FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss (Owen et al, 2014)

SNT Gatchaman

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FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss
Bryn M. Owen, Xunshan Ding, Donald A. Morgan, Katie Colbert Coate, Angie L. Bookout, Kamal Rahmouni, Steven A. Kliewer, David J. Mangelsdorf

The mechanism by which pharmacologic administration of the hormone FGF21 increases energy expenditure to cause weight loss in obese animals is unknown. Here we report that FGF21 acts centrally to exert its effects on energy expenditure and body weight in obese mice. Using tissue-specific knockout mice, we show that βKlotho, the obligate co-receptor for FGF21, is required in the nervous system for these effects. FGF21 stimulates sympathetic nerve activity to brown adipose tissue through a mechanism that depends on the neuropeptide corticotropin-releasing factor. Our findings provide an unexpected mechanistic explanation for the strong pharmacologic effects of FGF21 on energy expenditure and weight loss in obese animals.

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SNT Gatchaman

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Yes that might be good. They're tagged with fgf21, but once people have had a chance to read through, a general thread might be sensible. If this powerful hormone were inappropriately deactivated and its regulatory system broken, the effects could be very wide ranging.

At a high level, my subjective experience of the illness has felt like "enforced hibernation". Also, there seems to me to be a link to carbohydrates, which was profound at the outset, when I went from "OK" to literally "floored" within 20 minutes of a carb-heavy meal.

Other people will no doubt have had different experiences, but as @Pyrrhus and others would say "leave no stone unturned".
 

SNT Gatchaman

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I think that might happen in the case of ME/CFS if indeed FGF21 is upregulated.
And to emphasise, the key point being (maybe) that:

FGF21 might be upregulated because it is being inappropriately deactivated (e.g. possibly by fibroblast activation protein, compounded by exercise). This has equivalent effect to tissue insulin resistance -> elevated insulin levels, but in this case the tissues would still respond correctly, but the hormone itself is being rendered ineffective. System failure feedback might then result in more FGF21 being produced.

Important to know if what is measured in serum is total FGF21 vs bioactive FGF21. A key-points post to work from will be useful as this has some complexity.
 

Pyrrhus

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If this powerful hormone were inappropriately deactivated and its regulatory system broken, the effects could be very wide ranging.
FGF21 might be upregulated because it is being inappropriately deactivated (e.g. possibly by fibroblast activation protein, compounded by exercise).
A fascinating idea. Thanks for this!
 

Pyrrhus

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Circulating FGF21 and NT-proBNP levels were significantly higher (p < 0.0001 and p = 0.005, respectively) in ME/CFS patients than in healthy controls.
Although typically not expressed in skeletal muscle, FGF21 is induced in situations of muscle stress, particularly mitochondrial myopathies.
So, exercise leads to elevated FAP, which cleaves and inactivates FGF21...
FGF21 might be upregulated because it is being inappropriately deactivated (e.g. possibly by fibroblast activation protein, compounded by exercise).
So, in an attempt to combine the ideas from the different threads:
  1. Mitochondrial impairment might lead to increased FGF21 in the blood.
  2. Increased FGF21 in the blood could lead to large-scale metabolic changes in the body.
  3. Attempts to exercise might lead to elevated FAP, which inactivates the FGF21 in the blood.
 

SNT Gatchaman

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I haven't related the mitochondrial dysfunction / autophagy failure / phosphorylated ATG13 findings to FGF21 in my mind (despite the paper comments above). It might relate, of course - in either direction. But at the moment I'm considering them as two separate findings/theories. (Two studies have suggested them as separate biomarkers, so replication for both might be a priority.)

I was thinking of #1 being FGF21 gets deactivated, perhaps by inappropriately elevated baseline FAP somehow (coagulopathy?). Then #2 and #3 as you have them above.

Of course then the mitochondria might get injured down the line, due to chronic fuel starvation and resultant metabolic compensations. I guess there might be a path from damaged mitochondria to elevated FAP and/or FGF21 that creates the final arc of a vicious circle.

(I have a sense that if there isn't a bistable state - like the metabolic trap - then there will be one or more! vicious circles perpetuating the pathology).
 
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