Leptin

April 16, 2014

Andrew Gladman reflects upon the recent IACFS/ME conference and the buzz surrounding a small molecule, leptin.

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Leptin Molecule. Image by I, Vossman via Wikimedia Commons.

It’s safe to say that the past couple of weeks, following the IACFS/ME 2014 conference, have been something of a whirlwind in terms of new ME/CFS research being unveiled.

Now that the dust has had a chance to settle let’s take a step back and discuss a topic that many consider to be one of the most promising findings discussed at the conference.

Leptin seemed to be the word on many researcher lips. During the first day of the conference Anthony L. Komaroff, M.D. made clear his interest in this molecule, directly referencing his interest in the recent study by Younger et al.

“A hormone called leptin was found to be tightly correlated to many of these pro-inflammatory cytokines, and to be the most distinctive difference between CFS patients and control subjects.” 

 Clear markers between controls and ME/CFS patients have, in the past, proven very difficult to identify and even more so to verify in further studies and trial. This has unfortunately led to the ‘diagnosis by exclusion’ criteria which serve as such an anchor in slowing the progress into ME/CFS research.

Leptin on the other hand not only shows promise as a marker of disease activity but the recent research even goes so far as to suggest that fatigue severity is very closely correlated to leptin levels, potentially providing not only a marker of disease but even the potential of a marker for disease severity at a molecular level.

It is clear that many esteemed researchers and clinicians in the ME/CFS field seem to be very intrigued by the leptin abnormalities found relative to controls by these studies. Given the possibilities that serum leptin analysis could provide, it is clear why!

To better understand why these findings have such significance, we have to go back to the basics and understand what exactly this molecule is and what significance an abnormality in its concentration can have.

Very rarely in the modern world do single molecules get discussed in isolation from the systems in which they interact. Gone are the days where diseases are understood to be caused by sole problems with individual metabolites, chemicals or genes. Leptin appears to be providing a perfect stepping stone in the right direction for further research. 

What is Leptin?

 Leptin belongs to a group of molecules known as adipokines, a group generally defined as cytokines (cell signalling molecules) secreted almost exclusively by adipose tissue, better known as body fat. For this reason the serum concentration of leptin is usually proportional to the total body fat an individual has.

As a cytokine, leptin acts through binding to specific leptin receptors, the vast majority of which are located in the hypothalamus. Leptin was only discovered as recently as 1994 and since then it has gathered increasing amounts of attention from researchers the world over.

Leptin resistance is a common problem resulting from obesity

Leptin resistance is a common problem resulting from obesity. Image by Fj.toloza992 via Wikimedia Commons.

This small molecule has quite an array of functions specifically targeted towards the regulation of energy intake and expenditure including appetite and hunger, metabolism, and specific behaviors.

Under normal circumstances, leptin acts to oppose the action of appetite stimulants such as neuropeptide Y.

It suppresses appetite through binding to receptors in the hypothalamus while simultaneously binding receptors on cells producing these appetite stimulants and preventing the production of these molecules.

As a result of this action, individuals who produce little or no leptin are highly prone to developing massive obesity. Logically then you would assume that high leptin leads to malnutrition and severely underweight patients.

However, in obese patients where leptin levels are high as a result of the increased levels of adipose tissue, the chronically high levels of leptin in fact lead to leptin resistance through a near identical mechanism as is seen in type II diabetes where insulin resistance develops.

This leptin resistance means that the binding of leptin to its complementary leptin receptor is not happening correctly thereby the appetite reduction does not occur. The end result is therefore increasing weight gain without appetite suppression. This is an example of an out-of-control positive feedback mechanism as a result of the acquired leptin resistance.

While this seems a difficult loop to break, it has been demonstrated that diet-induced leptin resistance is for the most part a reversible phenomenon.

For quite a long time it was believed that leptin served no other functions in the body other than as an integral molecule in fat metabolism and storage. Now however, it is coming to light that leptin in fact has a much broader scope of functions and systems that it can directly influence. These include the circulatory system, functioning of the brain and the regulation of bone mass.

Interestingly, leptin is also known to exert quite a degree of influence upon the complex neuroendocrine systems, including the hypothalamic-pituatory-adrenal axis (HPA axis), a system which has long been discussed in relation to ME/CFS.

This vast degree of influence leptin has upon these system appears to stem primarily from the high energy demand required for these processes. As the molecule primarily regulating the largest store of energy in the body, that being body fat, leptin somewhat indirectly exerts a great deal of influence upon a majority of complex bodily systems.

Perhaps one of the most interesting findings of leptins many influences is the close ties that leptin has within the immune system.

Leptin and the Immune System

Leptin through its action as a cytokine can have a profound influence upon the bodys immune response

Leptin, through its action as a cytokine, can have a profound influence upon the body’s immune response.

Alongside the multitude of other systems, leptin influences the immune system also, through its action as a cytokine, and can drastically alter the homeostasis of the thymus. The thymus is a central organ in the functioning of a healthy immune system. 

Further to this, leptin also promotes Th1 cell differentiation in a similar fashion to many other proinflammatory cytokines. This can then lead to further cytokine production which then further stimulate cells of the immune system. Even more cytokines are produced and so the cycle continues, spiralling ever more out of control.

Given the actions leptin can have on the immune system as a whole, it is clear to see that leptin could easily propagate significant immune dysregulation and perhaps even be the primary cause of it.

Leptin is unique in that it bridges the gap between metabolism, the endocrine and immune systems in a way that very few molecules do. It is for this reason that it excites many researchers both within the ME/CFS field and beyond.

Interestingly, while in many other systems the influence leptin exerts is due to energy requirements, the immune system influence is a result of both this energy requirement and also the presence of leptin’s receptors in all cell types of innate and adaptive immunity. The binding of leptin to these receptors is what triggers many of the aforementioned immune responses. 

Undeniably one of the biggest hypotheses in the field of ME/CFS research currently is that of autoimmunity as a potential cause of disease. The primarily female patients cohort, frequent sudden onset, symptom flares and remissions have all long been speculated to be linked to autoimmune conditions. 

Recent research using the monoclonal antibody rituximab to successfully treat ME/CFS in a small number of cases has reignited interest in autoimmunity with regards to ME/CFS. Leptin fits almost too well with this line of thought.

We already know that leptin has a strong influence upon the functioning of the immune system. Recent evidence even indicates that leptin is involved in the dysregulated balance between Th1 and Th2 cytokines, a feature that has been observed in ME/CFS for many years.

There exist numerous research papers and articles exploring the role that leptin may play in autoimmune disease. It is well established that abnormal leptin levels are quite a common finding in those suffering from a variety of these autoimmune conditions, from being correlated to rapid progression of autoimmune diabetes to showing clear links with both the development and worsening of autoimmune thyroid diseases.

These links have been studied quite intensively and have been proved both in vitro and in vivo. Further to the previously mentioned examples, leptin appears to play quite a substantial role in the disease pathogenesis of multiple sclerosis (MS), being consistently elevated in these patients. Furthermore, leptin levels both in serum and cerebrospinal fluid (CSF) spike during periods of acute disease activity in these patients. 

This observation has been shown to not have any relation to the BMI of the studied patient cohort, likely as a result of leptin levels being observed to be much higher in the CSF than in serum. 

Clearly then, leptin appears be doing something much grander than simply providing a marker of disease activity. The vast array of systems leptin can influence is certainly intriguing in light of the multiple systems that appear to be dysfunctional as a result of ME/CFS.

Further to this however, the links to the immune system are likely the most intriguing of all theses systems that leptin has influence over. The last paragraphs provided a brief overview exploring some of the autoimmune diseases that leptin is shown to influence, and even that list including rheumatoid arthritis, lupus and more beyond! 

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22 comments

{ 22 comments… read them below or add one }

rosie26 April 16, 2014 at 1:17 pm

Leptin sounds a big influence.
Andrew for those of us who have symptoms of nausea, weakness, exhaustion and not wanting to eat during relapses, would that be Leptin resistance also but in a different way, or would it be sensitivity ? I don't fit the wanting to eat all the time. I get signals to stop and during relapses it is like my body doesn't even want anything at all to pass my lips. I really have to force myself to eat or swallow. Would it be resistance or sensitivity, or is it too difficult to explain. ?

I understand there is more involved than just the appetite regulation. But just wondering about this one at the moment.

Legendrew April 16, 2014 at 1:50 pm
rosie26

Leptin sounds a big influence.
Andrew for those of us who have symptoms of nausea, weakness, exhaustion and not wanting to eat during relapses, would that be Leptin resistance also but in a different way, or would it be sensitivity ? I don't fit the wanting to eat all the time. I get signals to stop and during relapses it is like my body doesn't even want anything at all to pass my lips. I really have to force myself to eat or swallow. Would it be resistance or sensitivity, or is it too difficult to explain. ?

I understand there is more involved than just the appetite regulation. But just wondering about this one at the moment.

Hmm good question, I know myself that when my symptoms flare up, usually during a secondary illness, I lose my appetite and usually get a degree of nausea. At this stage, given the very early stages of research, it's impossible to give a definite answer but I can certainly speculate.

I think my article puts across that to my mind it is the immune system side of leptin that ties so closely with ME/CFS and any appetite issues would perhaps be a by-product of this or even something else entirely. To my understanding, taking into account the research that was discussed at the conference, leptin levels appear to be fluctuating quite a bit in ME/CFS patients from normal(ish) levels during times of relative remission and often getting quite a bit higher during times of relapse, as is observed in many autoimmune conditions such as MS. If this proves to be the case then the loss of appetite during flare ups could certainly be attributed to the spiking leptin levels. The question is then why the leptin levels are becoming elevated during flares. Is the elevated leptin causing the flare? perpetuating it? These are all questions that need to be asked.

For me, while I think these findings are incredibly useful going forwards, I don't think leptin has much to do with the cause of ME/CFS. I think it is simply becoming up-regulated along with a whole host of other components of the immune system during times of disease activity. I think we should take away a lot from the fact that the pattern we are now seeing in ME/CFS leptin levels correlates so strongly with that seen in autoimmune conditions.

Bringing my answer back to your initial question, I think the loss of appetite could certainly be because of leptin spikes during flare ups of disease activity, the other symptoms you mention could but I think these are more attributable to autonomic dysfunction during flare ups and whatever system the autoimmunity is targeted towards (in case you haven't noticed I'm utterly convinced of autoimmunity being behind the disease but please don't let me sway your personal opinions!)

In all honesty this is a very complex topic that I still don't understand in its entirety, it is still at the cutting edge of research and because of this I think that it's very important we pursue it further and see where it may lead us

voner April 16, 2014 at 3:07 pm

That is one fine piece of writing about a very complex subject. Congrats!

I really enjoyed your speculation.

Did the study control for obesity in the participants? In this I mean, rule out the possiblity that they selected an obese population and thus have higher levels of leptin?

Legendrew April 16, 2014 at 3:25 pm
voner

That is one fine piece of writing about a very complex subject. Congrats!

I really enjoyed your speculation.

Did the study control for obesity in the participants? In this I mean, rule out the possiblity that they selected an obese population and thus have higher levels of leptin?

I can't say not having seen the study in its entirety but I'm guessing not, this is still quite preliminary research which is why I doubt they would have done so. I'm glad you enjoyed both the article and my musings, as you say its a complex subject at the best of times and when combined with ME/CFS and all the complexities therein it gets very tricky indeed.

searcher April 16, 2014 at 3:52 pm

@voner – The study had controls that were age and BMI-matches so obesity shouldn't be a factor in their findings, I think. Leptin corresponded to fatigue in six patients and only one control.

adreno April 16, 2014 at 9:19 pm

Why would leptin be high in people who are not overweight?

rosie26 April 16, 2014 at 11:19 pm

Thanks Andrew
I keep forgetting to mention it is mostly when my relapses are severe or moderate-severe that I get the awful extreme lack of appetite :rolleyes:Moderate – mild relapses I manage to eat but I still don't get the increased appetite with it.
I wonder the effects of low grade encephalitis (if that's what our head inflammation is) and the role it plays also in changing homeostasis, it could tilt things off as well. But that's off topic.

Edit – Be interesting to have an article on Encephalitis whenever you have some time ?:)

searcher April 16, 2014 at 11:38 pm

@adreno – My understanding (and @Legendrew can correct me if I am wrong) is that our absolute leptin levels aren't high; it's that the leptin fluctuations correlate with fatigue. This is one reason why leptin itself can't be a biomarker– it's only interesting when you look at the levels day-after-day and see that the relative levels are what are relevant for predicting fatigue.

Dr Younger mentioned at the conference that leptin levels were an even better predictor of pain in fibromyalgia patients than they were in predicting fatigue in CFS patients. They correlated with daily fatigue levels in 6/10 CFS patients and with pain levels in 9/10 fibromyalgia patients in a separate study.

lilpink April 17, 2014 at 1:45 am

I do find this line of research interesting. I wonder if the action of certain pain meds (I'm thinking personally and specifically about pregabalin/ Lyrica) produces changes in leptin and thus creates the (sometimes considerable) weight gain we see in people on these meds? My weight has increased marginally from being on them, but I know that without steely willpower it could increase considerably more. I crave carbs in a big way and I know this is indubitably related to taking this med. Interestingly other meds which are usually regarded as those which increase weight in those taking them such as HRT, had no influence on my weight at all. I'm not sure if this tells us anything about neuro pain of course..possibly only about this class of drugs…but then again maybe it does inform pain research too, all depending I suppose on whether leptin is indeed influenced by such drugs and then whether or not that influence is associated with the pain relieving action of the the drug….

aimossy April 17, 2014 at 2:57 am

Thankyou @searcher I had still been thinking levels of leptin were elevated for some reason.

Legendrew April 17, 2014 at 3:07 am
aimossy

Thankyou @searcher I had still been thinking levels of leptin were elevated for some reason.

Well it seems that they are fluctuating quite a bit so during flares they are much higher than normal while during remissions they seem to be around the normal range.

aimossy April 17, 2014 at 3:58 am

Thanks @Legendrew , I will have to go over some of the information I have read and found out. Leptin is also elevated when you are stressed and when your body is fighting infection. Well I'm sure I have read that in my searches.
It had made me wonder when we push ourselves is this in part to play for exacerbation of symptoms. Just makes you wonder, I mean how do we know anything really.:rolleyes::) But I definitely need to review my stuff.
What you have just said is in line with what I was thinking I new about the peaks. These cytokines do fluctuate easily so I'm looking forward to the publishing of the latest research. Thankyou for the article.:)

searcher April 17, 2014 at 11:31 am

There may be different findings in the various studies. In the Younger study to which Andrew linked (http://www.translational-medicine.com/content/11/1/93#B9), the authors said "The relationship we observed between leptin and fatigue existed even though leptin levels were not abnormally elevated, and there was no statistical difference in leptin values between the CFS and control groups" and "The results suggest that absolute leptin levels were not abnormal, and therefore the relationship with symptom severity might only be observed with a longitudinal design."

But it may be worth contacting Younger to confirm whether they saw leptin high during flares in CFS or fibromyalgia. Because it's possible they are talking about the average "absolute leptin levels" but that the higher variations still went over the normal range.

And I forgot to thank you earlier for the article Andrew! Leptin is a really fascinating topic, and frustratingly complex like the rest of the immune system.

MeSci April 19, 2014 at 11:31 am
searcher

@adreno – My understanding (and @Legendrew can correct me if I am wrong) is that our absolute leptin levels aren't high; it's that the leptin fluctuations correlate with fatigue. This is one reason why leptin itself can't be a biomarker– it's only interesting when you look at the levels day-after-day and see that the relative levels are what are relevant for predicting fatigue.

Dr Younger mentioned at the conference that leptin levels were an even better predictor of pain in fibromyalgia patients than they were in predicting fatigue in CFS patients. They correlated with daily fatigue levels in 6/10 CFS patients and with pain levels in 9/10 fibromyalgia patients in a separate study.

60% correlation isn't very good, is it?

searcher April 19, 2014 at 8:23 pm

@MeSci – I think the 60% is better than that statistic seems to indicate though when you look at the details of the study. In 6/10 patients daily leptin levels correlated with fatigue when charted on a daily basis for 25 days. Dr Younger showed a chart at Stanford and it was pretty impressive to see how linked they were over a longish time period; I think http://www.translational-medicine.com/content/11/1/93/figure/F1 is the chart. Leptin was only linked with self-reported fatigue in 1/10 controls. Strangely, it was negatively correlated with fatigue in one of the patients.

It would be great to see a replication on a larger scale, although having a large number of patients come in every day for 25 days is obviously an expensive and difficult project. I am really thankful that the initial group potentially sacrificed their health to participate.

I wonder if the issue for some of the other patients could be how hard self-reporting fatigue is? Giving a pain score may be easier, although I know that can be challenging too. This is just a random conjecture though because of my own experience; when I was severely fatigued every day it was hard to differentiate the levels day-by-day.

MeSci April 20, 2014 at 6:51 am
searcher

@MeSci – I think the 60% is better than that statistic seems to indicate though when you look at the details of the study. In 6/10 patients daily leptin levels correlated with fatigue when charted on a daily basis for 25 days. Dr Younger showed a chart at Stanford and it was pretty impressive to see how linked they were over a longish time period; I think http://www.translational-medicine.com/content/11/1/93/figure/F1 is the chart . Leptin was only linked with self-reported fatigue in 1/10 controls. Strangely, it was negatively correlated with fatigue in one of the patients.

It would be great to see a replication on a larger scale, although having a large number of patients come in ever day for 25 days is obviously an expensive and difficult project. I am really thankful that the initial group potentially sacrificed their health to participate.

I wonder if the issue for some of the other patients could be how hard self-reporting fatigue is? Giving a pain score may be easier, although I know that can be challenging too. This is just a random conjecture though because of my own experience; when I was severely fatigued every day it was hard to differentiate the levels day-by-day.

Interesting, thanks.

Yes, it can be difficult to grade one's fatigue, but I have started doing it more in my health diary which has enabled me to do it better, for example by how fatigable I am, which can be estimated by how much I can do before I have to stop, or become weak, for example. I can see how this would be harder in severe fatigue, but maybe it could be estimated by how long one can hold one's hand up, or sit up, etc.

I think that having patients come in for the research is a confounding factor, as different patients will have to travel different distances by different means, and it will add to the exertion. It would be better scientifically (and perhaps for patients too) for them to stay at the research centre.

aimossy April 21, 2014 at 8:05 pm

Thanks @searcher that was really helpful:)

Sing May 21, 2014 at 4:05 pm
adreno

Why would leptin be high in people who are not overweight?

I am thinking it is because they are sick. It is typical for people to lose their appetite when sick. This helps the body recover because the liver then doesn't have to take all its energy and time processing food but can instead support the body in fighting off the illness.

MeSci May 22, 2014 at 6:17 am
Sing

I am thinking it is because they are sick. It is typical for people to lose their appetite when sick. This helps the body recover because the liver then doesn't have to take all its energy and time processing food but can instead support the body in fighting off the illness.

I'm not sure what @adreno means by

Why would leptin be high in people who are not overweight?

The article says:

individuals who produce little or no leptin are highly prone to developing massive obesity. Logically then you would assume that high leptin leads to malnutrition and severely underweight patients.

So high leptin correlates with a lack of obesity. Low leptin correlates with obesity.

Sorry if my ME brain has missed something – I have certainly forgotten most of the article!

adreno May 22, 2014 at 2:35 pm

Again, from the article:

Leptin belongs to a group of molecules known as adipokines, a group generally defined as cytokines (cell signalling molecules) secreted almost exclusively by adipose tissue, better known as body fat. For this reason the serum concentration of leptin is usually proportional to the total body fat an individual has.

So how can individuals with low body fat have high leptin levels?

MeSci May 23, 2014 at 1:08 am
adreno

Again, from the article:

So how can individuals with low body fat have high leptin levels?

Dunno. Maybe someone else does!

Leopardtail June 9, 2014 at 2:19 am
MeSci
searcher

@adreno – My understanding (and @Legendrew can correct me if I am wrong) is that our absolute leptin levels aren't high; it's that the leptin fluctuations correlate with fatigue. This is one reason why leptin itself can't be a biomarker– it's only interesting when you look at the levels day-after-day and see that the relative levels are what are relevant for predicting fatigue.

Dr Younger mentioned at the conference that leptin levels were an even better predictor of pain in fibromyalgia patients than they were in predicting fatigue in CFS patients. They correlated with daily fatigue levels in 6/10 CFS patients and with pain levels in 9/10 fibromyalgia patients in a separate study.

60% correlation isn't very good, is it?

I agree with several of the points MeSci made and would like to add a couple of my own.

Unless I am brain fogged and have misunderstood. To me thus seems a bit suspect as a causal issues (Etiology) rather than just part of the Pathophysiology (chain reaction from the cause). Firstly when I first got ME rather than lack of appetite it went nuts, I was eating for six, not putting on weight and had bugger all energy. That would be consistent with low leptin.

Next (MeSci understands this better and may correct me) – A shift AWAY from the Th1 immune system and to the Th2 seems to have common agreement. My reading of the article was that Leptin created more Th1 cells.

As MeSci pointed it a 60% correlation is not strong enough for this to be the central issue wih ME – Howard's mito-function test has a MUCH stronger correlation than that. Like the mito test however it would also only be useful to show level of illness For example, my mum was far less ill on Chemotherapy than I am with ME, and the Mito test reflects that comparison. It also shows a strong correlation between results and levels of fatigue and even with ME-light fatigue markedly different results to the normal population.

However I suspect very low Leptin early in the illness and if that view is correct Leptin would measure us as 'over-fit' when we are more ill than the general population.

If it is correct though any severe illness would raise leptin, hence like the Mito test, it would not be a unique bio-marker for ME but a marker of serous illness.

Personally my appetite is "manic-depressive" and Sheppard lists "Pathological hunger" referring to this volatility as an ME symptom.

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