Could leptin be affecting both pain and fatigue in FM and ME/CFS?
Nobody in the chronic fatigue syndrome (ME/CFS) community had taken leptin – a hormone produced by fat cells – seriously, until Jarred Younger’s Stanford Good Day Bad Day study suggested that it might be the factor driving fatigue n ME/CFS. Younger wasn’t aiming at leptin; it was just one of many immune factors he analyzed in his unusual (and intense) study examining the blood of ME/CFS patients over 25 days. Now leptin is popping out again – this time in women with body-wide pain and fibromyalgia.
Association of Leptin with Body Pain in Women. Younger J, Kapphahn K, Brennan K, Sullivan SD, Stefanick ML.J Women’s Health (Larchmt). 2016 Jul;25(7):752-60. doi: 10.1089/jwh.2015.5509. Epub 2016 Mar 30.
This may be the first paper in the history of medicine to report on both a three person study and a 5000 person plus study at the same time. The proof of concept three person study mimicked the ME/CFS study; every day for 25 days three dedicated FM patients provided blood samples and estimates of their symptoms to Younger, who then analyzed about 50 factors in their blood. As in the bigger (but not much bigger) ME/CFS study leptin popped out again – but this time with regard to pain, not fatigue.
The 5676 person study queried the women regarding their pain levels and measured their BMI (obesity index) and leptin levels.
Both studies found that increased leptin levels were associated with increased pain. Increased (BMI) obesity was correlated with increased leptin levels as well. Putting the BMI factor aside, leptin was still associated with increased pain; i.e., leptin may be associated with increased obesity levels, but it also appears to increase pain whether you are fat or thin.
If leptin is increasing inflammation in diseases like rheumatoid arthritis, lupus, and multiple sclerosis and ME/CFS and FM it could do it in a couple of ways; by increasing cytokine levels (IL-6, IL-8), by activating the macrophages or by poking the microglia.
An Immune Factor to Keep an Eye On
Eotaxin is showing up more and more in FM and ME/CFS
Plus eotaxin, another factor that wasn’t discussed at all until a few years ago, but which has shown up recently in several ME/CFS as well as FM studies, appeared to be associated with leptin. Eotaxin, a chemokine which plays a role in allergic reactions, is definitely an immune factor to keep an eye one.
These recent studies underscore how important it is to analyze large numbers of immune factors – something that has been occurring more and more recently. Finally, leptin could help explain why women are so much more susceptible to FM and ME/CFS than men.
Reducing Leptin?
Because poor sleep and infections can upregulate leptin levels, improving sleep or knocking down infections could reduce them. Reducing caloric intake, weight reduction and exercise (none of which are easy in ME/CFS or FM) have also been shown to reduce leptin levels. Some studies suggest that fasting could help – an interesting idea given Dr. Courtney Craig’s success with intermittent fasting in ME/CFS and FM. On the alternative medicine side, genistein (an isoflavone) might be helpful.
Should leptin be found to be a big deal in FM and/or ME/CFS, grehlin is a possible leptin antagonist. Ghrelin is intriguing for its ability, among other things, to regulate how much of the energy in a cell goes to ATP production, fat storage, glycogen storage, and/or heat loss. According to Wikipedia, ghrelin “also activates the cholinergic–dopaminergic reward link and a brain circuit involved in “reward”. Miller’s ME/CFS study found that low reward was associated with increased fatigue in ME/CFS.
Younger is a long way, though, from recommending leptin antagonists. He acknowledged that the FM studies had some holes; the 25-day study had only three FM patients, pain severity testing in the larger study was imprecise, data collection times varied, and fat composition was not precisely measured.
Since no clinical standards for elevated leptin exist, Younger doesn’t recommend getting tested for it. (Leptin levels, in fact, were not markedly increased in ME/CFS patients relative to the healthy controls in Younger’s earlier study. That suggested increased sensitivity to leptin could have the same effect as increased leptin levels.)
More Study Needed
More study is needed to validate leptin’s effects in FM or ME/CFS
Younger cautioned that leptin needs more study before we can be confident it’s a major factor in ME/CFS or FM. A disappointing recent report on Dr. Newton’s promising pH, lactic acid and mitochondrial findings in the muscles of ME/CFS patient underscores how important it is to have large studies. The grace of Younger’s earlier ME/CFS study was its intensity (25 days of blood draws), but it included just ten people with ME/CFS – six of whom leptin was found to be a major factor in. The big NIH grant Younger snagged earlier this year and his continuing work with FM will tell us much about leptin’s possible role in these diseases.
At least for the moment, though, leptin is looking good.
On a side note, Younger posted an encouraging message on the Neuroinflammation, Pain and Fatigue Laboratories Facebook site recently
I’ve been traveling over the past few weeks in the northeast for a string of meetings. There are many things happening now! I can’t give details, but I was encouraged to see many new groups working on fibormyalgia and chronic fatigue syndrome. Pharmaceutical companies are showing growing interest in developing better treatments for these conditions, which is matching the greater attention we are seeing from federal health organizations. It has been a very long time coming, but I believe we are finally seeing a shift in emphasis that will lead to quicker discoveries and better treatments. More info coming soon!
Also check out Younger’s talk at the Solve ME/CFS Initiative here.
This is a post I made years ago. Leptin issues can increase inflammation. So many connections and pieces of the puzzle.
http://forums.dinet.org/index.php?/topic/20923-fatty-liver/#comment-194449
I recall some saying they have a fatty liver and didn’t think they were overweight.
I uncovered one cause of fatty liver as cytokine related to leptin. Since we are connecting other things to cytokines and inflammation – wondered about this one. I know one thing that can lower leptin insensitivity is Irvingia – it’s a type of mango, taken from the seed and can be gotten in pill form. It also makes a persons switch of being full to kick in and prevents over eating. It has been used to help in weight loss and can help to regulate blood sugars.
Issie
Irvingia – interesting and thanks for the links.
Interesting. I was diagnosed with non alcoholic fatty liver ages ago (before fibro). I was told to go on Tri-lipotropic supplements. The condition completely disappeared. Maybe its time to get my liver checked again. Thanks!
My liver enzymes spike every 2 years or so now (if not more frequently) with return of cytomegalovirus type symptoms and weight gain. I was slim pre CFS with exceptionally ripped lower body muscles from running up and down the hills in a national park near me and using the gym. that disappeared and my weight is up about 30% and seems impossible to drop, my CFS specialist is baffled.
I record using activity trackers and calorie counting and have tried all novel ratios of macronutrients but mostly being on around 1600 calories a day or less and getting my steps to ~3200 but nothing shifts.
I discussed Leptin with the doc and am on Metformin 1000mg twice daily – its about 5 months or so now. no change. still baffled and finding it one of the worst aspects of CFS now cause I am paranoid about others perceptions of me knowing that I am not working but also look like I over eat when I categorically do the opposite.
OH and I intermittent fast most days, first food happens after 11AM.
I might try the mango derivative on my next iherb order, will read a bit first 🙂 thanks
“…Reducing caloric intake, weight reduction and exercise (none of which are easy in ME/CFS or FM) have also been shown to reduce leptin levels…”
As I have found: make the diet ketogenic (low carb / Atkins), keep the exercise strictly “cardio” (not muscle-strengthening) and at “fat burning” intensity (65% of maximum heart rate) and massive improvements occur. Watch the dehyration, be ready to boost the magnesium supplementation again and again as necessary.
I have also posted a comment on your Forum about the disappointment re the “promising pH, lactic acid and mitochondrial findings” being rebutted.
That is a nice theory, but does not work for bedridden patients. Severely ill patients cannot do aerobic exercise – it is instantly anaerobic in nature because the M.E. means they inherently are not getting oxygen into their cells when they move their muscles. Their hearts are inefficient, and blood volume is often low. Working the heart harder in this state simply makes it less efficient than it already was, causing terrible brain fog, body-wide inflammation, a rise in flu symptoms, and other issues. Post-exertional immune collapse/inflammation and worsening of other symptoms has been proven in studies for M.E. patients… so no, aerobic exercise is NOT the answer. Just because it worked for you, does not mean it will work for other patients – we do not all actually have the same disease. For most with M.E., keeping heart rate low is essential to slowly regaining conditioning. But even then, it is not a cure.
Additionally, many patients such as myself barely have any energy to be able to leave a bedridden state as it is, and when you cut carbs, we lose the ability to even lift a glass of water to our own mouths. I have repeatedly tried reducing carb intake – when I lower it, I become unable to care for myself. When I raise it, I have increased energy so can get a little more done that usual before collapse.
According to wikipedia leptin “helps to regulate energy balance by inhibiting hunger. Leptin is opposed by the actions of the hormone ghrelin, the “hunger hormone”.”
So those with high levels of leptin would be thin.
Isn’t that a weird one. That’s contrary to what one would think given this sentence in the abstract:
“Both leptin and BMI were found to be independently associated with self-reported pain ( p = 0.001 and p < 0.001, respectively), with higher leptin levels and greater BMI each being associated with greater pain."
If you are not leptin resistant and your body was working correctly – your full switch would work and you wouldn’t over eat. But, those who are overweight actually have more leptin. The fat makes it. They are however leptin resistant and it doesn’t work properly in their body. People also tend to be insulin resistant. Yet maybe not a complete diabetic. There is also a connection to higher CRP and inflammation with leptin resistance and more overweight people. The nice thing about Irvingia is it addresses those things and makes the body more tuned in to leptin, makes the full switch work and helps with inflammation. I find it helpful for all those things. But, I wouldn’t say it has solved all my issues. It may be one piece of the puzzle. However, I think inflammation and autoimmune issues are the bottom line.
Issie
Thanks for explaining that.
I read the study and they’re saying elevated leptin levels and high BMI are each predictors of pain.
I just checked with Wikipedia and leptin is a satiety hormone, not an appetite hormone. When your fat cells are full enough, they put out leptin as a curb on appetite.
https://en.wikipedia.org/wiki/Leptin
But there is something called leptin resistance in which your leptin levels are high, but it doesn’t function properly and doesn’t turn off appetite.
I read about that too. I hardly ever feel satired. In fact my hunger pains / cravings / blood sugar dips are bad for years. I can’t function without having to over eat. Gained a lot of weight of course.
Here’s some info about leptin resistance:
http://articles.mercola.com/sites/articles/archive/2012/10/29/leptin-resistance.aspx
And, by the way, Cort, I love your newsletter! I depend on the information that you put out as I try to find a pathway out of this miserable illness. Thanks for all your hard work!
Here is some info on how to lower leptin. I really don’t know how reliable it is because I don’t see references. Maybe the books mentioned about how to lower leptin would have references.
http://www.wellnessresources.com/weight/articles/the_five_rules_of_the_leptin_diet/
I could certainly be wrong, but remembering that digestion of food is one of the 3 main uses of energy in the body (along with the brain and muscles, that blood is diverted to the digestive system, I’ve always felt it is just the digestion process itself that greatly increases my exhaustion. In the 41 years with this disease, more and more as the illness worsens, I notice a direct correspondence between the amount of food I have eaten and my exhaustion level, I think simply because the body has to work harder/use more energy the more I have eaten. Eating small amounts of easily digested food, spaced out throughout the day, greatly helps with the exhaustion, but is not a cure. I used to fast one day a week, and had much more energy on those days, but had to greatly limit my physical activity or spend the next day in bed unable to lift my head off the pillow. The fact that leptin is present doesn’t prove causation, nor does the fact that it goes up the more one eats. It could very well be that the body is just working so much harder/using up so much more energy when digesting which is when the leptin happens also to be higher.
I definitely have an energy deficit after eating. Digestion uses a huge amount of energy which is why I do much better with soups rather than raw vegetables, especially in winter when a lot of the energy is being used up to keep warm.
What I know about leptin is that it is a regulator of metabolism and thus is also the starvation hormone when its role is to preserve energy for vital functions and thus must limit energy to the muscles. This leads me to think that there is already an energy deficit in these illnesses and that the leptin is just doing its job for survival of the organism. Leptin inhibits cortisol production; cortisol increases ghrelin which makes one hungry for carbs but has no effect on the desire for protein or fat. Increasing cortisol levels require increasing amounts of carbs and so increasing levels of ghrelin are necessary. Studies have already shown that the adrenal glands are underfunctioning in response to ACTH so it is a case of which comes first, the low cortisol or the high levels of leptin.
Another factor involved here is the availability of progesterone as progesterone is the pre-cursor of cortisol and also inhibits leptin production. As the progesterone turns into cortisol, the levels of leptin go down and the levels of ghrelin go up. In turn, the progesterone comes from pregnenolone which is produced in the mitochondria and there’s those pesky mitochondria, again.
OK GUYS WHAT CAN I TAKE TO HELP SOME ANSWERS TOO COMPLICATED
So, what tests do we need to have done to check our Leptin levels? Who should we see, a functional medicine doctor?
Some time ago, Dr. Paul Cheney said that if only his ME/CFS patients didn’t have to eat, they would be a lot better. Maybe someone can recall the bigger context of his thinking. Seems to refer to the energy involved as well as the weight?
My leptin must have gone up when I was first getting sick as I didn’t want to eat at all. I was slim anyway. This frightened me so I forced myself and after awhile a normal appetite resumed.
One thing to keep in mind is that sick animals in nature often lose their appetites and just hole up or rest until they, hopefully, feel better. And this loss of appetite and not eating can also be part of a natural dying process.
My guess is that leptin isn’t a fundamentally causative factor for us but rather a link in the chain of physical events. We are essentially sick animals. Laying off the food, or cutting down, can be helpful. I once read that the liver is known to be able to do 500 or more processes, but when we are constantly giving it food or alcohol or drugs to detox, etc. it has to give those processes first priority and may not get around to the other processes we could use. So this is why occasional fasting or undereating can help the liver get around to other needed work.
I eat little during the daytime as it helps me stand up and walk then, but can also feel how it helps my body organize itself and feel better. It is later in the day when I catch up on eating what I need.
Cory, once again very interesting and informative. Thank you. I have a question off the subject of this post. Why don’t I hear more about the flu like symptoms of people here. The extreme sore throats , lasting for months, the low grade fevers, the lightening bolts of pain in legs, the burning sensations along face and arms, etc… Yes, always the heavy fatigue and brain fog, but being really really sick is the worst in my experience.
Sorry, Cort, small phone for typing and didn’t mean to misspell your name!!
No problem!
I am not saying that this is the case for everyone but I personally have recently found out I have biotoxin illness /Lyme and that implicates leptin issues due to low MSH. I have also gained about 30 lb in 3 years due to this illness.
That’s no fun! Good with the biotoxin/Lyme..
Jo, I have the same issues along with other things. It’s a long process to detox and manage. I’m 2 years trying and still working on it.
Issie
Jo, I’m sorry to hear that you have a biotoxin illness and Lyme. I think I might a mold biotoxin problem, too. I went down into my basement last Sunday to sort stuff in preparation for getting mold remediation and after an hour and a half, I got a ton of symptoms – migrating pains all over, headache, tingling in my hands, chest pain, brain fog, fatigue, and then itching all over. I took a lot of activated charcoal, which seemed to help, but joint pains keep recurring. Do you have a doctor who knows how to treat this biotoxin thing? Are you doing anything that helps? I learned about biotoxin illnesses from the Surviving Mold website based on Dr. Shoemaker’s work. I don’t know where to get good medical help – the whole thing sounds so complicated. Thanks for any info you might have and want to pass on.
See link below :
http://www.survivingmold.com/diagnosis/the-biotoxin-pathway
Jo, I should have read what you wrote more carefully. You have been finding gout about this from the Surviving Mold website. Do you have a good doctor who know about all this? Have you taken cholestyramine? If so, did it work?
Rachael, I’m not Jo – but I’ve been treating mine for 2 years now. I did take cholestyramine for 3 weeks. It was difficult to take and gave me really bad headaches. But I do think it helped. Doing other cleanses and detox, I feel, helped more. Also addressing Lyme and Protomyzoa Rehumatica has been a huge help.
What people don’t realize when it comes to mold exposure – everything in your house is exposed. You have to try to clean everything and it may not be possible. I had to get rid of so much. Some clothes also. It is so small and if you have gotten super sensitive – that small amount will bother you.
If you’d like to talk more, I’m on Healthrising Forum. Easier to have a back and forth conversation there.
One way to determine if you are suffering from mold is take a test at VCSTEST.COM It is very insightful.
Issie
Thanks for your reply, Issie! I’ll try to figure out how to get on the HealthRising forum. My chronic fatigue doc gave me the visual contrast test and I passed, but I understand that maybe 8% of people with a mold problem pass that test. I found out a week ago that I do have a mold problem because in the process of trying to get rid of the mold in my basement, I went down there for an hour and a half. Big mistake! I got aches and pains all over my body, chest pain, headache, tingling in my hands, and then itching all over. I took a lot of activated charcoal and that seemed to help, but the symptoms kept recurring. Eight days later I finally feel sort of OK. When I see my chronic fatigue doc, maybe I’ll ask about cholestyramine. I can see that you are right that it will be a huge job reducing the amount of mold in my house and that it won’t be 100% possible. Right now we’re concentrating on the basement.
I’m also being treated for Lyme, though it hasn’t been proven completely that I have it. I’m taking 3 antibiotics. And I get debilitating die off reactions, so I’m now taking 2 of them intermittently. The good news is that I have days when I feel better. Activated charcoal seems to help a lot but I’ve been warned not to take it too often. Confusing.
Let me try to find out how to get onto the forum. I’d love to find out what you know about all this and hear what you’ve done.
I just found this study about the Inviringa supplement and its affects on weight loss, cholesterol and triglycerides. Very interesting, except that it contains a high amount of fiber, which I’m supposed to avoid having gastroparesis. I might Tru it anyway. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1168905/?report=classic
Also, there is the Venus diet which is aimed at increasing Leptin/increasing sensitivity to Leptin for weight loss in women.
So what if you are over weight but your leptin is low and youve been diagnosed with CFS??