14 replies to this topic

[Ben K]

Citrus flavonoid naringenin prevents obesity, metabolic syndrome in mice

A new study using naringenin from citrus prevented weight gain and other signs of metabolic syndrome in mice that were given a "Western-style" diet.

It apparently "[genetically reprograms] the liver to burn up excess fat, rather than store it."

Note: The amount of the flavonoid were higher than you could get from eating fruit alone -- maybe someone can figure out what a similar dosage would be for humans? (Or, on the other hand, suggest any reasons people shouldn't take too much, before commercial "grapefuit diet" supplements start adding ever-larger amounts.)

One caution: naringenin slows the metabolism of many drugs and supplements.

Abstract (from Diabetes):

http://diabetes.diab...01-e194b0f35c35

Naringenin prevents dyslipidemia, apoB overproduction and hyperinsulinemia in LDL-receptor null mice with diet-induced insulin resistance.

Objective: The global epidemic of metabolic syndrome and its complications demand rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin has lipid-lowering properties and inhibits very low density lipoprotein (VLDL) secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance, in vivo.

Research Methods and Design: Low density lipoprotein receptor null (Ldlr^−/−) mice fed a high fat (western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant and obese. Four groups of mice (chow, western and western plus 1% or 3%, w/w naringenin) were fed ad libitum for 4 weeks. Very low density lipoprotein (VLDL) production and parameters of insulin and glucose tolerance were determined.

Results: We report that naringenin treatment of Ldlr^−/− mice fed a western diet, corrected VLDL overproduction, ameliorated hepatic steatosis and attenuated dyslipidemia, without affecting caloric intake or fat absorption. Naringenin: 1) increased hepatic fatty-acid oxidation through a PPARγ coactivator 1 alpha, (PGC1α)/PPARα-mediated transcription program; 2) prevented SREBP1c-mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis, 4) reduced both VLDL-derived and endogenously synthesized fatty acid preventing muscle triglyceride accumulation; 5) improved overall insulin sensitivity and glucose tolerance.

Conclusion: Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome.


Article from Science Daily:

Citrus-derived Flavonoid Prevents Obesity, Study Suggests
ScienceDaily (July 13, 2009) — A flavonoid derived from citrus fruit has shown tremendous promise for preventing weight gain and other signs of metabolic syndrome which can lead to Type 2 Diabetes and increased risk of cardiovascular disease. The study, led by Murray Huff of the Robarts Research Institute at The University of Western Ontario looked at a flavonoid (plant-based bioactive molecule) called naringenin.

In the study one group of mice was fed a high-fat (western) diet to induce the symptoms of metabolic syndrome. A second group was fed the exact same diet and treated with naringenin. Naringenin corrected the elevations in triglyceride and cholesterol, prevented the development of insulin resistance and completely normalized glucose metabolism. The researchers found it worked by genetically reprogramming the liver to burn up excess fat, rather than store it.

"Furthermore, the marked obesity that develops in these mice was completely prevented by naringenin," says Huff, Director of the Vascular Biology Research Group at Robarts and Professor of Medicine and Biochemistry at the Schulich School of Medicine & Dentistry. "What was unique about the study was that the effects were independent of caloric intake, meaning the mice ate exactly the same amount of food and the same amount of fat. There was no suppression of appetite or decreased food intake, which are often the basis of strategies to reduce weight gain and its metabolic consequences."

While grapefruit has long been linked to weight loss diets, the concentrations of the citrus-derived flavonoid being studied are at higher levels than you could get from dietary components. "We are examining the pharmacological properties of naringenin," explains Huff. "The next step is to find out if naringenin prevents heart disease in animal models and to explore the feasibility of clinical trials to determine its safety and efficacy in humans."

This study investigated naringenin's preventative properties, but Huff is also investigating whether it can treat obesity and other existing metabolic problems. "These studies show naringenin, through its insulin-like properties, corrects many of the metabolic disturbances linked to insulin resistance and represents a promising therapeutic approach for metabolic syndrome.

Edited by Ben K, 13 July 2009 - 07:36 PM.

[tunt01]

i also think there will be a lot of mileage in this naringenin flavanoid. i tried to point this issue out to one of these PhD bloggers who is in the "FRUCTOSE IS THE END OF THE WORLD" camp.

a previous study here: http://care.diabetes...6/1406.full.pdf gives some thought to Naringenin. it shows how the flavanoid inhibits ROS, such that foods like oranges become fairly healthy even while containing fructose.


In Vitro ROS results of additional Naringenin added to Orange Juice:




In Vivo C-Reactive Proteirn results of different liquids ingested by volunteers:





I think some people eat only berries and avoid fruits containing lots of fructose, but to me -- this fructose issue seems to mostly apply to HFCS or man-made/processed foods where fructose is added. Oranges seem fine to me.

Edited by prophets, 13 July 2009 - 07:31 PM.

[nameless]

I think some people eat only berries and avoid fruits containing lots of fructose, but to me -- this fructose issue seems to mostly apply to HFCS or man-made/processed foods where fructose is added. Oranges seem fine to me.

Have you seen this study?

http://www.pubmedcen...bmedid=19381015

Dr. Davis recently mentioned it on his blog. Seems fructose is worse than glucose. But there could certainly be a cut-off where a certain amount of fructose is safe, or the benefits of citrus (such as naringenin) outweighs any negative effects from the fructose. Just not sure what that safe level is exactly...

[tunt01]

interesting thx. did not see this. The doctor I was referring to is someone else (the cooling inflammation phd). I will tell you what I was looking for and if you (or anyone) comes across it, I would be really appreciate it.

Problem: Trying to find the citrus w/ the highest level of Naringenin (and other flavanols).

Background: The Okinawan Diet has this very unusual sour citrus food called Citrus Depressa. I was trying to figure out which citrus foods, whether it is sour limes or grapefruits might have more naringenin and what the standard orange might have in naringenin content by comparison. Also comparing the Okinawan citrus content, to more American options would be helpful.

This type of literature might give us better insight into dosing. But in the absence of direct facts, I personally think "everything in moderation," from reseveratrol dose to food consumption. So I typically eat one orange or so per day, often half an orange in the AM and half in the PM. I don't pound out a lot of high fructose food at once.

Edited by prophets, 13 July 2009 - 08:05 PM.

[Lufega]

I was reserching hesperidin and it's role in venous insufficiency. It seems that a lack of the former causes the latter. In any event, the highest concentration of hesperidin and the other bioflavonoids were found in the peel and pulp of oranges and also highest in tangerines.

[tunt01]

tangerines may be closest to the okinawan food, citrus depress.

this study shows that grapefruit beats orange juice in the naringenin area (http://jn.nutrition..../full/131/2/235).



this was a basic crossover experiment with 8 participants.

Edited by prophets, 14 July 2009 - 04:43 PM.

[kismet]

Just to make sure I understand all those who want to use high doses of naringenin: you are not trying to kill yourself, are you? Wasn't naringenin (the substance found in grapefruits) for a long time suspected to cause unpredictable changes in bio-availability of basically every substance ingested? Due to inhibition of metabolisation in the liver? Although, recently I've read that it was never proven that those two are causally interlinked and that other substances may be responsible for those effects.

If you really need high doses of this substance to get any of those speculative effects, then it's really not worth risking your life over it.

Edited by kismet, 14 July 2009 - 05:01 PM.

[Sillewater]

i also think there will be a lot of mileage in this naringenin flavanoid. i tried to point this issue out to one of these PhD bloggers who is in the "FRUCTOSE IS THE END OF THE WORLD" camp.

a previous study here: http://care.diabetes...6/1406.full.pdf gives some thought to Naringenin. it shows how the flavanoid inhibits ROS, such that foods like oranges become fairly healthy even while containing fructose.


In Vitro ROS results of additional Naringenin added to Orange Juice:




In Vivo C-Reactive Proteirn results of different liquids ingested by volunteers:





I think some people eat only berries and avoid fruits containing lots of fructose, but to me -- this fructose issue seems to mostly apply to HFCS or man-made/processed foods where fructose is added. Oranges seem fine to me.

Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon?

Lotito SB, Frei B.
Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331, USA.
Increased fruit and vegetable consumption is associated with a decreased incidence of cardiovascular diseases, cancer, and other chronic diseases. The beneficial health effects of fruits and vegetables have been attributed, in part, to antioxidant flavonoids present in these foods. Large, transient increases in the total antioxidant capacity of plasma have often been observed after the consumption of flavonoid-rich foods by humans. These observations led to the hypothesis that dietary flavonoids play a significant role as antioxidants in vivo, thereby reducing chronic disease risk. This notion, however, has been challenged recently by studies on the bioavailability of flavonoids, which indicate that they reach only very low concentrations in human plasma after the consumption of flavonoid-rich foods. In addition, most flavonoids are extensively metabolized in vivo, which can affect their antioxidant capacity. Furthermore, fruits and vegetables contain many macro- and micronutrients, in addition to flavonoids, that may directly or through their metabolism affect the total antioxidant capacity of plasma. In this article, we critically review the published research in this field with the goal to assess the contribution of dietary flavonoids to the total antioxidant capacity of plasma in humans. We conclude that the large increase in plasma total antioxidant capacity observed after the consumption of flavonoid-rich foods is not caused by the flavonoids themselves, but is likely the consequence of increased uric acid levels.
PMID: 17157175 [PubMed - indexed for MEDLINE]

I can't remember if I read it on this forum or somewhere else, but the decreased oxidative status (e.g. CRP) might be rom the uric acid produced from consuming fructose.


Apparently the fructose inhibits an enzyme that accelerates uric acid production:

Intermediary metabolism of fructose.

Mayes PA.
Department of Veterinary Basic Sciences, Royal Veterinary College, University of London, UK.
Most of the metabolic effects of fructose are due to its rapid utilization by the liver and it by-passing the phosphofructokinase regulatory step in glycolysis, leading to far reaching consequences to carbohydrate and lipid metabolism. These consequences include immediate hepatic increases in pyruvate and lactate production, activation of pyruvate dehydrogenase, and a shift in balance from oxidation to esterification of nonesterified fatty acids, resulting in increased secretion of very-low-density-lipoprotein (VLDL). These effects are augmented by long-term absorption of fructose, which causes enzyme adaptations that increase lipogenesis and VLDL secretion, leading to triglyceridemia, decreased glucose tolerance, and hyperinsulinemia. Acute loading of the liver with fructose causes sequestration of inorganic phosphate in fructose-1-phosphate and diminished ATP synthesis. Consequently, the inhibition by ATP of the enzymes of adenine nucleotide degradation is removed and uric acid formation accelerates with consequent hyperuricemia. These effects are of particular significance to potentially hypertriglyceridemic or hyperuricemic individuals.
PMID: 8213607 [PubMed - indexed for MEDLINE]

I am of the FRUCTOSE IS THE END OF THE WORLD CAMP, but I believe that some stimulation is good because I am also of the hormesis camp. So stressing the body with fruits might be good.

Edited by Sillewater, 14 July 2009 - 09:17 PM.

[nameless]

Grapefruits are my mortal enemy due to drug interactions, so I'm not interested in taking naringenin myself. But if anyone is considering lots of citrus fruits, wouldn't the fructose from citrus counteract some of the benefits found in that rodent study above? If naringenin inhibits VLDL, wouldn't fructose just do the opposite?

Edited by nameless, 14 July 2009 - 09:49 PM.

[aaCharley]

When I read the study I thought it was a tremendous result. Then I saw the questions regarding Grapefruit and drug interactions. In following up on the grapefruit/citrus problem, I found studies which indicate that there is a particular component of grapefruit which causes the drug interaction problem. That seems to be something called furanocoumarin which is not in oranges or other citrus fruit.

There are some very knowledgeabe and educated people who post here. My question is concerning whether the naringenin has the same effect as the furanocoumarin.

[niner]

This paper suggests that naringenin is OK:

Am J Clin Nutr. 2006 May;83(5):1097-105. Free Full Text

Erratum in:
Am J Clin Nutr. 2006 Jul;84(1):264.

A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.
Paine MF, Widmer WW, Hart HL, Pusek SN, Beavers KL, Criss AB, Brown SS, Thomas BF, Watkins PB.

Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, Chapel Hill, NC, USA.

BACKGROUND: Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear. OBJECTIVE: To ascertain whether furanocoumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine. DESIGN: With the use of food-grade solvents and absorption resins, furanocoumarins were removed (approximately 99%) from whole GFJ, whereas other major ingredients (flavonoids) were retained. In an open, 3-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with 1 of the 3 juices (240 mL). Blood was collected over 24 h. At least 1 wk elapsed between juice treatments. RESULTS: The median and range of the area under the curve and the maximum concentration of felodipine were significantly (P < 0.001) greater with consumption of GFJ [110 (range: 58-270) nmol . h/L and 21 (7.6-50) nmol/L, respectively] than with that of orange juice [54 (29-150) nmol . h/L and 7.6 (3.4-13.9) nmol/L, respectively] or furanocoumarin-free GFJ [48 (23-120) nmol . h/L and 8.3 (3.0-16.6) nmol/L, respectively]. GFJ, orange juice, and furanocoumarin-free GFJ did not differ significantly (P > 0.09) in median time to reach maximum plasma concentration [2.5 (1.5-6), 2.8 (1.5-4), and 2.5 (2-6) h, respectively] or terminal half-life [6.6 (4.2-13.6), 7.8 (4.4-13.2), and 6.8 (2.6-14.4) h, respectively]. CONCLUSION: Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism.

PMID: 16685052

In the text, they say: "Flavonoids initially were believed to be the active CYP3A4 inhibitors in GFJ because of their high concentrations in the juice and their inhibitory effects in vitro (10). The administration of purified forms of these compounds to human volunteers, however, failed to show an effect (11–13)."

[aaCharley]

That may be the study I found which identified the furanocoumarin as the culprit for the variation in absorption of the drugs. Thank you for posting that abstract. When I did a Google search for a source for naringenin I was able to locate it. However there was also a disclaimer / warning statement stating that the product may interfere with other drugs. My wife is taking Lipitor and it is one of those listed as having a possible conflict. If the naringenin is free of the furanocoumarin it would seem that there should not really be a problem, maybe. As I understand it there is not a problem with orange juice and Lipitor, just the grapefruit juice. And that seems to be because of the furanocoumarin. Although I CAN read pretty well, I'm also new to reading about these products, supplements, and possible interactions. I suppose I should check the source to see if the product is free of the furanocoumarin flavonoid.

[Ben K]

Swanson Health Products has a "100% Natural Naringen" supplement. The site doesn't say how it's extracted, though, or whether any of the other components of grapefruit would be present.

But there's one comment from a user that suggests it might have drug-absorption effects similar to whole grapefruit (in fact, that's why he took it):

"I used this supplement primarily to enhance the effects of caffeine. It inhibits enzymes in the liver and increases the half life of caffeine, making it last longer. I could definitely tell that my coffee lasted almost twice as long when I used it."

[niner]

"I used this supplement primarily to enhance the effects of caffeine. It inhibits enzymes in the liver and increases the half life of caffeine, making it last longer. I could definitely tell that my coffee lasted almost twice as long when I used it."

This really seems like the kind of thing where there might be a large placebo effect. Grapefruit juice interferes with CYP3A4 in the gut, but not in the liver. Caffeine is metabolized primarily by CYP1A isoforms, with lesser contributions by CYP2E and CYP3A. By "lesser contributions", I mean a lot less, if the following is any indication. They find an intrinsic clearance of 160 L/mmol*hr from CYP1A2, but only 0.6 L/mmol*hr from 3A. There is a lot of 3A in the liver, but that is not inhibited by grapefruit.

Eur J Clin Pharmacol. 1996;49(4):309-15.Links
Biotransformation of caffeine by cDNA-expressed human cytochromes P-450.
Ha HR, Chen J, Krahenbuhl S, Follath F.

Cardiovascular Therapy Research Unit, Cardiology Division, University Hospital Zuerich, Switzerland.

OBJECTIVES: The biotransformation of caffeine has been studied in vitro using human cytochrome P-450 isoenzymes (CYPs) expressed in human B-lymphoblastoid cell lines, namely CYP1A1, 1A2, 2A6, 2B6, 2D6-Val, 2E1 and 3A4, and microsomal epoxide hydroxylase (EH). In addition, CYP2D6-Met was also studied, in which a valine in the wild type (CYP2D6-Val) has been replaced by a methionine due to a G to A mutation in position 112. RESULTS: At caffeine 3 mmol center dot l-1, five CYPs (1A1, 1A2, 2D6-Met, 2E1 and 3A4) catalysed the biotransformation of caffeine. Among the enzymes studied, CYP1A2, which predominantly catalysed paraxanthine formation, had the highest intrinsic clearance (160 l center dot h-1 center dot mmol-1 CYP). Together with its high abundance in liver, it should be considered, therefore, to be the most important isoenzyme in caffeine metabolism. The affinity of caffeine for CYP1A1 was comparable to that of its homologue 1A2. CYP2D6-Met, which catalysed caffeine metabolism by demethylation and 8-hydroxylation, also had a relatively high intrinsic clearance (3.0 l center dot h-1 mmol-1 CYP), in particular for theophylline and paraxanthine formation, with kM values between 9-16 mmol center dot l-1. In contrast, the wild type, CYP2D6-Val, had no detectable activity. In comparison, CYP2E1 played a less important role in in vitro caffeine metabolism. CYP3A4 predominantly catalysed 8-hydroxylation with a kM value of 46 mmol center dot l-1 and an intrinsic clearance of 0.60 l center dot h-1 center dot mmol-1 CYP. Due to its high abundance in human liver, the latter CYP may contribute significantly to the in vivo formation of TMU. CONCLUSION: The findings of this study indicate that i) microsomes from transfected human B-lymphoblastoid cell lines give results close to those obtained with microsomes isolated from human liver, ii) at least four CYP isoforms are involved in caffeine metabolism, iii) at a substrate concentration <0.1 mmol center dot l-1, CYP1A2 and 1A1 are the most important isoenzymes, iv) at higher concentrations the participation of other isoenzymes, in particular CYP3A4, 2E1 and possibly also CYP2D6-Met, are important in caffeine metabolism, and v) the nucleotide composition at position 1120 of CYP2D6 determines the activity of this isoenzyme in caffeine metabolism.

PMID: 8857078

[aaCharley]

I have found what appears to be a very good paper describing the current level of understanding on the grapefruit and drug interactions.

Clinically Significant Grapefruit Juice-Drug Interactions
William W. McCloskey PharmD, RPh
Kathy Zaiken PharmD, RPh
R. Rebecca Couris PhD, RPh

Nutrition Today
January/February 2008
Volume 43 Number 1
Pages 19 - 26

<snip>
The drug-grapefruit juice interaction is caused by inhibition of the intestinal cytochrome P-450 enzyme system, particularly cytochrome P450 3A4 (CYP450 3A4), by 1 or more of the components in grapefruit juice.8 Many active components in grapefruit juice have been evaluated for potentially causing this interaction, including flavonoids such as naringenin, naringin, quercetin, and kaempferol,12,13 and nonflavonoids such as 6',7'-dihydroxybergamottin, bergaptol, and 6',7'-epoxybergamottin.14,15 Naringin, the glycoside of naringenin, is the most abundant flavonoid in grapefruit juice, constituting up to 10% of its dry weight. Naringin is not found in other citrus or fruit juices and is responsible for the distinctive smell and bitter taste of grapefruit juice. Naringin exerts no effect on the activity of the CYP450 system in vitro, but in vivo, its metabolite, naringenin, is a potent inhibitor of both the CYP 3A and CYP 1A2 isoforms.16 However, most research suggests the furanocoumarin 6',7'-didydroxybergamottin and/or its parent compound bergamottin to be the major CYP 3A4 inhibitors found in grapefruit juice.17

The concentrations of flavonoids and/or furanocoumarins in grapefruit juice vary considerably depending on the origin, fruit variety, maturity, quality of raw material, manufacturing procedures, and/or storage conditions.18,19 The amount of active ingredients ingested has an important influence on the mechanism, magnitude, and reproducibility of the grapefruit juice-drug interaction.20
<snip>

Edited by aaCharley, 08 August 2009 - 03:46 PM.