Fu, W.; Yang, Y.; Zhang, Z.; So, J.; Roh, H.-C.; Liu, T.; Xu, M.; Zheng, Y.; Huang, H.; Li, J.

Neurotensin (NTS) is a peptide produced by the lymphatic endothelial cells (LEC) in the adipose tissue. Our previous study revealed that NTS suppressed the activity of brown adipose tissue, which was confirmed in the current study by depleting the neurotensin receptor 2 (Ntsr2) in the brown adipocytes. In contrast, the depletion of Ntsr2 in the white adipocytes upregulated food intake, while the local treatment of NTS peptide in the white adipose tissues suppressed the food intake in a NTSR2 dependent manner. Mechanistic study revealed that the suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2 (CerS2) and increased the abundance of its products ceramide C20-C24, but not C16, in the white adipose tissues. The elevation of ceramide C20-C24, but not C16, downregulated the production of the hormone GDF15 from the adipocytes via unfolded protein responses and upregulated the food intake. With four independent populations, 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 directly controlling the lipid metabolism of the white adipocytes. The ceramide C20-C24 is a key factor to regulate food intake in mammals.