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