Losing circadian cortisol rhythm increases fat cell number and size

Of the many different variables we can manipulate to promote our health, time is rapidly becoming one of the most interesting and possibly important factors out there.  Most of us focus on what and how much, almost to a fault.  What kind of food?  What kind of exercise?  How much food?  How much exercise?  How much booze?  I could go on.

But where is the discussion on whenWhen should we eat?  When should we exercise?  When should we expose ourselves to light.  For decades we completely ignored when.  But now, thanks to a tidal wave of research, when is getting its time in the spotlight.

I have my News feed set up to notify me when articles about when pop up, and researchers just published a doozy of a study on when.  In this study, the researchers found that mice whose circadian rhythm of cortisocosterone was flattened put on twice as much fat in 21 days as mice with a regular circadian rhythm.  This happened even though both sets of mice ate exactly the same amount of food.  Note: In humans the primary glucocorticoid is cortisol, while in mice it’s corticosterone

There’s quite a bit of useful stuff in this one, so let’s dig in…

Circadian cortisol rhythm and fat accumulation

We’ve known for quite a while that people who work night shift are at a greater risk for obesity than people working day shift.  It’s also interesting to note that people under chronic stress, taking glucocorticoids, or with Cushing’s syndrome all have the same issue.  So the researchers wanted to find out if glucocorticoids, stress hormones and primary synchronizer of circadian clocks, had an impact on our ability to put on fat.

First they looked in cells to determine if having a glucocorticoid rhythm vs having a constant level that reflects the mean level had any effect on preadipocytes, cells that can become fat cells if provided the proper trigger.  Their hypothesis was that pulsing and/or circadian changes in glucocorticoids were ignored by preadipocytes while constant but equivalent glucocorticoid levels led to differentiation.  They were right.

Next, they decided to look if this held true in mice.  They implanted mice with corticosterone pellets to flatten out the circadian rhythm of cortisol or a placebo and found that the mice with the corticosterone pellets put on twice as much fat when fed the same diet as mice with the placebo.  This increase in fat storage was due to bigger fat cells as well as an increase in fat cell number in visceral fat.

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Image source

To see if this was due to the total dose or the absence of a rhythm, the researchers injected mice with a dose that spiked levels 40-fold.  As long as the pulses led to drops that were at least 12 hours apart, and thus mimicked the circadian variation in corticosterone output, there was no difference in fat gain between the placebo groups and the injection groups.

In the cell portion of the study, a constant dose of glucocortiocids caused preadipocytes to become adipocytes, but spikes that occurred within the typical circadian window caused none or minimal.  This happened even though both groups were exposed to the same average levels.  As the pulses lengthened and rhythm flattened, there was an increase in preadipocyte differentiation in to fat cells.  This jibes with the association between chronic stress and accumulation of visceral fat.

Why does this happen and what does it tell us?

The mechanism behind why this works is actually pretty interesting.  When cortisol levels reach a critical point, cellular levels of a protein called PPAR-gamma increase.  When PPAR-gamma levels reach a certain point in pre-adipocytes, this causes them to differentiate in to fat cells.

Apparently, this critical point of cortisol is below the level seen in a flattened circadian rhythm.  While PPAR-gamma may accumulate at a slow rate, it continues to accumulate until it forces you to produce more fat cells.  However, when your cortisol is allowed to follow its natural rhythm, the period of time when your cortisol level reaches its trough is long enough for PPAR-gamma to degrade and prevents differentiation.  Despite rising more than enough to trigger PPAR-gamma accumulation in the cell, PPAR-gamma degrades fast enough over a 12 hour period during the trough to prevent fat cell differentiation.

While preliminary, this study shows us something that has quite a bit of relevance in a number of situations.  In showing that losing your circadian cortisol rhythm promotes weight gain by increasing fat cell size and number, this study gives us a mechanism by which shift work or improper light exposure increases a person’s risk for obesity.

It also indicates that weight gain due to long term glucocorticoid use may be mitigated by dosing in a pulsatile manner early in the day and stopping at night so that there’s a rhythm.  In fact, I believe there’s pharmaceutical glucocorticoid under development that does just that.

Finally, this research points to the notion that perhaps doing things such as exercise, heat exposure, or coffee consumption that cause pulsatile spikes in cortisol are useful in reducing the likelihood that preadipocytes differentiate in to fat cells.  Of course, it’s important to time these things accordingly, and people with gut or adrenal problems should use these things in a logical and productive way rather than just throwing them in to your routine willy-nilly.

Conclusion

As circadian rhythms become recognized as important variables in optimizing health and treating disease, timing will become a more important factor in maximizing results.  With a large number of obese people and people taking glucocorticoids for numerous issues in the US, this study shows us how factors relating to circadian disruption can promote accumulation of fat.

Glucocorticoids, such as cortisol in humans, are powerful outputs of the circadian clock in all animals that also function as inputs throughout the organism.  In other words, the environment produces variation in glucocorticoids that promotes proper timing and communication between interdependent organ systems.  Since they’re also useful pharmaceutical drugs in reducing issues such as fatigue and pain, it’s important to pay attention to the physiological implications of messing with your circadian cortisol rhythm.

Whether you’re being exposed to circadian cues that disrupt your clocks or taking drugs that do the same, losing your circadian cortisol rhythm appears to promote an accumulation of fat cell number and size.  Neither one of these things are ideal in an already obese population.

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