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Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice

  • Franziska Schuster
  • Gianna Huber
  • Ines Stölting
  • Emily E. Wing
  • Kathrin Saar
  • Norbert Hübner
  • William A. Banks
  • Walter Raasch
Organ physiology
Part of the following topical collections:
  1. Organ Physiology

Abstract

Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain.

Keywords

Angiotensin II AT1-receptor blocker Blood-brain barrier Leptin resistance Obesity Telmisartan 

Abbreviations

AngII

Angiotensin II

ARB

Angiotensin II type 1 receptor blocker

AUC

Area under the curve

BBB

Blood-brain barrier

DIO

Diet-induced obesity

HFD

High-fat diet

ITT

Insulin tolerance test

NFD

Normal-fat diet

RAS

Renin-angiotensin system

RER

Respiratory exchange rate

TEER

Transendothelial electrical resistance

TEL

Telmisartan

Notes

Acknowledgments

This publication was supported by a grant of the German Research Foundation to the Graduiertenkolleg 1957 “Adipocyte-Brain Crosstalk,” University of Lübeck, by a grant (81X2700128F) of the German Centre for Cardiovascular Research (DZHK) and by the Robert Pflüger Stiftung.

We thank Prof. Marcus Altfeld and Urte Matschl from the Heinrich Pette Institute, Hamburg, for the measurements with the luminex system, and Prof. Jens Mittag from the Center of Brain, Behavior and Metabolism, Lübeck, who provided the blood pressure measurement system.

The authors gratefully acknowledge Sherryl Sundell for improving the English style.

Parts of the work presented in the article were presented at the 2nd Pharm-Tox Summit in Heidelberg, Germany, 2017 (Naunyn-Schmiedebergs Archives of Pharmacology, 390 (Suppl. 1, 39).

Author contributions

FS, GH, IS, KS, NH, and EEW performed the research; FS, WR, and WAB designed the research study; FS, WR, and WAB analyzed the data; and FS and WR wrote the paper.

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interest.

Supplementary material

424_2018_2178_MOESM1_ESM.docx (256 kb)
ESM 1 (DOCX 255 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Experimental and Clinical Pharmacology and ToxicologyUniversity of LübeckLübeckGermany
  2. 2.CBBM (Center of Brain, Behavior and Metabolism)LübeckGermany
  3. 3.Geriatric Research Education and Clinical Center-VA Puget Sound Health Care SystemSeattleUSA
  4. 4.Max Delbruck Center for Molecular Medicine in the Helmholtz AssociationBerlin-BuchGermany
  5. 5.DZHK (German Centre for Cardiovascular Research), partner site BerlinBerlinGermany
  6. 6.Division of Gerontology and Geriatric Medicine, Department of MedicineUniversity of Washington School of MedicineSeattleUSA
  7. 7.DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/LübeckLübeckGermany

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