Contribution of the blood-brain barrier to leptin resistance

In obesity the adipokine leptin is unable to reduce feeding and weight gain although plasma levels are elevated. This phenomenon is called leptin resistance. A reduced transport of leptin through the blood-brain barrier (BBB) of obese subjects is considered to be a cause of leptin resistance. However, the molecular identity of the transporter is still unclear. LRP1 and LRP2 are candidate transporters of leptin. Investigations of the BBB have largely depended on in vitro work. So far it was impossible to delete genes specifically in the BBB. To achieve this goal we have generated a BAC transgenic mouse line that expresses a Cre recombinase selectively in brain endothelial cells. Using this line we will investigate the function of putative leptin transporters in vivo.

We will investigate the transport of leptin into the brain in mice lacking putative leptin transporters in the BBB. Mice deficient of LRP1 and LRP2 in the BBB will be further investigated with respect to body weight regulation, energy consumption, and food intake. Furthermore, we will try to restore leptin transport across the BBB in obese mice by overexpressing putative leptin transporters in the BBB.

Topics for a PhD thesis are:

  • Identification of a leptin transporter at the blood-brain barrier in vivo
  • Role of leptin transport at the blood-brain barrier in body weight regulation and neuroendocrine signaling

We perform transport studies of leptin at the BBB both in vitro and in vivo. A central part of the project will consist in state-of-the-art metabolic phenotyping of mouse lines. This work will be supplemented by a detailed analysis of molecular changes using cell biology and molecular biology techniques (cell culture, immunohistochemistry, quantitative PCR, Western blotting, ELISA, etc.).

Publications

Storck, S. E., Meister, S., Nahrath, J., Meißner, J. N., Schubert, N., Spiezio, A. D., Baches, S., Vandenbroucke, R. E., Bouter, Y., Prikulis, I., Korth, C., Weggen, S., Heimann, A., Schwaninger, M., Bayer, T. A., and Pietrzik, C. U.: Endothelial LRP1 transports amyloid-β1-42 across the blood-brain barrier. J Clin Invest, vol. 126(1), pp. 123-36, 2016, doi: 10.1172/JCI81108 

Spiezio, A. D., Sandin, E. S., Dore, R., Müller-Fielitz, H., Storck, S. E., Bernau, M., Mier, W., Oster, H., Jöhren, O., Piertzk, C. U., Lehnert, H., and Schwaninger, M.: The LepR-mediated leptin transport across brain barriers controls food reward. Mol Metab, vol. NN, , 2017, doi.org/10.1016/j.molmet.2017.12.001