Tag Archives: Adipokine

Is a rational treatment for chronic fatigue syndrome at hand?

If an idea of mine is correct, it is possible that some patients with chronic fatigue syndrome (CFS) can be treated with specific medications based on the results of a few blood tests. This is precision medicine at its finest.  The data to test this idea has already been acquired, and nothing further needs to be done except to analyze it.

Athough the initial impetus for the idea happened only 3 months ago, there have been enough twists and turns that the best way explanation is by a timeline.

First some background:

As a neurologist I saw a lot of people who were chronically tired and fatigued, because neurologists deal with muscle weakness and diseases like myasthenia gravis which are associated with fatigue.  Once I ruled out neuromuscular disease as a cause, I had nothing to offer then (nor did medicine).  Some of these patients were undoubtedly neurotic, but there was little question in my mind that many others had something wrong that medicine just hadn’t figured out yet — not that it hasn’t been trying.

Infections of almost any sort are associated with fatigue, most probably caused by components of the inflammatory response.  Anyone who’s gone through mononucleosis knows this.    The long search for an infectious cause of chronic fatigue syndrome (CFS) has had its ups and downs — particularly downs — see https://luysii.wordpress.com/2011/03/25/evil-scientists-create-virus-causing-chronic-fatigue-syndrome-in-lab/

At worst many people with these symptoms are written off as crazy; at best, diagnosed as depressed  and given antidepressants.  The fact that many of those given antidepressants feel better is far from conclusive, since most patients with chronic illnesses are somewhat depressed.

The 1 June 2017 Cell had a long and interesting review of cellular senescence by Norman Sharpless [ vol. 169 pp. 1000 – 1011 ].  Here is some background about the entity.  If you are familiar with senescent cell biology skip to the paragraph marked **** below

Cells die in a variety of ways.  Some are killed (by infections, heat, toxins).  This is called necrosis. Others voluntarily commit suicide (this is called apoptosis).   Sometimes a cell under stress undergoes cellular senescence, a state in which it doesn’t die, but doesn’t reproduce either.  Such cells have a variety of biochemical characteristics — they are resistant to apoptosis, they express molecules which prevent them from proliferating and — most importantly — they secrete a variety of proinflammatory molecules collectively called the Senescence Associated Secretory Phenotype — SASP).

At first the very existence of the senescent state was questioned, but exist it does.  What is it good for?  Theories abound, one being that mutation is one cause of stress, and stopping mutated cells from proliferating prevents cancer. However, senescent cells are found during fetal life; and they are almost certainly important in wound healing.  They are known to accumulate the older you get and some think they cause aging.

Many stresses induce cellular senescence of which mutation is but one.  The one of interest to us is chemotherapy for cancer, something obviously good as a cancer cell turned senescent has stopped proliferating.   If you know anyone who has undergone chemotherapy, you know that fatigue is almost invariable.

****

One biochemical characteristic of the senescent cell is increased levels of a protein called p16^INK4a, which helps stop cellular proliferation.  While p16^INK4a can easily be measured in tissue biopsies, tissue biopsies are inherently invasive. Fortunately, p16^INK4a can also be measured in circulating blood cells.

What caught my eye in the Cell paper was a reference to a paper about cancer [ Cancer Discov. vol. 7 pp. 165 – 176 ’17 ] by M. Demaria, in which the levels of p16^INK4a correlated with the degree of fatigue after chemotherapy.  The more p16^INK4a in the blood cells the greater the fatigue.

I may have been the only reader of both papers with clinical experience wth chronic fatigue syndrome.  It is extremely difficult to objectively measure a subjective complaint such as fatigue.

As an example of the difficulty in correlating subjective complaints with objective findings, consider the nearly uniform complaint of difficulty thinking in depression, with how such patients actually perform on cognitive tests — e. g. there is  little if any correlation between complaints and actual performance — here’s a current reference — Scientific Reports 7, Article number: 3901(2017) —  doi:10.1038/s41598-017-04353.

If the results of the Cancer paper could be replicated, p16^INK4 would be the first objective measure of a patient’s individual sense of fatigue.

So I wrote both authors, suggesting that the p16^INK4a test be run on a collection of chronic fatigue syndrome (CFS) patients. Both authors replied quickly, but thought the problem would be acquiring patients.  Demaria said that Sharpless had a lab all set up to do the test.

Then fate (in the form of Donald Trump) supervened.  A mere 9 days after the Cell issue appeared, Sharpless was nominated to be the head of the National Cancer Institute by President Trump.  This meant Dr. Sharpless had far bigger fish to fry, and he would have to sever all connection with his lab because of conflict of interest considerations.

I also contacted a patient organization for chronic fatigue syndrome without much success.  Their science advisor never responded.

There matters stood until 22 August when a paper and an editorial about it came out [ Proc. Natl. Acad. Sci. vol. 114 pp. 8914 – 8916, E7150 – E7158 ’17 ].  The paper represented a tremendous amount of data (and work).  The blood levels of 51 cytokines (measures of inflammation) and adipokines (hormones released by fat) were measured in both 192 patients with CFS (which can only be defined by symptoms) and 293 healthy controls matched for age and gender.

In this paper, levels of 17 of the 51 cytokines correlated with severity of CFS. This is a striking similarity with the way the p16^INK4 levels correlated with the degree of fatigue after chemotherapy).  So I looked up the individual elements of the SASP (which can be found in Annu Rev Pathol. 21010; 5: 99–118.)  There are 74 of them. I wondered how many of the 51 cytokines measured in the PNAS paper were in the SASP.  This is trickier than it sounds as many cytokines have far more than one name.  The bottom line is that 20 SASPs are in the 51 cytokines measured in the paper.

If the fatigue of CFS is due to senescent cells and the SASPs  they release, then they should be over-represented in the 17 of the 51 cytokines correlating with symptom severity.  Well they are; 9 out of the 17 are SASP.  However although suggestive, this increase is not statistically significant (according to my consultants on Math Stack Exchange).

After wrote I him about the new work, Dr. Sharpless noted that CFS is almost certainly a heterogeneous condition. As a clinician with decades of experience, I’ve certainly did see some of the more larcenous members of our society who used any subjective diagnosis to be compensated, as well as a variety of individuals who just wanted to withdraw from society, for whatever reason. They are undoubtedly contaminating the sample in the paper. Dr. Sharpless thought the idea, while interesting, would be very difficult to test.

But it wouldn’t at all.  Not with the immense amount of data in the PNAS paper.

Here’s how. Take each of the 9 SASPs and see how their levels correlate with the other 16 (in each of the 192 CSF patients). If they correlate better with SASPs than with nonSASPs, than this would be evidence for senescent cells being the cause some cases of CFS. In particular, patients with a high level of any of the 9 SASPs should be studied for such correlations.  Doing so should weed out some of the heterogeneity of the 192 patients in the sample.

This is why the idea is testable and, even better, falsifiable, making it a scientific hypothesis (a la Karl Popper).  The data to refute it is in the possession of the authors of the paper.

Suppose the idea turns out to be correct and that some patients with CFS are in fact that way because, for whatever reason, they have a lot of senescent cells releasing SASPs.

This would mean that it would be time to start trials of senolyic drugs which destroy senescent cells on the group with elevated SASPs. Fortunately, a few senolytics are currently inc linical use.  This would be precision medicine at its finest.

Being able to alleviate the symptoms of CFS would be worthwhile in itself, but SASP levels could also be run on all sorts of conditions associated with fatigue, most notably infection. This might lead to symptomatic treatment at least.  Having gone through mono in med school, I would have loved to have been able to take something to keep me from falling asleep all the time.

Advertisements

What is a hormone? What is an endocrine organ?

We all knew what hormones were back in the day. They were chemicals released by an endocrine gland into the blood where they went everywhere and affected distant organs. The classic example were the sex hormones (estrogen, progesterone, testosterone) eleased by the gonads affecting the reproductive organs, and not least the brain.

Things have changed mightily, and just about every tissue in the body does this now. There are at least 20 adipokines released by fat — examples are adiponectin, adipsin, and of course leptin. Muscle may be also getting into the act with irisin (although that is controversial). Other muscle produced hormones (myokines)  include atrial natriuretic peptide released by the heart and skeletal muscle releases at least 8 more.

There is even more stuff released into local tissue fluids which don’t get into the blood so they aren’t hormones. You can regard all neurotransmission this way. Paracrines are compounds which act only on cells close to them (because they don’t get into the blood). Examples include the huge class of prostaglandins and polypeptide growth factors such as the 22 member fibroblast growth factor family.

What to make of [ Cell vol. 166 pp. 424 – 435 ’16 ] which describes PM20D1 (Peptidase M20 Domain containing 1) which is secreted by fat cells. It’s an enzyme which builds compounds from substances already in the blood. The chemistry is simplicity itself — it takes a long chain fatty acid and an amino acid and forms the fatty acid amide — or an N-acyl amino acid.

What does the product do? It causes uncoupling of oxidative phosphorylation by mitochondria, so it just produces heat (something useful to an animal in the cold). Administration of N-acyl amino acids to mice increases energy expenditure and improves glucose metabolism. It’s possible that they could be used therapeutically.

Another example of how little we knew about what is going on inside us.

No longer looking under the lamppost

Time flies. It’s been over 5 years since I wrote https://luysii.wordpress.com/2009/09/25/are-biochemists-looking-under-the-lamppost/, essentially a long complaint that biochemists (and by implication drug chemistry and drug discovery) were looking at the molecules they knew and loved rather than searching for hidden players in the biochemistry and physiology of the cell.

Things are much better now. Here are 3 discoveries from the recent past, some of which should lead to drugable targets.

#1 FAFHA — a possible new way to treat Diabetes. Interested? Take a long chain saturated fatty acid such as stearic acid (C18:0). Now put a hydroxyl group somewhere on the chain (the body has found ways put them at different sites — this gives you a hydroxy fatty acid (HFA). Next esterify this hydroxyl group with another fatty acid and you have a Fatty Acid ester of a Hydroxy Fatty acid (an FAHFA if you will). So what?

Well fat makes them and releases them into the blood, making them yet another adipokine and further cementing fat as an endocrine organ. Once released FAHFAs stimulate insulin release, and increase glucose uptake in the fat cell when they activate GPR120 (the long chain fatty acid receptor).

A variety of fatty acids can form the ester, one of which is palmitic acid (C16:0) forming Palmitic Hydroxy Stearic Acid (PAHSA) which binds to GPR120. if that weren’t enough PAHSAs are anti-inflammatory — interested read more [ Cell vol. 159 pp. 238 239, 318 – 332 ’14 ]. I don’t think the enzymes forming HFA’s are known, and I’m willing to bet that are other HFAs out there.

#2 Maresin1 (7S, 14S dihydroxy docosa 4Z 8E 10E, 12Z 16Z, 19Z hexaenoic acid to you) is the way you start making Specialized Proresolving Mediators (SPMs). Form an epoxide of one of the double bonds and then do an SN2 ring opening with a thiol (glutathione for one) forming what they call a sulfido-conjugate mediator. It appears to be one of the many ways that inflammation is resolved. It helps resolve E. Coli infection in mice at nanoMolar concentration. SPMs further neutrophil recruitment and promote macrophage clearance of apoptotic cells and tissue debris. Wouldn’t you like to make a drug like that? Think of the specificity of the enzyme producing the epoxidation of just one of the 6 double bonds. Also a drug target. For details please see PNAS vol. 111 pp. E4753 – E4761 ’14

#3 Up4A (Uridine Adenosine Tetraphosphate) — as you might expect it’s an agonist at some purinergic receptors (PO2X1, P2Y2, P2Y4) causing vasoconstriction, and vasodilatation at others (P2Y1). It is released into the colon when enteric neurons are stimulated. Another player whose existence we had no idea about. Certainly we have all the GI and vasodilating drugs we need. If nothing else it will be a pharmacological tool. Again the enzyme making it isn’t known — yet another drug target possibly. For details see PNAS vol. 111 pp. 15821 – 15826 ’14.

There is a lot more in these 3 papers than can be summarized here.

Who knows what else is out there, and what it is doing? Glad to see people are starting to look