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Development of obesity can be prevented in rats by chronic icv infusions of AngII but less by Ang(1–7)

  • Integrative Physiology
  • Published:
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Abstract

Considering that obesity is one of the leading risks for death worldwide, it should be noted that a brain-related mechanism is involved in AngII-induced and AT1-receptor-dependent weight loss. It is moreover established that activation of the Ang(1–7)/ACE2/Mas axis reduces weight, but it remains unclear whether this Ang(1–7) effect is also mediated via a brain-related mechanism. Additionally to Sprague Dawley (SD) rats, we used TGR(ASrAOGEN) selectively lacking brain angiotensinogen, the precursor to AngII, as we speculated that effects are more pronounced in a model with low brain RAS activity. Rats were fed with high-calorie cafeteria diet. We investigated weight regulation, food behavior, and energy balance in response to chronic icv.-infusions of AngII (200 ng•h−1), or Ang(1–7) (200/600 ng•h−1) or artificial cerebrospinal fluid. High- but not low-dose Ang(1–7) slightly decreased weight gain and energy intake in SD rats. AngII showed an anti-obese efficacy in SD rats by decreasing energy intake and increasing energy expenditure and also improved glucose control. TGR(ASrAOGEN) were protected from developing obesity. However, Ang(1–7) did not reveal any effects in TGR(ASrAOGEN) and those of AngII were minor compared to SD rats. Our results emphasize that brain AngII is a key contributor for regulating energy homeostasis and weight in obesity by serving as a negative brain-related feedback signal to alleviate weight gain. Brain-related anti-obese potency of Ang(1–7) is lower than AngII but must be further investigated by using other transgenic models as TGR(ASrAOGEN) proved to be less valuable for answering this question.

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Abbreviations

AngII:

Angiotensin II

AngI:

Angiotensin I

Ang(1–7):

Angiotensin-(1–7)

AOGEN:

Angiotensinogen

ARB:

AT1 receptor blocker

AT1 receptor:

Angiotensin II type 1 receptor

AUC:

Area under the curve

BBB:

Blood-brain barrier

BMI:

Body mass index

Bw:

Body weight

CD:

Cafeteria diet

Cmax :

Maximal concentration

EDTA:

Ethylenediaminetetraacetic acid

GFAP:

Glial fibrillary acidic protein

HDL:

High-density lipoproteins

HPA axis:

Hypothalamic-pituitary-adrenal axis

Ko:

Knock out

LepR:

Leptin receptor

LRT:

Leptin resistance test

MRI:

Magnetic resonance imaging

OGTT:

Oral glucose tolerance test

POMC:

Proopiomelanocortin

PPARγ:

Peroxisome proliferator-activated receptor delta

PPARδ:

Peroxisome proliferator-activated receptor gamma

RAS:

Renin-angiotensin system

RER:

Respiratory exchange rate

SBP:

Systolic blood pressure

SD:

Sprague Dawley rat

TEL:

Telmisartan

TG:

Transgenic rat

T2DM:

Type 2 diabetes mellitus

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Acknowledgments

MW, MB, FS, IS, SB, and WR performed the research, WR, MW, and MB designed the research study, WR and MW analyzed the data, and WR, MW, and MB wrote the paper. The authors gratefully acknowledge Sherryl Sundell for improving the English style.

Source(s) of funding

Martina Winkler received funding from the Konrad Adenauer Stiftung (Germany). Franziska Schuster was supported by a grant of the German Research Foundation to the Graduiertenkolleg 1957 ‘Adipocyte-Brain Crosstalk’, University of Lübeck. The study was supported by a grant of the German Centre for Cardiovascular Research (DZHK).

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany

    Martina Winkler, Franziska Schuster, Ines Stölting, Sonja Binder & Walter Raasch

  2. National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil

    Michael Bader

  3. Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany

    Michael Bader

  4. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany

    Michael Bader

  5. Center for Structural and Cell Biology in Medicine, Institute for Biology, University of Lübeck, Lübeck, Germany

    Michael Bader

  6. Charité – University Medicine Berlin, Berlin, Germany

    Michael Bader

  7. CBBM (Center of Brain, Behavior and Metabolism), Lübeck, Germany

    Franziska Schuster & Walter Raasch

  8. DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany

    Walter Raasch

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  1. Martina Winkler
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  2. Michael Bader
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  5. Sonja Binder
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Correspondence to Walter Raasch.

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Winkler, M., Bader, M., Schuster, F. et al. Development of obesity can be prevented in rats by chronic icv infusions of AngII but less by Ang(1–7). Pflugers Arch - Eur J Physiol 470, 867–881 (2018). https://doi.org/10.1007/s00424-018-2117-0

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