The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats

Martina Winkler; Johanna Schuchard; Ines Stölting; Florian M. Vogt; Jörg Barkhausen; Christoph Thorns; Michael Bader; Walter Raasch

doi:10.1111/bph.13461

The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats

Martina Winkler, Johanna Schuchard, Ines Stölting, Florian M. Vogt, Jörg Barkhausen, Christoph Thorns, Michael Bader, Walter Raasch^*

^*Corresponding author for this work

Charite - Universitatsmedizin Berlin

26 Citations (Scopus)

Abstract

Background and Purpose Reduced weight gain after treatment with AT₁ receptor antagonists may involve a brain-related mechanism. Here, we investigated the role of the brain renin-angiotensin system on weight regulation and food behaviour, with or without additional treatment with telmisartan. Methods Transgenic rats with a brain-specific deficiency in angiotensinogen (TGR(ASrAOGEN)) and the corresponding wild-type, Sprague Dawley (SD) rats were fed (3 months) with a high-calorie cafeteria diet (CD) or standard chow. SD and TGR(ASrAOGEN) rats on the CD diet were also treated with telmisartan (8 mg·kg^-1·d^-1, 3 months). Results Compared with SD rats, TGR(ASrAOGEN) rats (i) had lower weights during chow feeding, (ii) did not become obese during CD feeding, (iii) had normal baseline leptin plasma concentrations independent of the feeding regimen, whereas plasma leptin of SD rats was increased due to CD, (iv) showed a reduced energy intake, (v) had a higher, strain-dependent energy expenditure, which is additionally enhanced during CD feeding, (vi) had enhanced mRNA levels of pro-opiomelanocortin and (vii) showed improved glucose control. Weight gain and energy intake in rats fed the CD diet were markedly reduced by telmisartan in SD rats but only to a minor extent in TGR(ASrAOGEN) rats. Conclusions The brain renin-angiotensin system affects body weight regulation, feeding behaviour and metabolic disorders. When angiotensin II levels are low in brain, rats are protected from developing diet-induced obesity and obesity-related metabolic impairments. We further suggest that telmisartan at least partly lowers body weight via a CNS-driven mechanism.

Original language	English
Journal	British Journal of Pharmacology
Volume	173
Issue number	10
Pages (from-to)	1602-1617
Number of pages	16
ISSN	0007-1188
DOIs	https://doi.org/10.1111/bph.13461
Publication status	Published - 01.05.2016

Funding

The authors gratefully acknowledge Martin Michel (Boehringer Ingelheim Pharmaceuticals, Inc., Ingelheim, Germany) for his critical reading of the manuscript and his helpful comments and Sherryl Sundell for improving the English style. This study was supported by a grant from the Konrad Adenauer Stiftung (Germany). W. R. received telmisartan from Boehringer Ingelheim Pharmaceuticals, Inc. (Ingelheim, Germany).

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Academic Focus: Biomedical Engineering

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10.1111/bph.13461

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@article{48cd431e75ec487e9f9bac8b0a4b0c32,

title = "The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats",

abstract = "Background and Purpose Reduced weight gain after treatment with AT1 receptor antagonists may involve a brain-related mechanism. Here, we investigated the role of the brain renin-angiotensin system on weight regulation and food behaviour, with or without additional treatment with telmisartan. Methods Transgenic rats with a brain-specific deficiency in angiotensinogen (TGR(ASrAOGEN)) and the corresponding wild-type, Sprague Dawley (SD) rats were fed (3 months) with a high-calorie cafeteria diet (CD) or standard chow. SD and TGR(ASrAOGEN) rats on the CD diet were also treated with telmisartan (8 mg·kg-1·d-1, 3 months). Results Compared with SD rats, TGR(ASrAOGEN) rats (i) had lower weights during chow feeding, (ii) did not become obese during CD feeding, (iii) had normal baseline leptin plasma concentrations independent of the feeding regimen, whereas plasma leptin of SD rats was increased due to CD, (iv) showed a reduced energy intake, (v) had a higher, strain-dependent energy expenditure, which is additionally enhanced during CD feeding, (vi) had enhanced mRNA levels of pro-opiomelanocortin and (vii) showed improved glucose control. Weight gain and energy intake in rats fed the CD diet were markedly reduced by telmisartan in SD rats but only to a minor extent in TGR(ASrAOGEN) rats. Conclusions The brain renin-angiotensin system affects body weight regulation, feeding behaviour and metabolic disorders. When angiotensin II levels are low in brain, rats are protected from developing diet-induced obesity and obesity-related metabolic impairments. We further suggest that telmisartan at least partly lowers body weight via a CNS-driven mechanism.",

author = "Martina Winkler and Johanna Schuchard and Ines St{\"o}lting and Vogt, \{Florian M.\} and J{\"o}rg Barkhausen and Christoph Thorns and Michael Bader and Walter Raasch",

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T1 - The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats

AU - Winkler, Martina

AU - Schuchard, Johanna

AU - Stölting, Ines

AU - Vogt, Florian M.

AU - Barkhausen, Jörg

AU - Thorns, Christoph

AU - Bader, Michael

AU - Raasch, Walter

PY - 2016/5/1

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N2 - Background and Purpose Reduced weight gain after treatment with AT1 receptor antagonists may involve a brain-related mechanism. Here, we investigated the role of the brain renin-angiotensin system on weight regulation and food behaviour, with or without additional treatment with telmisartan. Methods Transgenic rats with a brain-specific deficiency in angiotensinogen (TGR(ASrAOGEN)) and the corresponding wild-type, Sprague Dawley (SD) rats were fed (3 months) with a high-calorie cafeteria diet (CD) or standard chow. SD and TGR(ASrAOGEN) rats on the CD diet were also treated with telmisartan (8 mg·kg-1·d-1, 3 months). Results Compared with SD rats, TGR(ASrAOGEN) rats (i) had lower weights during chow feeding, (ii) did not become obese during CD feeding, (iii) had normal baseline leptin plasma concentrations independent of the feeding regimen, whereas plasma leptin of SD rats was increased due to CD, (iv) showed a reduced energy intake, (v) had a higher, strain-dependent energy expenditure, which is additionally enhanced during CD feeding, (vi) had enhanced mRNA levels of pro-opiomelanocortin and (vii) showed improved glucose control. Weight gain and energy intake in rats fed the CD diet were markedly reduced by telmisartan in SD rats but only to a minor extent in TGR(ASrAOGEN) rats. Conclusions The brain renin-angiotensin system affects body weight regulation, feeding behaviour and metabolic disorders. When angiotensin II levels are low in brain, rats are protected from developing diet-induced obesity and obesity-related metabolic impairments. We further suggest that telmisartan at least partly lowers body weight via a CNS-driven mechanism.

AB - Background and Purpose Reduced weight gain after treatment with AT1 receptor antagonists may involve a brain-related mechanism. Here, we investigated the role of the brain renin-angiotensin system on weight regulation and food behaviour, with or without additional treatment with telmisartan. Methods Transgenic rats with a brain-specific deficiency in angiotensinogen (TGR(ASrAOGEN)) and the corresponding wild-type, Sprague Dawley (SD) rats were fed (3 months) with a high-calorie cafeteria diet (CD) or standard chow. SD and TGR(ASrAOGEN) rats on the CD diet were also treated with telmisartan (8 mg·kg-1·d-1, 3 months). Results Compared with SD rats, TGR(ASrAOGEN) rats (i) had lower weights during chow feeding, (ii) did not become obese during CD feeding, (iii) had normal baseline leptin plasma concentrations independent of the feeding regimen, whereas plasma leptin of SD rats was increased due to CD, (iv) showed a reduced energy intake, (v) had a higher, strain-dependent energy expenditure, which is additionally enhanced during CD feeding, (vi) had enhanced mRNA levels of pro-opiomelanocortin and (vii) showed improved glucose control. Weight gain and energy intake in rats fed the CD diet were markedly reduced by telmisartan in SD rats but only to a minor extent in TGR(ASrAOGEN) rats. Conclusions The brain renin-angiotensin system affects body weight regulation, feeding behaviour and metabolic disorders. When angiotensin II levels are low in brain, rats are protected from developing diet-induced obesity and obesity-related metabolic impairments. We further suggest that telmisartan at least partly lowers body weight via a CNS-driven mechanism.

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DO - 10.1111/bph.13461

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SN - 0007-1188

VL - 173

SP - 1602

EP - 1617

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 10

ER -

The brain renin-angiotensin system plays a crucial role in regulating body weight in diet-induced obesity in rats

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