Weight loss and hypophagia after high-dose AT1-blockade is only observed after high dosing and depends on regular leptin signalling but not blood pressure

Müller-Fielitz, Helge; Markert, Antonie; Wittmershaus, C.; Pahlke, Friedrich; Jöhren, Olaf; Raasch, Walter

doi:10.1007/s00210-011-0602-5

Cited by 24 publications

(39 citation statements)

References 55 publications

(62 reference statements)

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“…In experimental studies, high-dosed AT 1 receptor blockers (ARB) are established as a means to reduce body weight (Muller-Fielitz et al 2011, Miesel et al 2012. Weight loss has also been observed in patients during ARB therapy (Kintscher et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Influence of AT1 blockers on obesity and stress-induced eating of cafeteria diet

Gustaityte

Winkler

Stoelting

et al. 2019

Journal of Endocrinology

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Journal of Endocrinology240:1 65-79 V Gustaityte et al. ARB and stress eating of cafeteria diet AbstractBased on findings that treatment with AT 1 receptor blocker (ARB) prevents dietinduced obesity and that the activity of the hypothalamic-pituitary-adrenal (HPA) axis is stimulated by AngII and blocked by ARBs, we aimed to investigate whether ARB treatment can reduce stress-induced eating of cafeteria diet (CD), thus contributing to alterations in eating behavior. Sprague-Dawley rats were fed with chow or CD and treated with telmisartan (TEL, 8 mg/kg/day) or vehicle. At weeks 2 and 12, rats were stressed over five consecutive days by restraint stress (RS, 4 h) and by additional shaking at d5. Tail blood was sampled during RS to determine hormone levels. During the first period of RS, ACTH and corticosterone responses were diminished at d5 in CD-compared to chow-fed rats. Independently of feeding, TEL did not reduce stress hormones. Compared to food behavior before RS, the stress-induced CD eating increased in controls but remained unchanged in TEL-treated rats. After 12 weeks, TEL reduced weight gain and energy intake, particularly in CD-fed rats. Similar to the first RS period, corticosterone response was reduced in CD-fed rats at d5 during the second RS period. TEL did not further reduce stress hormones and did not lessen the CD eating upon RS. We conclude that CD feeding compensates for stress reactions. However, stress-induced CD eating was only reduced by TEL after short term, but not after longterm drug treatment. Thus, the potency of ARBs to lower HPA activity only plays a minor role in reducing energy intake to prevent obesity.

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Section: Introductionmentioning

confidence: 99%

Influence of AT1 blockers on obesity and stress-induced eating of cafeteria diet

Gustaityte

Winkler

Stoelting

et al. 2019

Journal of Endocrinology

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“…A number of AT 1 receptor antagonists such as candesartan, olmesartan or telmisartan have repeatedly been demonstrated to reduce body weight in lean (Zorad et al , ; He et al , ; Müller‐Fielitz et al , ) or obese rodents (Schupp et al , ; He et al , ; Miesel et al , ; Müller‐Fielitz et al , ; Vazquez‐Medina et al , ; Müller‐Fielitz et al , ; Müller‐Fielitz et al , ; Schuchard et al , ). In patients, a moderate weight loss was also observed during irbesartan therapy (Kintscher et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…These include peripheral‐associated pathways such as a reduced growth of adipocytes (Zorad et al , ; Müller‐Fielitz et al , ), anti‐inflammatory effects (Cole et al , ; Guo et al , ) or the activation of PPAR‐δ (He et al , ). The fact that high doses of AT 1 receptor antagonists are required to induce anti‐obesity effects (Müller‐Fielitz et al , ; Müller‐Fielitz et al , ) may indicate that the underlying mechanism involves the CNS because the lipophilicity of these antagonists is low, which limits blood‐brain barrier (BBB) penetration (Michel et al , ). Thus, high doses of AT 1 receptor antagonists may be necessary in particular to affect energy intake and expenditure, while normal doses may help to control glucose and regulate blood pressure (Müller‐Fielitz et al , ; Müller‐Fielitz et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…The fact that high doses of AT 1 receptor antagonists are required to induce anti-obesity effects (Müller-Fielitz et al, 2011;Müller-Fielitz et al, 2014) may indicate that the underlying mechanism involves the CNS because the lipophilicity of these antagonists is low, which limits blood-brain barrier (BBB) penetration (Michel et al, 2013). Thus, high doses of AT 1 receptor antagonists may be necessary in particular to affect energy intake and expenditure, while normal doses may help to control glucose and regulate blood pressure (Müller-Fielitz et al, 2011;Müller-Fielitz et al, 2014). The hypothesis of a brain-related mechanism is supported by the observations that (i) orally administered AT 1 receptor antagonists were able to antagonize pressure responses to centrally administered angiotensin II (AngII), giving evidence for BBB penetration of the antagonists (Gohlke et al, 2001;Gohlke et al, 2002); (ii) hypothalamic orexigenic peptides were suppressed during treatment with AT 1 receptor antagonists (Müller-Fielitz et al, 2011;Noma et al, 2011;Müller-Fielitz et al, 2015); (iii) the stress-induced stimulation of the hypothalamus-pituitary-adrenal (HP A) axis was attenuated in rats by AT 1 receptor antagonists, which was further associated with reduced intake of cafeteria diet (CD) (Miesel et al, 2012); and (iv) the leptin sensitivity was restored during treatment with AT 1 receptor antagonists (Müller-Fielitz et al, 2014;Müller-Fielitz et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Winkler

Schuchard

Stölting

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEReduced weight gain after treatment with AT 1 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. METHODSTransgenic 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 À1 ·d À1 , 3 months). RESULTSCompared 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. CONCLUSIONSThe 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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“…Moreover, angiotensin II (Ang II) inhibits 5′ AMP‐activated protein kinase (AMPK) activity, altering energy metabolism and also serum amyloid‐A, glucocorticoids, and myostatin‐altering muscle protein metabolism . Moreover, blockage of angiotensin II type 1 (AT1) receptors in the brain leads to body weight loss due to hypophagia . Earlier studies indicated that Ang II infusion in rats induces CHF, leading to weight loss , .…”

Section: Introductionmentioning

confidence: 99%

1‐Sarcosine–angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat model

Cichello

Weisinger

Schuijers

et al. 2014

J cachexia sarcopenia muscle

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BackgroundThere are a myriad of proteins responsible for modulation of expenditure of energy. Angiotensin II (Ang II) is a vital component of renin-angiotensin system that affects blood pressure and also linked to both cachexia and obesity via fat and muscle metabolism. Previous research suggests that the direct action of Ang II is on the brain, via angiotensin II type 1 receptor protein, affecting food intake and energy expenditure. The objective of the study is to investigate the effect of 1-sarcosine (SAR)-Ang II infusion on energy expenditure and metabolism in a rat model of congestive heart failure cachexia.MethodsAdult female rats of the Sprague Dawley strain (n = 33) were used (11 pair-fed control, 12 ad libitum and 10, 1-sarcosine–angiotensin II-infused rats). Body weight, faecal excretion, feed intake (in grams), water intake (in milliliters) and urine excreted were recorded daily. The measurements were recorded in three different periods (4 days prior to surgery, “pre-infusion”; day of surgery and 5 days postsurgery, “infusion period”; days 7 to 14, “recovery” period). Different analytical methods were used to measure energy expenditure per period, uncoupling protein 3 mRNA expression, crude protein and adipose tissue body composition.ResultsDuring the infusion period, the SAR–Ang II group experienced rapid weight loss (p < 0.05) in comparison to the ad libitum and pair-fed groups. The SAR–Ang II group displayed lower (p < 0.05) body fat content (in percent) than the controls. There was also increased (p < 0.05) uncoupling protein 3 (UCP3) mRNA expression in the SAR–Ang II group and pair-fed group when compared to the controls.ConclusionIn summary, the results suggest that SAR–Ang II infusion impairs appetite and decreases body weight by wasting predominantly adipose tissue, which may be due to elevated energy expenditure via mitochondrial uncoupling (UCP3 protein activity).

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Weight loss and hypophagia after high-dose AT1-blockade is only observed after high dosing and depends on regular leptin signalling but not blood pressure

Cited by 24 publications

References 55 publications

Influence of AT1 blockers on obesity and stress-induced eating of cafeteria diet

Influence of AT1 blockers on obesity and stress-induced eating of cafeteria diet

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

1‐Sarcosine–angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat model

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