ceramide in the white adipocytes.