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Resveratrol stimulates AMP kinase activity in neur


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#1 zoolander

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Posted 20 April 2007 - 03:29 AM


The last thing I want to do is add another topic on resveratrol into the forums but I'm all about reporting the research so in this case I'm forced (1 arm behind back) to do it.

Proc Natl Acad Sci U S A. 2007 Apr 16;

    Resveratrol stimulates AMP kinase activity in neurons.


        * Dasgupta B,
        * Milbrandt J.

    Departments of Pathology and Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.

    Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.

    PMID: 17438283 [PubMed - as supplied by publisher]



#2 edward

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Posted 20 April 2007 - 12:31 PM

Very cool find, thanks. I'm all for good resveratrol news, lol though yes there certainly are enough threads on resveratrol... Maybe someone should combine some of them.

One thing though zoolander, when I try to click on the hyperlink above "Resveratrol stimulates AMP kinase activity in neurons" I get an error. Could you re-post the link?

Click HERE to rent this advertising spot to support LongeCity (this will replace the google ad above).

#3 xanadu

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Posted 20 April 2007 - 07:00 PM

And how about a translation for us ignorant types? What does this all mean? It sounds like one of the things rsv does is act as a stimulant. Would that be a correct conclusion? It sure seems to feel stimulating at certain doses though it's a mild and long lasting stimulant without most of the side effects of common stimulants.

I like to see all sorts of info on important subjects like this. Why would it be wrong to post more material just because there are lots of other threads?

#4 Shepard

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Posted 20 April 2007 - 09:31 PM

Hmm, interesting since most people have reported their appetite was curbed by taking resveratrol. Although, I could see AMPK increasing in people taking resveratrol due to the lack of appetite.

#5 zoolander

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Posted 21 April 2007 - 12:30 AM

Ok, I'll attempt to explain why this study was conducted and what they found.

We all know how the story goes............

CR was found to increase longevity and to delay the onset of chronic disease supposedly through the activation of an NAD dependant deacetylase protein called Sir2 which has a mammilain equivalent called Sir1. Resveratrol was identified in a screen for Sit2 activators as the most potent agonist of Sir2 activity (1) and so the story begun and resevatrol was thrust into the lime light.

The primary justification for conducting the above study is related to the the ability of both Resveratrol and CR to cause metabolic changes such as a decreased insulin/IGF signalling and increased mitochondrial biogensis (2, 3) . Parelleling this, alterations in insulin signaling and mitochondrial activity also result from activation of AMP activated kinase (AMPK), which plays an important roles in maintaining cellular energy homoestasis. AMPK's function is to act as a metabolic master switch regulating several intracellular systems. For example, as a muscle biochemist, I have been looking at the energetic changes within the muscle as a result of creatine supplementation in aged subjects. AMPK has the ability to detect and react to fluctuations in the AMP:ATP ratio that take place during rest and exercise (muscle stimulation). In short, when the cell undergoes stress and the demand for ATP increases, AMPK steps in to upregulate process that increase ATP production, which protects the cell and maintains homeostasis. Times of stress where AMPK would/might be activated include hypoxia, oxidative stress, glucose deprivation, and exercise. Additionally, there is research that shows that AMPK is also activated by the drug Metformin (4).

Now, the authors of the above paper hypothise that because some of the metabolic changes caused by resveratrol mimic those observed in response to AMPK activation they believe that AMPK activation might be an important mediator of resveratrol actions in neurons.

To test this they tested whether resveratrol altered AMPK in cultured neuronal cells. Their main findings

1. resveratrol activates AMPK by mechanisms other than an increase in the AMP: ATP ratio
2. suggested that resveratrol activates AMPK and thus promotes mitochondrial biogenesis
3. resveratrols effects on AMPK are independant to it's effects on Sir1 activity therefore there maybe another upstream activator involved
4. resveratrol activates AMPK through the an unpstream AMPK kinase (AMPKK), LKB1 and that Sir1 is not involved in this process
5. resveratrol acutely activates AMPK in the brain of mice (in vitro)

Here's a nice little flow chart that might help you visualise what's going on (not from the above mentioned paper)

Posted Image

On the left you can see how cellular stress and nutrient deprivation (CR?) activates AMPK. The above mentioned studies demonstrates that resveratrol activates AMPK but not through changes in the cellular energetic status or nutrient deprivation but via an upstream AMPK activator, AMPKK LKB1 (also shown on left). So essential you can just draw resveratrol on the above diagram with and arrow pointed towards the LKB1 kinase.

and once actived, AMPK effects a multitude of metabolic process

Posted Image

and here's another diagram that looks at the activation of AMPKK LKB1

Posted Image

I guess this explains why we are seeing resveratrol promoted as a therapeutic in many different situations.

#6 zoolander

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Posted 21 April 2007 - 12:46 AM

Hmm, interesting since most people have reported their appetite was curbed by taking resveratrol. Although, I could see AMPK increasing in people taking resveratrol due to the lack of appetite.


well if you look at the above diagram, if resveratrol activates AMPK-LKB1 then it would trigger the hypothalamus to increase hunger and thus increase food intake. This makes sense because resveratrol is a CR mimetic. Essentially in CR you have a decrease in caloric intake that would stimulate a negative feedback mechanism (increase hunger and food intake) to correct the imbalance. However, there would most likely be no such deprivation with resveratrol supplementation. Activation of AMPK-LKB1 by resveratrol without the requirement for nutrient would still increase hunger and food intake and therefore one would assume promote weight gain.

#7 zoolander

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Posted 21 April 2007 - 12:48 AM

NOTE: on the front page of the page in small print there is a conflict of interest warning that states

"J.M (Author) and Washington university have a financial interest in Sirtris Pharmaceuticals. Sirtris Pharmaceuticals did not support this work."

#8 Shepard

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Posted 21 April 2007 - 01:14 AM

well if you look at the above diagram,  if resveratrol activates AMPK-LKB1 then it would trigger the hypothalamus to increase hunger and thus increase food intake. This makes sense because resveratrol is a CR mimetic. Essentially in CR you have a decrease in caloric intake that would stimulate a negative feedback mechanism (increase hunger and food intake) to correct the imbalance. However, there would most likely be no such deprivation with resveratrol supplementation. Activation of AMPK-LKB1 by resveratrol without the requirement for nutrient would still increase hunger and food intake and therefore one would assume promote weight gain.


Yeah, so if resveratrol has a direct effect on AMPK we should be seeing the opposite with regards to body composition changes and hunger reports, right? There is the rumor that it has caused significant T/E changes, but nothing solid has been shown, as far as I know.

I really need to catch up on the resveratrol research.

#9 zoolander

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Posted 21 April 2007 - 01:32 AM

actually is has an indirect effect on AMPK but a direct effect on AMPK-LKB1

here is AMPK-LKB1 actions
Adipose tissue: decrease fatty acid synthesis, decreased lipolysis
Heart and skeletal muscle: increased glucose uptake, increased glycolysis, increased fatty acid uptake, increased mitochondrial oxidation
Brain/hypothalamus: Increased sense of hunger, increased food intake

#10 Brainbox

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Posted 21 April 2007 - 07:29 AM

Zoo, could you explain the semantics of the red and green lines? I guess red is activation and green is inhibition, but, just a guess.

Could it make sense that people at the lower end of BMI experience increase of appetite while at the higher end appetite is decreased? (As stated by anecdotal reports in the 500mg thread?)

The increased mitochondrial oxidation could be a bit worrying I guess... ;)

#11 xanadu

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Posted 21 April 2007 - 06:19 PM

Thanks zoo, that is much better. We are not a class of graduate biochemistry students and we need our jargon watered down a little. At least I do. Stuff like this tends to make me scratch my head since I'm not into it like you are

"Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK."

RSV does not seem to increase appetite, that is one flaw I can see in the reasoning. Of course many things do not work exactly as they might be expected to in theory. If not for that, we would just use theory and never test anything. The anecdotal reports on rsv indicate either a decrease in appetite or no reported effects either way. I have not heard any reports of greater hunger though they may exist. In fact some people have reported weight loss. I myself lost some weight on it but I was trying to lose weight I'd picked up near the end of last year so I can't say I really saw a lot in that area. I just recently upped my dose and am still playing around with it.

It does seem to be stimulating but many have said the effects wear off or you get used to them after a while. It may be that just after upping your dose you might notice effects like that. I cut back recently even though I was using only a fraction of what some people are using. Some can use 400mg a day and not notice a thing. Some take 4gm a day. Not me, I've seen too many bad things come from megadosing on stuff that is good for you. Is there anything in the world that won't hurt you if you use too much of it?

#12 tamalak

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Posted 22 April 2007 - 03:14 AM

A noob question I've been wanting to ask about resveratrol (go easy on me, I've only had two courses in bio)

Studies have shown that lab animals who are given doses of resveratrol over long periods of time eventually have more mitochondria in their cells. These mitochondria are also more efficient (which presumably means less side product and free radicals per ATP generated).

While it's obviously good to have more efficient mitochondria, wouldn't having MORE total in cells increase metabolic rate, and thus any aging processes that are related to metabolism?

I thought one of the beneficial effects of a calorie-restricted diet was a decrease in metabolic rate (the body "turns down the thermostat") so how is resveratrol mimiking the effects of a CRON diet with this opposite effect?

#13 niner

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Posted 22 April 2007 - 04:01 AM

Regarding resveratrol's effect on hunger, I think the AMPK mediated effects may be swamped at first by the serotonin/norepinephrine reuptake inhibition reported for the compound. This latter effect is certainly consistent with most of the reports in this insanely long thread. It seems that for many people, the SNRI effect wears off relatively quickly, so the AMPK mediated increase in hunger might appear later. It would be kind of ironic if we all ended up really healthy, but incredibly obese donut junkies.

Edited by niner, 22 April 2007 - 04:37 AM.


#14 proteomist

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Posted 22 April 2007 - 06:47 AM

I don't think the statement below that AMPK activation increases hunger and weight gain is correct, as direct activation of AMPK with metformin leads to appetite suppression and weight loss. If anything, AMPK activation suppresses hunger, which makes sense to me from a mechanistic perspective. It makes little sense for an organism to feel severe hunger when food is in chronic short supply. It's just distracting and disabling, which may get in the way of actually getting more food. Conversely, when food is plentiful it is in the organisms best interest to binge while the getting is good, so hunger threshold is lowered and intensity increased. Subjectively, I definitely feel more hunger, and feel it more easily, between meals in a period of high overall calorie intake.

In the paper, they show that the effect on AMPK is independent of Sirt1. One has to wonder about the possible involvement of Sirt's 2 through 7.


Essentially in CR you have a decrease in caloric intake that would stimulate a negative feedback mechanism (increase hunger and food intake) to correct the imbalance. However, there would most likely be no such deprivation with resveratrol supplementation. Activation of AMPK-LKB1 by resveratrol without the requirement for nutrient would still increase hunger and food intake and therefore one would assume promote weight gain.



#15 proteomist

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Posted 22 April 2007 - 06:56 AM

There is a process called apoptosis by which cells commit suicide. Mitochondria are centrally involved in this process, and cells with poor mitochondrial functional are more likely to kill themselves and are more vulnerable to stress. So, in a starving animal investing energy into preserving mitochondrial function is a good way to keep tissues alive and healthy to try to survive until the next period of good eating. This is particularly important for minimally replaceable tissues like brain. So, I think it isn't so much an issue of boosting metabolism as shifting energy expenditure priorities, IMO.

A noob question I've been wanting to ask about resveratrol (go easy on me, I've only had two courses in bio)

Studies have shown that lab animals who are given doses of resveratrol over long periods of time eventually have more mitochondria in their cells. These mitochondria are also more efficient (which presumably means less side product and free radicals per ATP generated).

While it's obviously good to have more efficient mitochondria, wouldn't having MORE total in cells increase metabolic rate, and thus any aging processes that are related to metabolism?

I thought one of the beneficial effects of a calorie-restricted diet was a decrease in metabolic rate (the body "turns down the thermostat") so how is resveratrol mimiking the effects of a CRON diet with this opposite effect?



#16 Brainbox

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Posted 22 April 2007 - 08:55 AM

Zoo, could you explain the semantics of the red and green lines? I guess red is activation and green is inhibition, but, just a guess.

Perhaps someone else could? ;)

#17 zoolander

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Posted 22 April 2007 - 10:25 AM

Zoo, could you explain the semantics of the red and green lines? I guess red is activation and green is inhibition, but, just a guess.


Yes that is correct. Or the arrows are activation pathways and the T-bars inhibition pathways.

Regarding resveratrol's effect on hunger, I think the AMPK mediated effects may be swamped at first by the serotonin/norepinephrine reuptake inhibition reported for the compound.


What compound and how and when did SSRI and SNRI's come into this?

I don't think the statement below that AMPK activation increases hunger and weight gain is correct, as direct activation of AMPK with metformin leads to appetite suppression and weight loss.


What is the explanation for the direct activation of AMPK with metformin leading to appetite suppression and weigh loss? Are thoughts about my statement/comment based on the results of this study?

have a look at the above diagrams again and think about it logically. AMPK is a metabolic switch that acts to correct energetic changes in the cell such as an incrase in cellular AMP as a result of ATP breakdown. Doesn't it seem logical to increase hunger in these situations? Hunger generally means increase in food intake = increase in fuel available to cell to produce ATP through metabolic processes = correct decrease on ATP. That's a pretty straight forward negative feedback loop IMO.

Decreasing hunger would decrease the food intake and fuel required to produce the ATP. This means that would have to draw stores. If there is a lack of glucose then you would see an increase in gluconeogenesis but from the above diagrams, Activation of AMPK inhibits gluconeogenesis.

#18 proteomist

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Posted 22 April 2007 - 05:41 PM

I already did, and I proposed a reason for why it makes sense to down regulate hunger in times of chronic food shortage. To repeat, if food is very scarce, feeling extremely hungry just impairs your ability to hunt. If anything, you need protection from the disabling feeling of hunger in order to search farther afield for new food sources. In contrast, when food is abundant, it makes sense to eat all you possibly can before it goes away or your neighbor gets it. So, feel ravenous.

We need to make a distinction between short term and long term effects. Of course when energy runs low the effect is to increase hunger. But I'm saying that if energy is chronically low, then the hunger threshold gets elevated and the subjective feeling of hunger gets decreased.

The diagram above may indicate that AMPK activity in the thalamus increases hunger, but this is in conflict with everything we know about the effects of metformin, and now of resveratrol. To be clear, I'm talking about the effects of prolonged AMPK activation as you would get in chronic food shortage. Maybe short term activity in a calorie rich context gives a hunger increase.


have a look at the above diagrams again and think about it logically. AMPK is a metabolic switch that acts to correct energetic changes in the cell such as an incrase in cellular AMP as a result of ATP breakdown. Doesn't it seem logical to increase hunger in these situations? Hunger generally means increase in food intake = increase in fuel available to cell to produce ATP through metabolic processes = correct decrease on ATP. That's a pretty straight forward negative feedback loop IMO.

Decreasing hunger would decrease the food intake and fuel required to produce the ATP. This means that would have to draw stores. If there is a lack of glucose then you would see an increase in gluconeogenesis but from the above diagrams, Activation of AMPK inhibits gluconeogenesis.



#19 xanadu

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Posted 22 April 2007 - 06:57 PM

When there is a gap between theory and practice, believe what you see in practice. That has always been my approach. In practice, people have not reported increased hunger on rsv. Many have reported losing weight. I lost weight during the period I have used the stuff but one case does not prove it by itself. We can theorize all day about what it should or should not do but the actual results in the field are what count.

Have their been studies on total life span of animals dosed with rsv? I seem to recall hearing that it increased lifespan but I'm not sure. It may make us healthier but live shorter lives as has been speculated about with fish oil. Another question we need the answer to is what is the optimal dose.

#20 Shepard

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Posted 22 April 2007 - 08:04 PM

I don't think the statement below that AMPK activation increases hunger and weight gain is correct, as direct activation of AMPK with metformin leads to appetite suppression and weight loss. If anything, AMPK activation suppresses hunger, which makes sense to me from a mechanistic perspective. It makes little sense for an organism to feel severe hunger when food is in chronic short supply. It's just distracting and disabling, which may get in the way of actually getting more food. Conversely, when food is plentiful it is in the organisms best interest to binge while the getting is good, so hunger threshold is lowered and intensity increased. Subjectively, I definitely feel more hunger, and feel it more easily, between meals in a period of high overall calorie intake.


While AMPK is a very important regulator of metabolism, it isn't the only one. You seem to be leaving quite a few other adaptations out of this speculation.

#21 zoolander

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Posted 22 April 2007 - 10:31 PM

This is a great discussion. We're presenting the sceince and discussing the various aspects of this science from the way we each personally see it.

Let me post the diagram again showing what happens when the upstream activating kinase LKB1 is activated

Posted Image

As mentioned, activation of AMPK-LKB1 increases hunger. Note though that the activation of AMPK-LKB1 essentially initiates a catabolic situation that acts to correct the change in the cellular energetic status. We see an increase in glycolysis, fatty acid uptake and mitochondrial oxidation.

It appears that AMPK is a metabolic upregulator. Re. loss of weight......well the increase in metabolic rate that occurs with AMPK activation may be greater than the food intake and hence weight would be lost. I haven't really had a great deal of time to search for studies that show a decrease in weight as a result of AMPK acivation but from what I have read so far it is plausible.

Circ Res. 2007 Feb 16;100(3):328-41.

    AMP-activated protein kinase in metabolic control and insulin signaling.

        * Towler MC,
        * Hardie DG.

    Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.

    The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.

    PMID: 17307971 [PubMed - indexed for MEDLINE]



#22 proteomist

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Posted 22 April 2007 - 10:39 PM

I don't understand what problem you see with my argument, can you be more specific about what you think may be incorrect? I certainly never alleged AMPK was the only regulator of metabolism, and I know clearly that it is not.

Maybe you're saying that the hunger-suppressing effects of metformin might act through some pathway other than activation of AMPK? In that case, if the 'AMPK->hunger' model is correct, than metformin would have to be doing something else that is so massively appetite suppressing as to counteract its own appetite-promoting effects via AMPK and still come out with net suppression. Doesn't seem like the most elegant solution, but I suppose it's possible.

If you're simply alleging that it's false to say that metformin suppresses appetite, then maybe you can find me one person who will reliably indicate that metformin made them hungry. I bet you can't. [lol]

I don't think the statement below that AMPK activation increases hunger and weight gain is correct, as direct activation of AMPK with metformin leads to appetite suppression and weight loss. If anything, AMPK activation suppresses hunger, which makes sense to me from a mechanistic perspective. It makes little sense for an organism to feel severe hunger when food is in chronic short supply. It's just distracting and disabling, which may get in the way of actually getting more food. Conversely, when food is plentiful it is in the organisms best interest to binge while the getting is good, so hunger threshold is lowered and intensity increased. Subjectively, I definitely feel more hunger, and feel it more easily, between meals in a period of high overall calorie intake.


While AMPK is a very important regulator of metabolism, it isn't the only one. You seem to be leaving quite a few other adaptations out of this speculation.


Edited by proteomist, 22 April 2007 - 10:58 PM.


#23 proteomist

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Posted 22 April 2007 - 10:45 PM

Hi Zoolander,

Do you have a specific reference for the idea that AMPK activity upregulates hunger, besides that chart? And do they make a distinction between acute and chronic activation? IMO, there's no reason to think that the results would be the same on different time scales, and many precedents in kinase signaling to indicate the contrary.

This is a great discussion. We're presenting the sceince and discussing the various aspects of this science from the way we each personally see it.

Let me post the diagram again showing what happens when the upstream activating kinase LKB1 is activated

Posted Image

As mentioned, activation of AMPK-LKB1 increases hunger. Note though that the activation of AMPK-LKB1 essentially initiates a catabolic situation that acts to correct the change in the cellular energetic status. We see an increase in glycolysis, fatty acid uptake and mitochondrial oxidation.

It appears that AMPK is a metabolic upregulator. Re. loss of weight......well the increase in metabolic rate that occurs with AMPK activation may be greater than the food intake and hence weight would be lost. I haven't really had a great deal of time to search for studies that show a decrease in weight as a result of AMPK acivation but  from what I have read so far it is plausible.

Circ Res. 2007 Feb 16;100(3):328-41.

    AMP-activated protein kinase in metabolic control and insulin signaling.

        * Towler MC,
        * Hardie DG.

    Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, Scotland, UK.

    The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca(2+)-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKbeta. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the alpha subunit being catalytic, the beta subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.

    PMID: 17307971 [PubMed - indexed for MEDLINE]



#24 Shepard

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Posted 22 April 2007 - 11:20 PM

Do you have a specific reference for the idea that AMPK activity upregulates hunger, besides that chart?


AMP-activated protein kinase plays a role in the control of food intake.

    * Andersson U,
    * Filipsson K,
    * Abbott CR,
    * Woods A,
    * Smith K,
    * Bloom SR,
    * Carling D,
    * Small CJ.

Medical Research Council Clinical Sciences Centre, Cellular Stress Group and Endocrine Unit, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 ONN, United Kingdom.

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.

PMID: 14742438 [PubMed - indexed for MEDLINE]



#25 Shepard

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Posted 22 April 2007 - 11:26 PM

I don't understand what problem you see with my argument, can you be more specific about what you think may be incorrect? I certainly never alleged AMPK was the only regulator of metabolism, and I know clearly that it is not.


Mostly when you're looking at long-term famine. At that point, we're looking at a whole host of metabolic changes that affect appetite.

If you're simply alleging that it's false to say that metformin suppresses appetite, then maybe you can find me one person who will reliably indicate that metformin made them hungry. I bet you can't. [lol]


I imagine I can find some that say they couldn't eat due to GI distress. Do you have any references for metformin inducing weight loss in non-diabetic subjects?

#26 proteomist

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Posted 22 April 2007 - 11:31 PM

I've seen a number of papers and reviews now that confirm the statement that AMPK activation in the hypothalamus increases appetite. So what's going on with metformin and appetite suppression? Is it not affecting AMPK activity in the thalamus? Is it doing something else that overwhelms any pro-appetite effects? Or is it still possible that long term activation, or massive activation, of the pro-appetite pathway gives feedback inhibition that increases the hunger threshold?


I don't understand what problem you see with my argument, can you be more specific about what you think may be incorrect? I certainly never alleged AMPK was the only regulator of metabolism, and I know clearly that it is not.


Mostly when you're looking at long-term famine. At that point, we're looking at a whole host of metabolic changes that affect appetite.


Edited by proteomist, 22 April 2007 - 11:45 PM.


#27 proteomist

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Posted 22 April 2007 - 11:47 PM

I imagine I can find some that say they couldn't eat due to GI distress. Do you have any references for metformin inducing weight loss in non-diabetic subjects?


I'll see what I can find. I know of several people who are taking it as a CR mimetic, who do not have diabetes, and who have reported weight loss. As almost all studies are performed in a disease state context, it may be hard to find formal treatment of the matter in non-diabetics.

Here's one anecdotal account:

Metformin use often results in weight loss, and may optimize insulin sensitivity and blood glucose, fasting insulin levels, even in "normal" people.  It does have known issues (most notorious metabolic acidosis usually only occurs in severely ill folk with multiple medical issues.) 

For me, it's a quite powerful appetite suppressant. I've tried a variety of hoodia preparations with variable results that STM to be unpredictable.

t-resv. also suppresses my appetite, at least at relatively high doses (~500mg/day).

Green tea, forskolin, caffeine, ephedra, all have known effects.  Many bodybuilders have used nicotine, although a rather controversial issue. 

Sesamin- from studies of metabolic mechanistic effects seems like a great idea. Personally I didn't notice much, if any, effect, and some have reported libido suppression.

Omega-3s, fer sure, regardless of weight issues, seem like a plus.

CLA- controversial, at best.

I've been taking Benagene for a coupla months, and have lost a little weight, inadvertently, but effects confounded by simultaneous ramp up of t-rsv. over same period.

etc.....



#28 Shepard

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Posted 23 April 2007 - 12:08 AM

So what's going on with metformin and appetite suppression?


Maybe something to do with it's effect on glycolysis?

#29 zoolander

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Posted 24 April 2007 - 09:14 AM

proteomist, have you any science for you claims yet?

once again

Posted Image

AMPK increases hunger and therefore goes against testimonials that resveratrol decreases appetite. See attached research.

NOTE: in the above diagram that there is a question mark against metformin activating the CNS. This may explain our discrepancy. Metformin increases fatty acid oxidation by increasing AMPK in the periphery. Perhaps there is no increase in hunger? We are talking about resveratrol with the research quoted in this topic. This research shows activation of an upstream activating Kinase (LKB1) in the CNS by resveratrol.

Something extra in the above diagram is the arrow that shows that dietary alpha lipoic acid decreases AMPK in the CNS and hence decreases hunger/appetite

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#30 proteomist

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Posted 24 April 2007 - 04:09 PM

I know AMPK activation in the CNS increases hunger. I acknowledged that two posts ago. I'm asking you to speculate how we can resolve the actual observed effects with the theory. Finally, thankfully, you address that a little here by putting up a diagram that speculates exactly what I just did, that metformin fails to activate AMPK in the CNS

proteomist, have you any science for you claims yet?

once again

Posted Image

AMPK increases hunger and therefore goes against testimonials that resveratrol decreases appetite. See attached research.

NOTE: in the above diagram that there is a question mark against metformin activating the CNS. This may explain our discrepancy. Metformin increases fatty acid oxidation by increasing AMPK in the periphery. Perhaps there is no increase in hunger? We are talking about resveratrol with the research quoted in this topic. This research shows activation of an upstream activating Kinase (LKB1) in the CNS by resveratrol.

Something extra in the above diagram is the arrow that shows that dietary alpha lipoic acid decreases AMPK in the CNS and hence decreases hunger/appetite






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