AMPK Inhibitors

HIT4ME

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I've been doing a little research (been a long time since I had time for this) and I am wondering if anyone on this board might be aware of any herbal ingredients that actually inhibit AMPK? Everyone is looking for ways to increase this compounds, but I have some theories that I would like to test out and given I have such limited time to search, I haven't found any ingredients with studies showing any ingredients actually prevent AMPK from binding to receptors, reduce levels of AMPK, etc.?

If you have ideas, it would be great to hear them.
 

Jeremyk1

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Last I remember reading much on AMPK, it tends to follow an inverse relationship with mTOR. I don’t think it’s necessarily causally linked, more just that they have opposite methods of being activated. But there’s at least possibility that anything which activates mTOR could decrease AMPK. Other than that, I don’t know anything which specifically lowers it.
 
xR1pp3Rx

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berberine maybe.. venpocentine maybe? ?
 
HIT4ME

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Last I remember reading much on AMPK, it tends to follow an inverse relationship with mTOR. I don’t think it’s necessarily causally linked, more just that they have opposite methods of being activated. But there’s at least possibility that anything which activates mTOR could decrease AMPK. Other than that, I don’t know anything which specifically lowers it.
This is one angle, yes. I mean, there's a lot going on with this molecule and I am just really digging into it now so there is plenty of room for mis-interpretation on my behalf, but I REALLY want to test out something that will reduce AMPK.

It seems everyone is pushing AMPK increases for longevity, increased fat burning, etc. - but I'm not so sure it's that simple.

I know someone on here will find something :)
 
HIT4ME

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berberine maybe.. venpocentine maybe? ?
These are good thoughts - I have to look into this. Berberine I thought increase AMPK but ....that may have been an assumption based on it's comparisons to metformin.

edit: looks like both activate AMPK.

It's a head scratcher.
 
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xR1pp3Rx

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perhaps looking into things that raise Mtor would be mor efruitful
 
HIT4ME

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ironkill

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Ive gone down this rabbit hole also and didnt come up with much in terms of compounds that reduce ampk. Exercise and eating seem to be the major drivers there. Epicat and high levels of phosphocreatine is suppose to increase mtor, thereby reducing ampk.
 
nostrum420

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Glucose. Maybe IGF-1.


That being said, I can find zero research on *intentionally* suppressing AMPK and there's probably good reason for that. 😬🤷‍♂️
 
HIT4ME

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Ive gone down this rabbit hole also and didnt come up with much in terms of compounds that reduce ampk. Exercise and eating seem to be the major drivers there. Epicat and high levels of phosphocreatine is suppose to increase mtor, thereby reducing ampk.
It is hard. Phophocreatine and PEP seem to be possible candidates....PEP more from a theory standpoint. Hadn't seen the epicat suggestion...will check it out. Thanks.

Glucose. Maybe IGF-1.


That being said, I can find zero research on *intentionally* suppressing AMPK and there's probably good reason for that. 😬🤷‍♂️
Well, you raise some good points - and given the current perception of AMPK, I think it's a little en vogue to study its effects by raising it. It also, at first glance, appears to inhibit tumors, so obviously the thinking of, "If high ampk inhibits tumors, do we want to lower it?"

But, on the other hand, cancer and Alzheimer's don't often happen together, and there is evidence of elevated AMPK in AD patients. So, maybe that plays a role...they have AD because of high levels of AMPK, but also have resistance to cancer. Althought, this is an obvious oversimplification on my part.

It is further complicated by the fact that AMPK in some cancers actually seems to make the cancer worse...."AMPK - friend or foe?"

But from a supplement standpoint, it seems that AMPK upregulates lipolysis and people actually are assuming this is good for fat loss. I might disagree. I think increased fat burning is detrimental to fat loss. Yeah, crazy, I know.

I am unaware of any "natural" substances that are often used to inhibit AMPK - but Compound C is pretty well known and used in studies for this purpose. And it's crazy expensive. I have a couple ideas for natural substances that show potential, from this thread and from friends...but we will see how well they work.

Again, your points are good and you are probably taking the right angle...I'm just looking at a different angle to see where it goes.
 
Rocket3015

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Two deep for me !
 
rob112

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Last I remember reading much on AMPK, it tends to follow an inverse relationship with mTOR. I don’t think it’s necessarily causally linked, more just that they have opposite methods of being activated. But there’s at least possibility that anything which activates mTOR could decrease AMPK. Other than that, I don’t know anything which specifically lowers it.
Yea I remember when I used to read a lot of this stuff coming to a similar understanding. Also I came to the belief that AMPK is very necessary so you wouldn’t want it to just stop happening anyways. Man it’s been years. Just want to second your post.
 

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@HIT4ME , read Mike Arnold's write up for his product Insuligen if you haven't already. I think he is talking along the lines of what you might be thinking.
 
HIT4ME

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@HIT4ME , read Mike Arnold's write up for his product Insuligen if you haven't already. I think he is talking along the lines of what you might be thinking.
I'm not exactly sure - what I am thinking is pretty crazy and "sort of" goes against the way we view a lot of things....and basically it actually positions AMPK as being a molecule that conserves muscle in a strange way. If it were to be overly simplified.

My theory also makes AMPK counter-productive for fat-loss.

Crazy huh?
 

THEstudent

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I'm not exactly sure - what I am thinking is pretty crazy and "sort of" goes against the way we view a lot of things....and basically it actually positions AMPK as being a molecule that conserves muscle in a strange way. If it were to be overly simplified.

My theory also makes AMPK counter-productive for fat-loss.

Crazy huh?
That is exactly what he is talking about...
 
HIT4ME

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Iwilleattuna

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phosphocreatine? Would this just be standard creatine in general?


“ AMPK is also allosterically inhibited by physiological concentrations of phosphocreatine (Ponticos et al., 1998), consistent with the proposed physiological role of the kinase as a sensor of cellular energy status.”
 
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Iwilleattuna

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I'm not exactly sure - what I am thinking is pretty crazy and "sort of" goes against the way we view a lot of things....and basically it actually positions AMPK as being a molecule that conserves muscle in a strange way. If it were to be overly simplified.

My theory also makes AMPK counter-productive for fat-loss.

Crazy huh?
Well, it has been shown to increase glucose uptake into cells , so I see where you’re going with this . Maybe it’s a response to possibly prevent catabolism from ampk increase productivity negative feedback loop. Where it’s opposite with high levels of mtor? Similar to how if you pin insulin on an empty stomach it will take you into Keto and an extreme fat burning state , but you’ll probably die lol. Once you eat carbs, it is all stored

And shoot, now that I think about it, what increases mtor at a great amount but also raises insulin? Leucine . Everyone now says to avoid isoleucine:valine:leucine on an empty stomach because they raise insulin which would induce catabolism as the body tries to look for the remaining amino acids. Could this catabolism cause great fat catabolism? 🤔

Seems like ampk is rather a response to fasting which could trigger storage
 
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Rocket3015

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Well, it has been shown to increase glucose uptake into cells , so I see where you’re going with this . Maybe it’s a response to possibly prevent catabolism from ampk increase productivity negative feedback loop. Where it’s opposite with high levels of mtor? Similar to how if you pin insulin on an empty stomach it will take you into Keto and an extreme fat burning state , but you’ll probably die lol. Once you eat carbs, it is all stored

And shoot, now that I think about it, what increases mtor at a great amount but also raises insulin? Leucine . Everyone now says to avoid isoleucine:valine:leucine on an empty stomach because they raise insulin which would induce catabolism as the body tries to look for the remaining amino acids. Could this catabolism cause great fat catabolism?🤔

Seems like ampk is rather a response to fasting which could trigger storage
Could this catabolism cause great fat catabolism?

This is what I need !!
 
Whisky

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I see a lot on activating it in the longevity space where I read a lot. Issue for us is that AMPK and Mtor are directly opposed when it comes to muscle building goals. Most people I follow who have both an interest in longevity and building lean mass try to significantly increase both but at specific times (I.e mtor on training days and AMPK on non).

food (nutrients) are the biggest factor in the suppression of AMPK that I’m aware of. The link below might be of interest. This is one of the reasons why periods of fasting are so heavily linked to longevity (alongside autophagy).

so eat a crap diet, consistently through the day and you should suppress it 🤷

from a body composition perspective I’m really struggling to see where the benefits will lie though (from deliberately suppressing ampk rather than intentionally increasing mtor)?

 
HIT4ME

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Ok, so - I hate to lay out all my theories where someone can take my ideas and either open myself up to criticism or have anything that may be beneficial taken and used for profit....but...there are some really crazy ideas I have and here they go.

The first thing that you have to be willing to accept in order to see where I am coming from is that using fat for energy is actually NOT conducive to fat loss. Crazy, I get it. But for most of us, when we are trying to lose fat, we are not actually trying to burn more energy - what we REALLY want is to burn more MASS. Using fat for energy is a mass conservation strategy. If I need 36 calories I can get that from 4 grams of fat or 9 grams of carbohydrate - obviously if it comes from carbohydrate I lose twice as much mass. Of course, you say, "But that's carb, not fat mass" - sure.

But what happens if I can only burn fat? What happens if I can only burn carbs? Having an "only" situation in real life is unrealistic, but the ability to swap between sources is impaired in obese individuals. If I can ONLY burn fat - then what do I do with those carbs? Well, I store what I can as carbs, burn what little I can, and anything in excess gets converted to fat and stored as fat. Only, I've now converted a gram of gasoline into a gram of rocket fuel. So, now that 4 calories has 9 calories.

If I can only burn carbs - well - what happens to all the fat I take in? I burn what little I can, store what I can, and convert whatever I can over into carbs through gluconeogenesis. Only, now that gram of fat goes from being rocket fuel to being gasoline - it has 4 calories instead of 9.

It sounds crazy, especially considering how often we hear, "You want to lose weight? You need to increase your fat burning!!"

But guess who is really good at burning fat for fuel? Fat people are really good at it. They have an abundance of fat in their system, and a resultant increase in Pyruvate Dehydrogenase Kinase - which makes it easier to burn fat and harder to burn carbs. They are already burning more fat than carbohydrate.

And everyone claims there is "metabolic slowdown" when dieting - well, yeah - because you're using fat instead of carbs for energy - so your mass loss reflects a slowdown, even though you're not using any less energy at all. You are just conserving mass.

So, how does AMPK play into this? Well, AMPK appears to be a braking mechanism for all of this. Energy levels fall, and AMPK turns on to start converting the machinery over to burn more fat, increases lipolysis and thus conserving mass in general, by getting your energy needs from less mass of course. So, yeah, while AMPK may inhibit mTOR and prevent the growth of tissue - it also conserves energy which prevents the breakdown of lean tissue and, well, all tissue in general.

But there are also other factors regarding AMPK and Leptin signaling, and possibly the different responses to AMPK found in neurological tissue vs. muscles that I'm more interested in.

It's all crazy, maybe the theory has some holes. It really turns a lot of ideas that are out there on their head, but maybe I'm just misinterpreting things.
 
nostrum420

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Ok, so - I hate to lay out all my theories where someone can take my ideas and either open myself up to criticism or have anything that may be beneficial taken and used for profit....but...there are some really crazy ideas I have and here they go.

The first thing that you have to be willing to accept in order to see where I am coming from is that using fat for energy is actually NOT conducive to fat loss. Crazy, I get it. But for most of us, when we are trying to lose fat, we are not actually trying to burn more energy - what we REALLY want is to burn more MASS. Using fat for energy is a mass conservation strategy. If I need 36 calories I can get that from 4 grams of fat or 9 grams of carbohydrate - obviously if it comes from carbohydrate I lose twice as much mass. Of course, you say, "But that's carb, not fat mass" - sure.

But what happens if I can only burn fat? What happens if I can only burn carbs? Having an "only" situation in real life is unrealistic, but the ability to swap between sources is impaired in obese individuals. If I can ONLY burn fat - then what do I do with those carbs? Well, I store what I can as carbs, burn what little I can, and anything in excess gets converted to fat and stored as fat. Only, I've now converted a gram of gasoline into a gram of rocket fuel. So, now that 4 calories has 9 calories.

If I can only burn carbs - well - what happens to all the fat I take in? I burn what little I can, store what I can, and convert whatever I can over into carbs through gluconeogenesis. Only, now that gram of fat goes from being rocket fuel to being gasoline - it has 4 calories instead of 9.

It sounds crazy, especially considering how often we hear, "You want to lose weight? You need to increase your fat burning!!"

But guess who is really good at burning fat for fuel? Fat people are really good at it. They have an abundance of fat in their system, and a resultant increase in Pyruvate Dehydrogenase Kinase - which makes it easier to burn fat and harder to burn carbs. They are already burning more fat than carbohydrate.

And everyone claims there is "metabolic slowdown" when dieting - well, yeah - because you're using fat instead of carbs for energy - so your mass loss reflects a slowdown, even though you're not using any less energy at all. You are just conserving mass.

So, how does AMPK play into this? Well, AMPK appears to be a braking mechanism for all of this. Energy levels fall, and AMPK turns on to start converting the machinery over to burn more fat, increases lipolysis and thus conserving mass in general, by getting your energy needs from less mass of course. So, yeah, while AMPK may inhibit mTOR and prevent the growth of tissue - it also conserves energy which prevents the breakdown of lean tissue and, well, all tissue in general.

But there are also other factors regarding AMPK and Leptin signaling, and possibly the different responses to AMPK found in neurological tissue vs. muscles that I'm more interested in.

It's all crazy, maybe the theory has some holes. It really turns a lot of ideas that are out there on their head, but maybe I'm just misinterpreting things.
Questions that spring to mind:

Why don't study models where AMPK is elevated show resulting weight/fat gain? Why does it tend to be the opposite?

If an organism is not "burning" (metabolizing) body fat, how do you propose the fatty tissue would be depleted or excreted in your model?
 
Whisky

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Ok, so - I hate to lay out all my theories where someone can take my ideas and either open myself up to criticism or have anything that may be beneficial taken and used for profit....but...there are some really crazy ideas I have and here they go.

The first thing that you have to be willing to accept in order to see where I am coming from is that using fat for energy is actually NOT conducive to fat loss. Crazy, I get it. But for most of us, when we are trying to lose fat, we are not actually trying to burn more energy - what we REALLY want is to burn more MASS. Using fat for energy is a mass conservation strategy. If I need 36 calories I can get that from 4 grams of fat or 9 grams of carbohydrate - obviously if it comes from carbohydrate I lose twice as much mass. Of course, you say, "But that's carb, not fat mass" - sure.

But what happens if I can only burn fat? What happens if I can only burn carbs? Having an "only" situation in real life is unrealistic, but the ability to swap between sources is impaired in obese individuals. If I can ONLY burn fat - then what do I do with those carbs? Well, I store what I can as carbs, burn what little I can, and anything in excess gets converted to fat and stored as fat. Only, I've now converted a gram of gasoline into a gram of rocket fuel. So, now that 4 calories has 9 calories.

If I can only burn carbs - well - what happens to all the fat I take in? I burn what little I can, store what I can, and convert whatever I can over into carbs through gluconeogenesis. Only, now that gram of fat goes from being rocket fuel to being gasoline - it has 4 calories instead of 9.

It sounds crazy, especially considering how often we hear, "You want to lose weight? You need to increase your fat burning!!"

But guess who is really good at burning fat for fuel? Fat people are really good at it. They have an abundance of fat in their system, and a resultant increase in Pyruvate Dehydrogenase Kinase - which makes it easier to burn fat and harder to burn carbs. They are already burning more fat than carbohydrate.

And everyone claims there is "metabolic slowdown" when dieting - well, yeah - because you're using fat instead of carbs for energy - so your mass loss reflects a slowdown, even though you're not using any less energy at all. You are just conserving mass.

So, how does AMPK play into this? Well, AMPK appears to be a braking mechanism for all of this. Energy levels fall, and AMPK turns on to start converting the machinery over to burn more fat, increases lipolysis and thus conserving mass in general, by getting your energy needs from less mass of course. So, yeah, while AMPK may inhibit mTOR and prevent the growth of tissue - it also conserves energy which prevents the breakdown of lean tissue and, well, all tissue in general.

But there are also other factors regarding AMPK and Leptin signaling, and possibly the different responses to AMPK found in neurological tissue vs. muscles that I'm more interested in.

It's all crazy, maybe the theory has some holes. It really turns a lot of ideas that are out there on their head, but maybe I'm just misinterpreting things.
I guess my main question here is what is the rationale behind looking into this?

if it’s genuinely to explore the way the human body works and make advances in our understanding of these mechanisms then fair enough.

if it’s to actually lose weight/fat/mass then why? We have tried and tested methods that do work for even those currently obese (you know my background).

I definitely don’t know enough to say if this theory would or wouldn’t work but I do know that the sheer number of interactions involved mean that unintended consequences would be pretty likely imo. For example maybe you inhibit ampk excessively but that spikes the hell out of cortisol which we know causes fat gain 🤷 (literally just giving an example to make a point, not one I’ve considered the science behind).
 
Rocket3015

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I am enjoy the reading, (and I understand about half of it)
 
HIT4ME

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Questions that spring to mind:

Why don't study models where AMPK is elevated show resulting weight/fat gain? Why does it tend to be the opposite?

If an organism is not "burning" (metabolizing) body fat, how do you propose the fatty tissue would be depleted or excreted in your model?
Great questions - of course this is a theory and the validity of any idea is based on the experiment. I've tried to find studies showing elevated or depleted levels of AMPK in the obese and have not found any - not saying they are out there, but I've just not been able to dig them up yet. I have found some studies linking diabetes to reduce AMPK, but not obesity itself. Not saying they aren't out there and I think if anyone has them on this board, it may be you, so I expect you will save me some searching and show me up haha.

I have found studies showing that AMPK is elevated in the brains of Alzheimer's patients.

I have found studies showing that AMPK does NOT protect against weight gain during over-feeding and, conversely, the reduced AMPK mice (through gene deletion) had better insulin sensitivity than normal mice with almost a 2-fold increase in glucose uptake.

In another angle, it appears that AMPK is not necessary for gluconeogenesis, but plays a critical role in metabolic flux (tying it back to PDK).

The second question is partially answered in the info above - gluconeogenesis or something along those lines. There's chemistry magic involved in the theory at the moment, admittedly, but if I have to convert fat to carbs just to burn them = double your metabolism.

I guess my main question here is what is the rationale behind looking into this?

if it’s genuinely to explore the way the human body works and make advances in our understanding of these mechanisms then fair enough.

if it’s to actually lose weight/fat/mass then why? We have tried and tested methods that do work for even those currently obese (you know my background).

I definitely don’t know enough to say if this theory would or wouldn’t work but I do know that the sheer number of interactions involved mean that unintended consequences would be pretty likely imo. For example maybe you inhibit ampk excessively but that spikes the hell out of cortisol which we know causes fat gain 🤷 (literally just giving an example to make a point, not one I’ve considered the science behind).
Well, it's to explore the ideas on the largest level. Basically, I think there's a lot of diet advice out there that's just NOT really accurate - like "metabolic slowdown", and lots of things that we do that seem effective, but are unknowingly damaging.

For instance, take the keto diet and apply my theories above. You would come to the conclusion that, of course it works - you have avoided the broken machinery altogether. If you cannot metabolize carbohydrates, then not eating them will avoid the issue.

But hey, if the reason you cannot metabolize carbohydrates has more to do with the fact that you're obese and you have too much PDK in your system to efficiently burn carbohydrates - then going on a keto diet will just further increase PDK, make your issue worse, and make it more likely you gain the weight back when you are all over. And also make it harder for you to lose the weight the second time around.

To add insult to injury - you've damaged the pathway that burns mass the quickest in favor of a pathway that, by design, conserves mass (giving the appearance of metabolic slowdown).

And so that person looks at a keto diet as the greatest thing because it made them lose weight, but then can't seem to keep the weight off and doesn't know what to do.

And, I think you're right with the final paragraph - there are a lot of factors here. And I think it's more complicated than "AMPK promotes lipolysis and inhibits mTOR"...I guess that's what I'm getting at on some level too. From a certain angle, AMPK may actually make fat loss harder and preserve mass.

Like you've said, everyone who is into building muscle AND longevity sees AMPK as kind of a mixed bag - but what if it wasn't that cut and dry. What if AMPK actually had a role in preserving muscle during low energy states (by turning on fat burning - if you're buning fat preferentially, you're going to spare muscle more than if you're burning carbs) - but also prevents the addition of new muscle under that state?

I'm not sure if it's really to directly lose weight, as much as to maybe understand how to keep it off or what prevents people from keeping it off and improve the details of how things work. And then take your link you provided above and figure out how to implement it into an appropriate strategy that doesn't obliterate it, but gets it back to normal.
 
HIT4ME

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nostrum420

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I've tried to find studies showing elevated or depleted levels of AMPK in the obese and have not found any - not saying they are out there, but I've just not been able to dig them up yet.

The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways



Genetic Liver-Specific AMPK Activation Protects against Diet-Induced Obesity and NAFLD


Obesity impairs skeletal muscle regeneration through inhibition of AMPK

 
nostrum420

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The second question is partially answered in the info above - gluconeogenesis or something along those lines. There's chemistry magic involved in the theory at the moment, admittedly, but if I have to convert fat to carbs just to burn them = double your metabolism.
"There's no real need to create glucose from fat. Your body can create an incredible amount of ATP from fat already. Even if your body is lacking in blood glucose, it can break down muscle and turn it into glucose using amino acids."


I think in humans who have not had genes deleted, you'd need an incredibly glucose depleted state to achieve gluconeogenesis from fats.
 
nostrum420

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As for the relatively high concentrations of AMPK in the brains of Alzheimer's patients, "In Alzheimer’s disease, creatine kinase activity is reduced by as much as 86% along with a reduction of in creatine kinase protein expression of 14%, which suggests that the Alzheimer’s disease brain has lower levels of phosphocreatine in the beginning stages of the disease"


So, this issue is not the abnormally high AMPK. The abnormally high AMPK is a result of the issue which is diminished phosphocreatine.
 
HIT4ME

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@nostrum420 - great stuff...will be reading through jt.
 
HIT4ME

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The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways



Genetic Liver-Specific AMPK Activation Protects against Diet-Induced Obesity and NAFLD


Obesity impairs skeletal muscle regeneration through inhibition of AMPK

Ok, your responses deserve and require much more time than I have to a lot today, but to discuss what I can. To be clear I am stretching here and just appreciate the discussion and I am not saying I am "right" - just hypothesizing some things here, so I appreciate the intelligent responses.

The first study gives some evidence that Quercetin upregulates AMPK and also causes apoptosis of rat fat cells in a petri-dish setting, which I would say on some level gives reason to believe AMPK plays a role in apoptosis. But it's not really conclusive, and leaves some room for misinterpretation, perhaps? It is in a petri-dish and in a vacuum and as we've all agreed, there are a lot of chemical interactions going on. And we do all seem to agree that AMPK increases lipolysis.

The second study on obesity and NAFLD is very interesting and I am going to be reading and re-reading it for a while. I can say that the authors agree that:

Recent studies have reported that AMPK activation in liver does not acutely lower blood glucose levels or improve glucose homeostasis (Cokorinos et al., 2017, Esquejo et al., 2018, Woods et al., 2017). We also observed only small to no effects on glucose homeostasis after sustained AMPK activation in liver in chow-fed mice (Figures 2C and S2B–S2F).
and that:

Previous studies on AMPK activation have reported several deleterious effects stemming from whole-body AMPK activation. The best-known example of this is AMPK-induced accumulation of cardiac glycogen and cardiac hypertrophy, first identified in humans with Wolff-Parkinson-White syndrome, a condition caused by activating AMPKγ2 mutations (Blair et al., 2001).

But it is very interesting none-the-less because it aims to focus only on liver-specific AMPK activation and thus, did find some benefits there - particularly around protecting against weight-gain during a high fat diet. This actually makes sense, because AMPK increases lipolysis and inhibits lipogenesis.

This study, Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation, IMO, goes hand-in-hand with the study above. I would say that they are different but overlapping and the study you've provided is potentially more interesting though:

Also tied to this - Reciprocity Between Skeletal Muscle AMPK Deletion and Insulin Action in Diet-Induced Obese Mice - shows that mice that lack AMPKa1a2 preserve insulin function. Now this is a little confusing because it's not as simple as that; they seem to regulate energy function in the cell by "preserving" function to limit it to the necessary functions of creating energy - but this does improve glucose uptake. This study, however, found that the wild mice had teh same weight gain and adiposity as knock-out mice.

For the third study - Obesity impairing skelatal muscle regeneration through inhibition of AMPK is pretty interesting - because a lot of what we've been discussing is that AMPK operates directly in opposition to mTOR - so you would think impaired AMPK would not impair muscle cell regeneration; yet applying my thought process above I did suggest that AMPK was potentially a tissue-conserving substance. i.e. - impairing the substance which prevents muscle from being used as energy (in my theory) would also impair, potentially, regeneration?

Again this gets to a more nuanced view of how a lot of us have viewed AMPK - where it opposes mTOR and increases lipolysis so it must be good for fat loss and bad for muscle gains; it isn't really either entirely - it turns on fat break down and prevents muscle catabolism (potentially); but also prevents lipogenesis and myogenesis - myogenesis possibly because energy signaling is low.

This study, though, is interesting and I have to think on it more because it does show a correlation (as I asked) between impaired AMPK levels and obesity.

Good discussion. Thanks for working through this.
 
HIT4ME

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"There's no real need to create glucose from fat. Your body can create an incredible amount of ATP from fat already. Even if your body is lacking in blood glucose, it can break down muscle and turn it into glucose using amino acids."


I think in humans who have not had genes deleted, you'd need an incredibly glucose depleted state to achieve gluconeogenesis from fats.
I didn't imply there is a "need" to convert glucose to fat - that's the point. Your body is VERY good at preserving itself, and we have evolved to have mechanisms which conserve mass in times of energy depletion. Utilizing fat as an energy source is one of the major mechanisms. When you have a period where the balance of fat to glycogen is high, or if energy is depleted (like you are starving) your body will increase its use of fat. This is not an attempt to burn MORE mass, it's an attempt to CONSERVE.

And mathematically it makes sense, in the presence of Pyruvate Dehydrogenase Kinase, we can inhibit the PDC and obtain ATP directly from fat - in abundance. When times are hard and energy is low, it's a way to squeeze MORE energy out of less mass.

The problem is, we only need so much energy - so breaking down more fat to directly turn into ATP is not really the answer. But, if you were to impair the ability to utilize fat and start burning more carbs, I wonder if there's a way to start converting that fat back to carbs because your body will realize that it needs to in order to survive - gluconeogenesis being one possibility.

Since you cannot create nor destroy energy or matter - well, you will never be able to manufacture more than 1 gram of carbohydrate from 1 gram of any combination of materials. 1 gram of fat, with perfect conversion, would thus have 9 calories in the beginning of the process but have only 4 calories once converted to carbohydrate - thus doubling the amount of fat you need to burn to obtain the same energy. Now, of course this is incredibly simplified - you are going to mix probably .6 grams of fat with some water and some enzymes, etc. and maybe in the end you have 5.4 calories from fat (or some other random amount between 4-9 calories) that gets burned as 4 calories.

But this isn't how your body is MEANT to work, and thus we do not NEED to convert fat to carbs; we've evolved to go the other way because it's efficient and conserves mass. And part of that evolution involves using AMPK to preserve energy during periods of low-energy status.

An interesting side point - this math starts to explain why people perceive "metabolic slowdown" during diets - they are still using the same amount of energy/calories. But those calories start burning less and less mass. It eliminates the need for a magical thermostat that operates in non-sensical ways. What I mean is, why would you EVER increase the calories you burn beyond what is necessary to accomplish a task. You wouldn't, you would store them. And if you've never increased beyond that point, you cannot accomplish the task with any reduction - you either avoid the task or burn the energy. No efficient, survival-oriented organism would just waste energy on a task.

As for the relatively high concentrations of AMPK in the brains of Alzheimer's patients, "In Alzheimer’s disease, creatine kinase activity is reduced by as much as 86% along with a reduction of in creatine kinase protein expression of 14%, which suggests that the Alzheimer’s disease brain has lower levels of phosphocreatine in the beginning stages of the disease"


So, this issue is not the abnormally high AMPK. The abnormally high AMPK is a result of the issue which is diminished phosphocreatine.
I pretty much agree with you - it is certainly a complexity and the roles are not clear. I would submit this article - which isn't the best I've read on this, but it's the one that I can find and I have to run...

Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer's disease

An interesting note from the discussion in this study:

"AMPK, a serine/threonine kinase straddling a cellular metabolic regulatory role with a concurrent influence on tau-driven AD pathology, has been reported to be activated in the hypothalamus of mice as a consequence of atypical antipsychotic exposure [57]. AMPK plays a central role in cellular energy homeostasis, and is activated by metabolic stress (hypoxia, ischemia, poor nutrient availability) [58]. The activation of AMPK is associated with increased food intake; the use of antipsychotic medications (including haloperidol but more dramatically the atypicals) [59] has been associated with weight gain and metabolic syndrome, including an atherogenic lipid profile and emergent diabetes mellitus [60]. "
 
BCseacow83

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"AMPK is a heterotrimeric complex containing one catalytic α-subunit and two regulatory β- and γ-subunits.1 In mammals, AMPK α- and β-subunits have two isoforms each, and AMPK γ-subunit has three isoforms. This suggests the presence of 12 potential combinations of AMPK, each with different functions under different physiological conditions."



I think to really get specific effects your going to potentially need to be very specific with which "version/form/sub-type" you manipulate.
 
HIT4ME

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"AMPK is a heterotrimeric complex containing one catalytic α-subunit and two regulatory β- and γ-subunits.1 In mammals, AMPK α- and β-subunits have two isoforms each, and AMPK γ-subunit has three isoforms. This suggests the presence of 12 potential combinations of AMPK, each with different functions under different physiological conditions."



I think to really get specific effects your going to potentially need to be very specific with which "version/form/sub-type" you manipulate.
Agree 100%!!!

I think this really further complicates things. I wonder if different tissues may react differently as well - maybe because the subunits are simply different, but maybe because each subunits responds differently in different environments.
 

johnny412

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i have a theory that i want to test......are all of you people starscream ripdanduchaine??? :p
 
HIT4ME

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Sorry I'll go back to debating which under-dosed pre tastes the best..................
Hey, does anyone know of a really good tasting protein bar that might inhibit AMPK?
 
BCseacow83

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Stumbled upon this saved on my comp from who knows when:

209567


Make sure you shove AMPK in the right direction, thats a whole lotta arrows to keep track of lol.
 
HIT4ME

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There is so much going on in there - and you are right. I honestly just think that a lot of what we read about is, "Increase AMPK" for longevity and to lose weight, and your point really shows how much more complicated it is.

Off this chart but something else that has come to mind - Thyroid Hormone increases AMPK. I also found a study somewhere, which I cannot dig up now, that implied the presence of AMPK may inhibit the action of T3. This makes some sense - if T3 is elevating it, and AMPK is a messenger - it's a molecule that provides negative feedback on the level of T3 potentially.


 

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