Category Archives: melatonin

Carb Back-Loading and the Circadian Regulation of Metabolism

Carb Back-Loading (CBL) redux, part I

Step 1: eat little in the morning (maybe some fat+protein; definitely no carb)
Step 2: exercise in the afternoon/evening
Step 3: eat the carbs, all of them.  Preferably high glycemic carbs.
Other: no dietary fat post-workout; protein periodically throughout the day.

What makes CBL different from its predecessors is the stress on the timing – exercise and carbs in the evening.  John Berardi’s “Massive Eating” dietary guidelines are similar: protein+fat meals all day except pre- and post-workout, which are protein+carb meals.  Martin Berkan’s “LeanGains” is fasting most of the time (including pre-workout), exercise in the afternoon, then a big post-workout meal (quite similar to CBL).  My only tweak, as discussed below (and previously here and here), would be a pre- rather than post-workout meal [in some contexts].

There’s a summary of this blog post at the bottom… it might be helpful to read that first (see: “Tl;dr:”).  Also, please note that much of this post is about the fringe of theoretically optimizing nutrient partitioning, like improving from 85 to 90%, or 40 to 45%, not 40 to 90%…  I’m not that deluded.

My initial take, in general, is that this book is loaded with gems about nutrition, exercise, biochemistry, and physiology.  It’s also very readable and has a lot of good recommendations.  In this post, I want to discuss one specific aspect of CBL: tissue-specific circadian regulation of metabolism.


nutrient timing


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Fasting, circadian biology, and epigenetics

From the best I can gather, one of the more immediate players in circadian biology is the coenzyme nicotinamide adenine dinucleotide (NAD), which participates in a variety of redox reactions.  Fasting increases the intracellular NAD/NADH ratio, setting off a cascade of events involving epigenetics and the regulation of metabolism.  HT to Jack Kruse for really cracking into this nut.

NAD activates sirtuins, a family of deacetylase enzymes.  This is epigenetics.



SIRT1 regulates the activity of BMAL1 and CLOCK, two circadian transcription factors, which target NAMPT, an enzyme that synthesizes NAD.  And in a curious feed-forward mechanism, CLOCK and BMAL1 enhance SIRT1 expression… genetic deletion of any of these players induces insulin resistance (Zhou et al., 2014), and this can be recapitulated with constant darkness: reduced BMAL1 and SIRT1, hepatic insulin resistance; the latter can be reversed with resveratrol (which may or may not be acting through SIRT1; this is controversial).  While alcohol does no great favors for circadian biology, if you’re going to imbibe, perhaps a resveratrol-rich Argentinian malbec served, and this might be the important part, at night, when all of this stuff is going on… coincidentally [fortunately], that’s precisely when most choose to imbibe.

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Melatonin is the chemical expression of darkness.

Melatonin is secreted from the pineal gland, the seat of the soul, the third eye.   Pinealectomy induces circadian arrhythmia and has interesting effects on adipose tissue biology.

Exhibit A.  In 2004, Alonso-Vale and colleagues showed that 6 weeks after pinealectomy, [melatonin-deficient] rats subjected to fasting exhibited an impaired energy conservation response.  That is, they lost more weight and significantly depleted their adipocytes:


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Pharmaceutical-grade circadian manipulation.

BMAL1 and CLOCK, ‘positive’ regulators of circadian gene expression, activate transcription of the negative regulators Per, Cry, and Rev-erb.  PER and CRY inhibit BMAL1 and CLOCK, whereas Rev-erb inhibits Bmal1.  It is said that Rev-erb is “an important link between the positive and negative loops of the circadian clock.”  You don’t really need to know any of that to follow this blog post.

circadian genes

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Circadian disruptions impact behavior and metabolism in a tissue-specific manner.

The control of circadian gene expression is complex, with layer upon layer of suppressors and enhancers, numerous transcription factors, and a lot of interactions.  A gross oversimplification: Clock and Bmal1 are positive regulators of circadian gene expression; Per and Cry are negative (you don’t really need to know any of this).


Some pretty cool progress has been made in examining the effects of global and tissue-specific deletion of circadian rhythm-related transcription factors.  Bear with me :)

For example, global Bmal1 knockout mice (ie, mice that don’t express Bmal1 anywhere in their whole body.  Zero Bmal1.  Nil.) (Lamia et al., 2008).  These mice are obese, and exhibit impaired glucose tolerance yet improved insulin sensitivity.

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Circadian biology: jet lag, mood, & potential role of BP regulatory peptides

There are enough connections here to suggest it’s an interesting rabbit hole.  Besides the effects of ARBs & desmopressin on mood and cognition, blood pressure regulation is not interesting <– fact.  But if it ties into fertility, circadian biology, and seasonal changes in how we should be doing things…

Way back in 1998 when I was graduating high school, Murphy and colleagues were screwing with “light-entrainable” and “food-entrainable” oscillators of circadian rhythmicity (1998).  They did this in two lines of rats, one with intact vasopressin signaling and one without.  With little mechanistic work, they showed vasopressin mediates circadian effects driven by light; and rats without vasopressin were more entrainable by meal timing.  N.B. in addition to the posterior pituitary, vasopressin is also found in the famous circadian light-regulated SCN neurons (Rosving 2010).

While it is speculated to play a role in social behaviors and sexual motivation, vasopressin is primarily known for its anti-hypotensive effects.  When plasma volume drops, vasopressin is secreted to decrease urinary water loss and increase blood pressure.  This is antagonized by alcohol, which is thought to be one reason why alcohol can dehydrate you.

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Fiat lux

Humans have a peculiar relationship with light: differences in brightness, wavelength, and even circadian timing all have biologically meaningful effects.

The right combination of timed light exposure and hot Blue Blockers is probably not only the solution to jet lag, but also to a whole host of other health problems.  Maybe you can’t completely escape the bane of the modern condition, but there are some tools, widely available, accessible, and even free in some cases (eg, sun), that may be of benefit.  

The frequency of light impacts circadian rhythms. 

Wright showed this in 2004.  The subjects wore special glasses with LEDs that emitted light of varying frequency for 2 hours, from 6 to 8 in the morning (65 uW/cm2).  Salivary melatonin measurements commenced at 7 pm.  As seen in the figure below, blue but not red light induced a significant phase advance in melatonin onset:

AM blue light phase advance

And for the whole group:all colors

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The hot Blue Blocker Experiment

The eyes are the window through which light must pass, regardless of sightedness.

FACT: we don’t realize the importance of circadian biology.  Or at least we don’t act like it.  And we’re certainly not going to turn off our iPhones & laptops when we’re supposed to.  Potential intervention: hot Blue Blockers.  They’re a band-aid, no doubt, but they might help.  Jane Plain raised a potential concern with this here.  In brief, we can block blue light from molesting circadian biology with hot Blue Blockers, but extraocular light exposure could betray such feeble attempts.  I read something to a similar effect on Dr. Kruse’s blog.

It seems to be based, in part, on an experiment by Campbell & Murphy (1998).  They tried to experimentally screw circadia by exposing an isolated spot of skin on the back of the knee to 3 hours of bright light.  Melatonin data weren’t shown, but the authors said they mirrored body temperature:

Campbell Murphy

It worked (for body temperature, at least).

But FAR more interestingly, Czeisler showed bright light-induced melatonin suppression in blind people was reversed if they covered their eyes!!!Czeisler

This is wild.  Unless there is something CircadianlyMagical about the skin on the back of the knees, then these findings refute those of Campbell.  Czeisler’s findings were confirmed by Hatonen (1999) in sighted people: black circles = no light exposure; open squares = full-face light exposure with eyes closed (partially blunted melatonin secretion); and open circles = full-face light exposure with eyes open (fully blunted melatonin):Hatonen

Of note, blind eyes and closed eyes aren’t the same as covered eyes.  There were, however, 2 people who exhibited no melatonin inhibition with closed eyes.  Perhaps some are intrinsically more light-resistant, or have robust eyelids or something.

It seems as though we needn’t worry about Campbell’s findings after all because they were directly refuted by Hebert (1999):Hebert

The light exposure protocol in both of the studies was identical: 13000 lux to the back of the knees for 3 hours.


Perhaps we should’ve demanded to see Campbell’s melatonin data?  Or not.  Lushington confirmed Hebert’s findings (albeit with only 11000 lux):Lushington

In 2000, Lindblom blasted 10000 lux at a much larger surface area – chest & abdomen – and found no effect on melatonin:Lindblom

The eyes are the window through which light must pass, regardless of sightedness.

Was all of this blog post irrelevant until now?  Maybe. (sorry)

Sasseville compared bright light-induced melatonin suppression in people wearing boring shades (top graph) or hot Blue Blockers (SolarShield Orange Lenses) (bottom graph):


The orange lenses transmit slightly less light than the boring ones (32 vs. 52%), so they accounted for this by hitting the hot Blue Blockers with more lux (4000 vs. 2200… this is directly in their faces, so it couldn’t be >10000 lux like in the previous studies)… this still resulted in more irradiance hitting the hot Blue Blockers, so the odds were stacked against them (I think, #physics).

Lux: luminous flux per unit area
Irradiance: electromagnetic radiation per unit area

Melatonin suppression is important, but what we’re really talking about here is SLEEP.  And in 2009, Burkhart showed just that.  When assigned to hot Blue Blockers (NoIR Polycarbonate Lasershields), sleep quality markedly improved:


(granted, randomization was horribly bollixed, but it is what it is).

Sasseville came through again in 2009, this time for shift workers.  Their subjects had to wear hot Blue Blockers (Uvex Skypers) when they were leaving work [in the morning].   It worked.

Sasseville II

In sum, don’t sweat extraocular light exposure, and anyone with a metabolic disturbance who lives a remotely modernized existance, paleo or otherwise, might benefit from these.

calories proper

hot Blue Blocker experiment: expectations = none.  I’m a “non-responder.”  This might not be the best time of year to conduct such an experiment, but the combination of high motivation and low patience prevailed.  And I still use my computer a lot at night.

This is a diary of sorts.
day 1: initial observations.
Started wearing them about 2 hours before sunset.  Outside sky prior to dusk looks like insane alien invasion.  But creepy red bathroom light looks exactly the same.  #physics.

Morning of day 2: Usually wake once or twice in the middle of the night, but didn’t…

Evening of day 2: Started rocking the shades 2 hrs prior to bedtime.  Same awesome yellow-ness and crisp resolution of the sunset.  It really looks like another planet.  I also could’ve probably stared directly at the sun with impunity (but didn’t).

Morning of day 3:  new conclusion: I think I usually wake up a few hours prior to dawn, but hot Blue Blockers prior has shifted this to a few hours earlier.

Morning of day 4:  same!  Hot Blue Blockers make me need to pee 4 hours sooner after falling asleep <– I’m a “responder!”
Mood, sleep quality, & energy levels stable <– “non-responder,” but willing to give it more time.  Burkhart’s study showed a near doubling of sleep quality, but it took 3 weeks.

P.S. FWIW, I’m wearing these, so definitely not going out in public places.