High dose of dietary resveratrol enhances insulin sensitivity in healthy rats but does not lead to metabolite concentrations effective for SIRT1 expression

Andersen, Gaby; Burkon, Alexander; Sulzmaier, Florian J.; Walker, Joel M.; Leckband, Gunhild; Fuhst, Rainer; Erbersdobler, Helmut F.; Somoza, Veronika

doi:10.1002/mnfr.201100292

Cited by 15 publications

(17 citation statements)

References 40 publications

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“…Resveratrol, a natural compound found in grapes and red wine has been shown as an effective SIRT1 activator (Howitz et al, 2003). Numerous studies conducted on animals demonstrated that resveratrol improves glucose metabolism (Baur and Sinclair, 2006; Baur et al, 2006; Barger et al, 2008; Andersen et al, 2011; Kang et al, 2012; Marchal et al, 2012), reduces inflammation (Rivera et al, 2009), reverses non-alcoholic fatty liver disease (Bujanda et al, 2008) and prevents obesity (Dal-Pan et al, 2010). On the other hand the results of clinical studies using resveratrol are controversial.…”

Section: Discussionmentioning

confidence: 99%

Regulation of neurons in the dorsal motor nucleus of the vagus by SIRT1

Jiang

2014

Front. Neurosci.

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Neurons in the dorsal motor nucleus of the vagus (DMV) play a critical role in the regulation of autonomic functions. Previous studies indicated that central activation of sirtuin 1 (SIRT1) has beneficial effects on homeostasis, most likely via modulation of the autonomic output. Sirtuins are NAD+-dependent deacetylases and have been associated with longevity. SIRT1 is one of the best-characterized sirtuins expressed in mammals, and may be involved in the regulation of metabolism. Resveratrol, a SIRT1 activator reduced hyperglycemia likely through activation of vagal output; however, the cellular mechanisms of action have not been determined. In this study, whole-cell patch-clamp electrophysiology on acute brainstem slices was used to test the hypothesis that activation of SIRT1 with resveratrol enhances neurotransmission in DMV neurons. Application of resveratrol increased the frequency of spontaneous excitatory postsynaptic currents (sEPSC). This effect was KATP channel-dependent and was prevented with pre-application of SIRT1 inhibitor, EX527. Resveratrol also increased miniature EPSC (mEPSC) frequency without change in amplitude. Furthermore, our data demonstrated that resveratrol regulates excitatory neurotransmission in a PI3 kinase-dependent manner, since wortmannin, a PI3K inhibitor prevented the increase of mEPSC frequency caused by resveratrol. In conclusion, our data demonstrate that resveratrol via SIRT1 increases excitatory neurotransmission to DMV neurons. These observations suggest that activation of SIRT1 may regulate the function of subdiaphragmatic organs through controlling the activity of parasympathetic DMV neurons.

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Section: Discussionmentioning

confidence: 99%

Regulation of neurons in the dorsal motor nucleus of the vagus by SIRT1

Jiang

2014

Front. Neurosci.

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“…In the majority of in vivo studies where insulin sensitivity was diminished (as a consequence of HFD or STZ-induced diabetes), RES lowered glucose and/or insulin levels and/or improved insulin sensitivity independently of dose and exposition time (Supplementary Table ), particularly in rodents [165,184, 194,196,197,199-205]. In one study, AMPK seemed to be required for the insulin sensitivity enhancing effect of RES in mice [206].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Tomé‐Carneiro

Larrosa²,

González‐Sarrías

et al. 2013

CPD

397

294

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Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a non-flavonoid polyphenol that may be present in a limited number of food-stuffs such as grapes and red wine. Resveratrol has been reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet have drawn the worldwide attention of many research groups over the past twenty years, which has resulted in a huge output of in vitro and animal (preclinical) studies. In line with this expectation, many resveratrol-based nutraceuticals are consumed all over the world with questionable clinical/scientific support. In fact, the confirmation of these benefits in humans through randomized clinical trials is still very limited. The vast majority of preclinical studies have been performed using assay conditions with a questionable extrapolation to humans, i.e. too high concentrations with potential safety concerns (adverse effects and drug interactions), short-term exposures, in vitro tests carried out with non-physiological metabolites and/or concentrations, etc. Unfortunately, all these hypothesis-generating studies have contributed to increased the number of ‘potential’ benefits and mechanisms of resveratrol but confirmation in humans is very limited. Therefore, there are many issues that should be addressed to avoid an apparent endless loop in resveratrol research. The so-called ‘Resveratrol Paradox’, i.e., low bioavailability but high bioactivity, is a conundrum not yet solved in which the final responsible actor (if any) for the exerted effects has not yet been unequivocally identified. It is becoming evident that resveratrol exerts cardioprotective benefits through the improvement of inflammatory markers, atherogenic profile, glucose metabolism and endothelial function. However, safety concerns remain unsolved regarding chronic consumption of high RES doses, specially in medicated people. This review will focus on the currently available evidence regarding resveratrol’s effects on humans obtained from randomized clinical trials. In addition, we will provide a critical outlook for further research on this molecule that is evolving from a minor dietary compound to a possible multi-target therapeutic drug.

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“…It was found that in HFD-fed Wistar rats, resveratrol (50 or 100 mg/kg/day) treatment for 13 weeks significantly suppressed body weight gain [26]. Andersen et al showed that resveratrol treatment (300 mg/kg/day) in male Wistar rats for 8 weeks decreased the fasting serum insulin level and insulin resistance [27]. In another study, resveratrol treatment (400 mg/kg/day) for 9 weeks reduced body weight and enhanced insulin sensitivity, as measured by a hyperinsulinemic euglycemic clamp in C57BL6/J mice fed a HFD [28].…”

Section: Accepted Manuscriptmentioning

confidence: 97%

“…First, the doses of resveratrol that were used in the animal experiments were very broad, ranging from 2.5 to 400 mg/kg/day [26,27,28,50]. We decided to choose the dose of 100 mg/kg/day because it is a middle and safe dose that was suggested by previous studies [ 26,27,28,50,51].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats

et al. 2015

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High dose of dietary resveratrol enhances insulin sensitivity in healthy rats but does not lead to metabolite concentrations effective for SIRT1 expression

Abstract: These results suggest that the improved insulin sensitivity after dietary administration of 300 mg resveratrol/kg body weight does not involve increased protein expression of SIRT1.

Cited by 15 publications

References 40 publications

Regulation of neurons in the dorsal motor nucleus of the vagus by SIRT1

Regulation of neurons in the dorsal motor nucleus of the vagus by SIRT1

Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence

Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats

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