Involvement of the angiotensin system in the regulation of adipogenesis

After chronic treatment with AT1-receptor blockers (ARBs) we observed a loss in body weight and a (partial) preservation of leptin sensitivity although rats were fed with a high calorie cafeteria diet (CD). We hypothesize that transport of leptin across the blood brain barrier is improved by AT1-blockade, thus participating in reducing body weight of obese individuals.

The aim of this project is to investigate how components of the RAAS affect leptin transport at the BBB in vitro and further investigate the effect of AT1 blockade in vivo by using AT1/AT2 knockout mice. Additionally, the clinical relevance of the experimental findings shall be investigated in a clinical trial by including patients featuring symptoms of metabolic syndrome that receive high dose telmisartan treatment.

For cell culture experiments we are establishing models of the blood brain barrier and the blood-cerebrospinal fluid barrier respectively in different cell lines: immortalized murine brain endothelial cells (bEnd.3), immortalized rat choroidal epithelial cells (Z310) and primary murine brain endothelial cells. With these models we will investigate the impact of cardiovascular peptides, such as angiotensin, on leptin transport into the brain in vitro.

In vivo the effect of AngII and ARB on leptin mechanisms will be assessed by determining 1) body weight and energy expenditure, 2) penetration of leptin into the brain and 3) biochemical markers of leptin resistance in a) wild type mice and b) mice lacking AT1-/AT2-receptors.

Body weight and alterations in energy expenditure/intake will be monitored in obese patients after chronic ARB-treatment. Since adipose tissue offers a potential link between obesity and hypertension and components of the RAAS are expressed in adipocytes, we will further study in isolated human abdominal subcutaneous adipocytes whether TNFa-induced AngII secretion and angiotensinogen expression is decreased in ARB-treated patients and whether AngII-induced secretion of leptin is reduced. These experiments will be performed in cooperation with H. Randeva from Medical School, University of Warwick.

Publications

Elias Rawish and Laura Nickel and Franziska Schuster and Ines Stölting and Alex Frydrychowicz and Kathrin Saar and Norbert Hübner and Alaa Othman and Lars Kuerschner and Walter Raasch: Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets. Journal of Endocrinology, no. 244(1), pp. 95-110, 2020

 

Dapper, C., Schuster, F., Stölting, I., Vogt, F., Alenina, L. A. C. e. S., Bader, M. and Raasch, W.: The antiobese effect of AT1 receptor blockade is augmented in mice lacking Mas Naunyn Schmiedebergs Arch Pharmacol, no. 392(7), pp. 865-877, 2019

Schuster, F., Huber, G., Stölting, I., Wing, E. E., Saar, K., Hübner, N., Banks, W. A., and Raasch, W.: Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice. Pflugers Arch, no. 470(11), pp. 1673-1689, 2018, doi: 10.1007/s00424-018-2178-0

Huber, G., Schuster, F., and Raasch, W.: Brain renin-angiotensin system in the pathophysiology of cardiovascular diseases. Pharmacol Res., vol. pii: S1043-6618(17), pp. 30514-5, 2017, doi: 10.1016/j.phrs.2017.06.016

Schuchard, J., Winkler, M., Stölting, I., Schuster, F., Vogt, F. M., Barkhausen, J., Thorns, C., Santos, R. A., Bader, M., and Raasch, W.: Prevention of weight gain after AT1 receptor blockade in diet-induced rat obesity is at least partially related to an angiotensin(1-7)/Mas-dependent mechanism. Br J Pharmacol, vol. 172(15), pp. 3764-78, 2015, doi: 10.1111/bph.13172