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Animal Models

Green tea reduces body fat via upregulation of neprilysin

Abstract

Background/Objective:

Consumption of green tea has become increasingly popular, particularly because of claimed reduction in body weight. We recently reported that animals with pharmacological inhibition (by candoxatril) or genetic absence of the endopeptidase neprilysin (NEP) develop an obese phenotype. We now investigated the effect of green tea extract (in drinking water) on body weight and body composition and the mediating role of NEP.

Subjects/Methods:

To elucidate the role of NEP in mediating the beneficial effects of green tea extract, ‘Berlin fat mice’ or NEP-deficient mice and their age- and gender-matched wild-type controls received the extract in two different doses (300 or 600 mg kg−1 body weight per day) in the drinking water.

Results:

In ‘Berlin fat mice’, 51 days of green tea treatment did not only prevent fat accumulation (control: day 0: 30.5% fat, day 51: 33.1%; NS) but also reduced significant body fat (green tea: day 0: 27.8%, day 51: 20.9%, P<0.01) and body weight below the initial levels. Green tea reduced food intake. This was paralleled by a selective increase in peripheral (in kidney 17%, in intestine 92%), but not central NEP expression and activity, leading to downregulation of orexigens (like galanin and neuropeptide Y (NPY)) known to be physiological substrates of NEP. Consequently, in NEP-knockout mice, green tea extract failed to reduce body fat/weight.

Conclusions:

Our data generate experimental proof for the assumed effects of green tea on body weight and the key role for NEP in such process, and thus open a new avenue for the treatment of obesity.

Introduction

Green tea and its flavonoids have been subjected to many scientific studies to characterize its long-purported health benefits. Some evidence suggests that regular green tea drinkers have lower risks of circulatory disease1 and of developing cancer.2, 3 Furthermore, epigallocatechin 3-gallate (EGCG), the main flavonoid in green tea has been shown to induce thermogenesis and to stimulate fat oxidation in humans.4

Human obesity has been frequently characterized as the ‘pestilence of the 21st century’. Undoubtedly, the typical form of obesity is a polygenetic disease. Obesity is associated with an immense burden of severe co-morbidities (for example, hypertension, myocardial infarction and diabetes). The prevalence for overweight and obesity has rapidly increased over the past decades, and obesity has become pandemic even reaching developing countries.5 The treatment of obesity puts a tremendous burden on public health budgets; >5% of the total budget in industrialized nations.6 However, actual treatment options for obesity are limited and none of them leads to satisfying results. Therefore, new and innovative strategies to address the problem are urgently needed.

Polygenetic causation of human obesity7 has been modeled using especially grown fat animals, as well as of genetically modified animals. In 2010, we reported that neprilysin (NEP)-knockout mice develop an obese phenotype.8 These results were fully confirmed by a pharmacological approach; wild-type mice also accumulate fat, increase the food intake and gain weight after NEP inhibition with the orally active NEP inhibitor Candoxatril.8 Interestingly, NEP (EC 3.4.24.11) is a potent, widely spread metallo-peptidase, known to degrade a vast number of orexigenic peptide hormones.9, 10, 11

These results point to a possible therapeutic application of NEP activation to reduce body fat and thus body weight. However, such upregulation is still not yet pharmacologically practicable under in vivo conditions. However, Melzig and Janka described a selective upregulation of NEP activity in in vitro cultivated hybridoma cells (SK-N-SH) after 72 h treatment with extracts of green tea.12 Interestingly, first experiments showed that green tea extracts or its polyphenols reduce the body weight of obese mice.13, 14 Bringing all such findings together, the hypothesis of our present study is that the reported reduction in body fat mass and body weight after long-term treatment with extracts of green tea is causally connected to NEP upregulation. We postulated that an increased NEP activity leads to a reduced amount of selected orexigenic peptides, followed by less food intake, and thus to a reduction in body weight.

Materials and methods

Animals and animal treatment

NEP-knockout mice used for the experiments were originally generated by Lu et al.15 and maintained in the breeding stocks of TW Experimental animals were bred from parents, which were F2 after hemizygous mating and being on a C57Bl/6NCrl background.

BMFI mice were generated by and maintained in the breeding stocks of GB16 at the Humboldt-University Berlin.

Animals were housed in 2–3 animals per group at 22±1 °C in a 12 h/12 h light/dark cycle. Animals had unrestricted access to food and tap water or water admixed with green tea extract, respectively. Concentration of green tea extract (‘Green Tea Special Extract EFLA942’, Frutarom, Wädenswil, Switzerland) was 600 mg kg−1 body weight/day (Experiment 1) and 300 mg kg−1 body weight/day (Experiment 2). The manufacturing process of the green tea extract has been described before.17 To neutralize the bitter taste of the green tea, sweetener was added to the tea. The corresponding concentration of saccharin has been determined in preliminary tests. During all experiments, the mice drank the same volume tea as the control mice drank water. Water, as well as green tea admixed water were renewed at least every third day, conterminously with weight control of drinking fluids. Three times per 2 weeks the food was renewed, exactly weighed in and the food consumption per cage calculated. In addition, in the beginning and end of the experiments, body composition was measured by nuclear magnetic resonance (NMR) spectroscopy using Minispec MQ10 NMR Analyzer (Bruker, Billerica, Massachusetts, USA).

Experiments on adult mice were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996) and the Federal Law on the Use of Experimental Animals in Germany, and were approved by the local authorities.

Biochemical experiments

After sacrificing the animals, organs were taken and homogenized and activities of the peptidases NEP, ACE and ACE2 were measured by HPLC (high-performance liquid chromatography). NEP activity was measured by degradation of the substrate [D-Ala,2 Leu5]enkephalin (DALEK),8, 11 ACE activity by degradation of Hip–His–Leu, and ACE2 activity by degradation of Mca-APK (Dnp) as described before.18

To investigate changes of expression in NEP, homogenates were separated into cytosolic and membrane fractions as described previously.10 For western blot analysis of membrane fractions, samples were diluted in 6 × SDS sample buffer, boiled and applied on 10% SDS-polyacrylamide gel electrophoresis followed by transfer to polyvinylidene fluoride membranes. Polyvinylidene fluoride membranes were blocked for 1 h in tris buffered saline with tween 20 containing 7% non-fat dried milk, followed by overnight incubation at 4°C with a primary antibody against NEP (NEP12-M, Alpha Diagnostic Intl. Inc., Texas, USA) or calreticulin (Ab2907, Abcam, Cambridge, UK) diluted in the blocking medium. The primary antibody was detected by HRP-coupled secondary antibodies (anti-rat: A5795, Sigma-Aldrich, Munich, Germany; anti-rabbit: P0448, Dako, Hamburg, Germany) using ECL detection kit (GE Healthcare, Freiburg, Germany) and NEP expression was normalized to calreticulin.

The concentrations of the orexigenic peptides galanin and neuropeptide Y (NPY) were measured as described previously.11

Quantification of NEP mRNA

Cells were stimulated with green tea extract in 12-well plates for 24 h. Afterwards, the cells of each well were lysed with 500 μl TRIzol Reagent (Life Technologies; Darmstadt, Germany), and RNA was isolated according to the manufacturer’s protocol. For the qRT-PCR a LightCycler (Roche, Mannheim, Germany) was used. The QuantiTect SYBR Green PCR-Kit (Qiagen, Hilden, Germany) was used with 10 ng of total RNA of each sample, according to the manual. QuantiTect Primer Assays (Qiagen) Hs_MME_1_SG for NEP and Hs_GAPDH_2_SG for the house-keeping gene GAPDH were used.

Statistics

All data were expressed as mean±s.e.m. For all statistical comparisons, Student’s t-test, One-way analysis of variance (ANOVA) with Bonferroni's Multiple Comparison, determination of Pearson’s correlation coefficients, Graph Pad Prism 5.01 (Graph Pad Software Inc., San Diego, California, USA) was used. A P-value of 0.05 was defined as significant.

Results and discussion

To proof our hypothesis, we provided green tea in drinking water for 51 days to an obese inbred mouse line (‘Berlin Fat Mouse’, BFM) that has been generated by selective breeding over several generations and is characterized by significant fat accumulation.16 As expected, adult animals that drank only tap water increased their body weight significantly (Figure 1a, left columns) over the 51 days of the experiment. This increase was not only prevented in mice with green tea in their tap water, but such mice have been characterized by a significant reduction in body weight over the treatment period (Figure 1a, right columns). Notably, the highly significant difference has occurred for the first time within the third week of treatment (Figure 1b). This effect was even more obvious when calculating the differences for each mouse over the 51 days. Although the control mice gained 4.8g (±0.5 g) body weight, mice with green tea in their drinking water lost 3.7g (±0.9 g). NMR analysis showed that the increase in body weight in mice with control water was mainly caused by a significant increase in body fat mass (Figure 1c, left columns), while the green tea mice have been characterized by a significant fat reduction (Figure 1c, right columns). That the reduction in body weight in such mice drinking green tea (Figure 1a) is caused by a reduction in body fat mass is also illustrated by a significant reduction in the fat-to-body weight ratio in green tea-drinking animals (Figure 1d). To investigate the reason for the reduction in body weight, we measured the food intake in mice with and without green tea. As shown in Figure 1e, mice, which drank green tea, ate significantly less, whereby the effect appeared already within the first third of the experiment and became, as expected, less prominent with reaching normal body weight.

Figure 1
figure1

Treatment of BFMI mice over 51 days with green tea extract supplemented in drinking water (nine mice, 600 mg kg−1, gray columns) and water controls (eight mice, white columns). (a) Average body weight (g per animal) per group on the first and the final day of experiment (day 0 and day 51). (b) Comparison of the development of mean body weight during treatment (data are summarized per week). (c) Total fat amounts on day 0 and day 51. (d) Average ratio of total fat (gram) to body weight (gram) on the first and the final day of experiment (day 0 and day 51). (e) Mean food intake over time divided in three periods (g per day per animal). For a, c-d: *P < 0.05, **P < 0.01, ***P < 0.001 vs. related day 0; For b: **P < 0.01, ***P < 0.001 vs. control animals at the same day.

After killing the mice, we measured NEP activity in a variety of organs. Although green tea did not lead to an increase in activity in the brain, NEP activity was significantly increased in the kidney and even doubled in the small intestine (Figure 2a). This is in accord with and supports further our previous data where Candoxatril increased body weight by only inhibiting peripheral but not central NEP.8 To confirm that the modulation of NEP activity is directly associated with alteration in body fat, we performed correlation analysis showing a highly significant negative correlation (Pearson coefficient=−0.6146, R2=0.3778, P<0.01) between NEP activity and body fat mass (Figure 2b).

Figure 2
figure2

NEP activity and NEP expression in membrane fractions at the end of experiment. (a) NEP activity (TAG per min per mg protein) in membranes of kidneys, small intestine and whole brain (water control, white; green tea treatment, gray). (b) Correlation between body weight change and renal NEP activity. (c) Upper part shows NEP and calreticulin levels of intestinal membrane fractions detected by western blot analysis and lower part the quantification of NEP protein levels of both groups. (d) Quantification of NEP mRNA in neuronal cells (SK-N-SH; left diagram) and endothelial cells (HUVEC; right diagram). *P < 0.05, ***P <0.001 vs. control group (water).

To exclude that green tea increases generally the activity of peptidases, we also measured the influence of green tea on some related peptidases like ACE and ACE2 activity, but could not find alterations in their activity after green tea treatment in the investigated organs (data not shown).

To investigate whether the increased activity was caused by conformational changes of NEP or increased quantities, we measured NEP protein content in the small intestine. As shown in Figure 2c, NEP protein quantities were significantly higher after green tea treatment.

To identify the mechanism the increase in NEP protein is based on and thus to investigate whether the upregulation is on transcriptional or post-translational level, we performed in vitro experiments using SK-N-SH cells as a model of neuronal cells and human umbilical cord vein endothelial cells (HUVEC) as a model of peripheral endothelial cells. Although the stimulation with green tea did not initiate mRNA upregulation in the neuronal cells after 24 h (Figure 2d, left diagram), green tea upregulated NEP mRNA in the peripheral endothelial cells (Figure 2d, right diagram). These data identify the mechanism for the upregulation of peripheral NEP activity by green tea in vivo, showing that NEP mRNA is upregulated in peripheral cells but not in neuronal.

These findings on NEP regulation by green tea extract add further strength to our hypothesis. Although our previous experiments showed that a deficiency in NEP, either pharmacologically or genetically, led to a significant increase in body weight caused by an increase in food intake,8 green tea is opposing such regulation. It leads to an increase in NEP quantity/activity and thus to a reduction in food intake, and consequently to a significant reduction in body fat mass (body weight). Consistent with our previous findings, the effect of NEP modulation on body fat mass is restricted to regulation in peripheral organs and does not affect the neuronal NEP activity. By illustrating first that green tea extract stimulates NEP activity under in vivo conditions, our data also confirm former in vitro findings showing upregulation of NEP activity by green tea in cell culture.12, 19

To substantiate our findings, we repeated our experiments in BMFI mice using a lower dose of green tea to test for dose-dependent regulation (again for 51 days). Although less pronounced then for 600 mg, 300 mg green tea extract per kilogram and day still led to a significantly lower body weight in comparison to tap water (Figure 3a). This was again caused by significant less body fat mass (Figure 3b) leading to a reduced body fat mass to body weight ratio (Figure 3c).

Figure 3
figure3

Treatment of BFMI mice over 51 days with green tea extract supplemented in drinking water (16 mice, 300 mg kg−1, gray columns) and water controls (14 mice, white columns) (ad) or of NEP-knockout mice (NEP-KO; each 12 mice, gray columns) and on their wild-type controls (12 resp. 10 mice, white columns) over 42 days (600 mg kg−1, gray columns) (e, f). (a) Average body weight (g per animal) per group on day 0 and at the end of the experiment (day 51). (b) Total fat amounts (measured by NMR) on day 0 and day 51. (c) Ratio of total fat (gram) to body weight (gram) on the first and the final day of experiment. (d) Green tea induced changes (kidney NEP activity, intestinal galanin concentration, intestinal NPY concentration, body weight, abdominal fat amounts, total fat amounts) in relation to corresponding water controls. (e) Average body weight (g per animal) per group on the first and the final day of experiment (day 0 and day 42). (f) NEP activity (TAG per min per mg protein) of intestine membranes. For a-c: *P < 0.05 vs. control group (water); For d: *P < 0.05, **P < 0.01 vs. control animals set as zero for each parameter; For e, f: *P < 0.05 vs. control animals (water) of same genotype.

As NEP is involved in the metabolism of a variety of orexigens, we investigated whether the increase in NEP activity under green tea treatment led to a decrease in two prominent orexigens that are degraded by NEP, galanin and NPY (Figure 3d). As shown in the same figure, the increase in NEP activity led to a significant reduction in intestinal galanin and NPY concentrations. Thus, our findings build a causality chain: consumption of green tea extract increases NEP activity, leading to a decrease in orexigens, consequently reducing food intake, resulting in less body fat and finally a loss in body weight.

To accumulate final proof for such relationship, we investigated whether green tea effects are conclusively NEP depending. We investigated NEP-deficient male mice and their age- and gender-matched wild-type controls in response to application of green tea for 42 days. To prevent that the gain in body weight in such knockouts, we described to begin to be significant in an age of ~6 months,8 might influence the experiment, we used 3-month-old mice to insure no basal weight differences between both genotypes during the application of green tea. Wild-type animals and NEP knockouts gained significant body weight as expected without differences between the groups (Figure 3e, left columns). As mice at this age are gaining weight as a combination of both body fat mass and muscle accumulation, green tea could only reduce weight gain accumulation though this was significant in these wild-type mice. However, green tea failed to reduce the gain in body weight in NEP-deficient mice (Figure 3e, right columns). As shown in the previous experiments, the green tea extract increased peripheral (intestine, Figure 3f) but not central NEP activity (data not shown) in wild-type animals. Notably, there was only background activity in both organs of the knockouts.

We and others have shown that the genetic deficiency as well as the pharmacological inhibition of NEP leads to a significant gain in body weight due to fat accumulation.8, 20 Although this might have clinical implications in the treatment of cachexia, there would be much more interest to increase NEP activity for the treatment of obesity. However, as for most of the metallopeptidases there are only very limited pharmacological tools to directly increase the activity of such enzymes. Therefore, it is the more promising approach to identify substances that can activate the promoter of the peptidase of interest. Due to indications by the literature that green tea can perform such stimulatory properties12, 19 and first hints that green tea can lead to a reduction in body weight,13, 14 we here corroborated our hypothesis that green tea extract stimulates the generation of peripheral NEP and that the consequent increase in enzymatic activity leads to a reduction in body fat mass by acting as an appetite suppressant. Such findings might be in contrast to experiments showing that EGCG, one of the main components of green tea reduces body weight primarily by decreasing energy absorption and increasing fat oxidation.13, 21 However, in contrast to our study, the authors used highly purified EGCG and thus concentrations significantly above the one we used. Probably, more critical is the fact that the green tea extract we used contains still many other substances, which are marginal in their concentration or disappeared in EGCG preparations. As for many other natural products, it requires the combination of different substances rather than only one substance to generate the effect of the natural product, in our case, green tea. Although our experimental data clearly implicate that green tea extract primarily acts as an appetite supressant, the lack in measurement of energy expenditure is a limitation of our present preclinical study. Consequently, when bringing new clinical trials in place with green tea extract, they do not only have to fulfill scientific standards, what was often not the case for published clinical studies so far, they have to focus especially on a distinction between increased energy expenditure and decreased energy intake in obese patients treated with green tea extract.

It is most likely that the increase in NEP activity by green tea shows its effect on body weight by a higher degradation rate of orexigens that are known to be hydrolyzed by NEP as galanin8 and NPY.22 Although both, galanin23 and NPY24 antagonists, caused significant weight loss in animal models via reduction of food intake, substantial clinical trials with NPY antagonists were disappointing.25 However, this is unlikely a translational problem but might more likely relate to the lack in specificity of such receptor family blockers used. Although the new generation of specific NPY or galanin receptor subtype blockers might generate the positive clinical data one would expect from the animal studies and our own work in NEP-deficient mice,8 the use of NEP-stimulating substances as green tea extract might be the more elegant approach, also because of mirroring the polygenetic approach of obesity.

Taken together, our data give the first rational mechanistic explanation for the often described weight-reducing effect of green tea. They also confirm our hypothesis that a stimulation of NEP activity is a promising pharmacological approach for the treatment of one of the most pandemic diseases of civilization, obesity. Furthermore, the identification of an extract of a natural product, green tea, as a potent stimulator of NEP activity might open the avenue for a fast translational approach turning our findings in a clinical trial. Finally, our results might be also of significant importance for other diseases of civilization as Alzheimer’s disease, where NEP activation as a new treatment option would be of great attraction.

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Acknowledgements

The research has been supported by grants from the Deutsche Forschungsgemeinschaft (DFG; WA1441/18-1, SI483/8-1; WA1441/18-2, SI483/8-2). The authors thank Frutarom for providing the green tea extract free of charge. Furthermore, the intense discussions with Professor Stephen Atkin (Hull York Medical School) and the technical support by Esther-Pia Jansen, Bettina Kahlich, and Stephanie Führl are greatly appreciated.

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Muenzner, M., Tappenbeck, N., Gembardt, F. et al. Green tea reduces body fat via upregulation of neprilysin. Int J Obes 40, 1850–1855 (2016). https://doi.org/10.1038/ijo.2016.172

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