Commentary
I know, the party's over, the debris cleared away, but I have finally read this paper, and I like it.
Why Leptin?
The interesting thing about Leptin in general is that (as others pointed out here) it's involved in energy metabolism regulation and immune regulation, where it acts like an inflammatory cytokine. It's also been linked with fatigue in a number of conditions, including IBS and chronic hepatitis C.
On top of that, in animal studies leptin has been shown to increase cytokine secretion by microglia, the brain's immune cells and so contributing to sickness response (gratuitous plug for my recent blog:
Brain Cells Making us Sick? The microglia connection in ME/CFS & Fibromyalgia). So Leptin is a plausible candidate for playing a role in mecfs.
Good things about this study
Tracking fluctuations
The most impressive thing for me about this study isn't the Leptin finding at all, but the longitudinal, 25-day design looking at correlation between leptin levels and fatigue. We all know about fluctuations in this illness so it makes sense to probe this by following individuals over time.
One reason this is particularly important is that there is huge variation in cytokine levels
between healthy people, or to put it another way, a lot of noise in the data. Tracking one person over time really helps, as you are using the same individual at each time point (such 'within-patient' designs are generally reckoned to be a good thing)
In fact, there was no overall difference in leptin levels
between patients and controls in this study.(as @Valentjin pointed out).
Strong correlations
Overall, there was a modest correlation between leptin and fatigue in CFS patients (r=0.3 [0-1.0 scale], p<0.01).
However, what really stands out is the data for individuals: there was a strong to very strong positive correlation in 5 of the 10 patients, and strong negative correlation in one and a marginal correlation in one other patient. By contrast, there was a marginal correlation in one control only. So this looks like something is going on.
Not data mining
The study looked at 51 cytokines in all, but the primary outcome was designates as just leptin in advance. There are some good theoretical reasons to suspect leptin (as above), plus pilot data on 3 fibromyalgia patients indicated that leptin alone correlated with fatigue. So the researchers didn't just get a stack of cytokine data and cherry-pick for interesting results, which is encouraging.
Other points about the study
Obviously, it's very, very small with just ten patients, and one patient had lower levels of leptin with more fatigue while 5 had higher levels with more fatigue. Plus 4 more had no strong pattern, so it's a bit of a mixed bag.
However, at the IACFS/ME conference Jarred Younger reported that a larger, NIH-funded replication is planned. Which is fantastic news, and exactly what's needed.
It's a little surprising that there was no difference in leptin levels overall between patients and controls - given that patients were much more fatigued than controls. Mady Hornig and Ian Lipkin have reported that Leptin levels were higher in patients than controls in their large but as-yet-unpublished study.
8/10 patients had fibromyalgia too; they also had more other illnesses than controls eg arthritis and Graves disease, and took more medication, though I'm not sure if these factors could explain the leptin correlation.
Finally, numerous cytokines have been implicated with fatigue eg IL-1, Interferon gamma, and it's a little surprising that none of these cytokines correlated with fatigue either. But maybe that's how it is.
Conclusion
- An innovative study design, tracking fluctuations in fatigue and cytokines, that other researchers might want to follow.
- Fascinating results because of the very strong positive correlation between fatigue and Leptin in half of patients.
- What's really needed now is replication, and it appears that is in hand.
added:
I just wanted to add a really important point made by @
searcher about this study. The levels of leptin, and the range of leptin levels was similar in patients and controls. What seemed to be different was how patients responded to those fluctuations in leptin - as if patients were hypersensitive to changes in leptin. This might be because they have 'primed', excitable microglia (blog on
microglia priming hypothesis).
Also, we don't know if leptin is driving this or just correlated, perhaps as a downstream effect of something that is driving the process. The authors of this paper suggest that this could be tested by injecting paitents with synthetic leptin (synthetic cytokines are often used in medicine, eg as a treatment such as interleukin 1 in cancer and interferon-alpha in hepatitis C).
