Category Archives: chronopharmacology

Artificial light regulates fat mass: no bueno.

“despite not eating more or moving less”

We’ve seen this time and time again: LIGHT IS A DRUG.

 

above quote is extrapolated from this rodent study: “Prolonged daily light exposure increases body fat mass through attenuation of brown adipose tissue activity.”

 

Artificial light impacts nearly every biological system, and it doesn’t even take very much to have an appreciable effect (think: checking your smart phone or watching a television show on your iPad in bed at night).  In this study, adding 4 hours to the usual 12 hours of light slammed the autonomic nervous system, disrupting sympathetic input into brown adipose leading to a significant increase in body fat  “despite not eating more or moving less.”

 

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LIGHT, Leptin, and Environmental Mismatch

For a long time, the melanocortin system was basically thought to control the color of skin and hair.  It still does, and many redheads are redheaded due to polymorphisms in one of the melanocortin receptors.

Fast forward to 2015: to make a long story short, melanocortins are HUGE players in circadian biology.

 

POMC ACTH a-MSH

 

Brief background (also see figure above):

Fed state -> high leptin -> a-MSH -> MC4R (the receptor for a-MSH) = satiety, energy production, fertility, etc.

Fasted state -> low leptin -> AgRP blocks MC4R = hunger, energy conservation, etc.

MC4R polymorphisms in humans are associated with obesity.  Melanotan II causes skin darkening (marketed as “photoprotection” [no bueno, imo]), enhanced libido, and appetite suppression.

 

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Dark Skies and Light Pollution

The mission of the International Dark-Sky Association is “to preserve and protect the night time environment and our heritage of dark skies through quality outdoor lighting.”  They’re all about stressing the importance of lighting on health, light pollution, and some really interesting stuff.

For more on the topic, check out their website, darksky.org, and Paul Bogard’s book, The End of Night: Searching for Natural Darkness in an Age of Artificial Light.

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Circadian Disruption Impairs Survival in the Wild

…just read that huge disasters, ranging from Exxon Valdez to Chernobyl, may have been due, in part, to ignorance of basic principles of circadian rhythms.  Gravitas.

 

circadian rhythms

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Meal timing and peripheral circadian clocks

More on why breakfast in the morning, with light onset is important to avoid circadian desynchrony.

FOOD is excellent at entraining peripheral circadian clocks: if you restrict animals to one meal per day, their peripheral circadian clocks rapidly become entrained to this, regardless of when the meal is administered (Hirao et al., 2010):

 

zeitgeber entraining

ZT0 = “zeitgeber time 0,” or “lights on.” pZT indicates a phase shift coinciding almost exactly with meal timing. Mice normally eat at night, but this doesn’t stop their peripheral clocks from entraining to the day time if that’s when their fed.

This study took it to the next level: they fed 2 meals per day, varying in size, time of day, and duration between meals in almost every conceivable combination.  Actually, it was a quite epic study… some poor grad students working, literally, around the clock, for months…

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Entraining Central and Peripheral Circadian Rhythms

“Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake, can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and type 2 diabetes.”

If you haven’t been following along, a few papers came out recently which dissect this aspect of circadian rhythms — setting the central vs. peripheral clocks.

In brief (1):  Central rhythms are set, in part, by a “light-entrainable oscillator (LEO),” located in the brain.  In this case, the zeitgeber is LIGHT.

Peripheral rhythms are controlled both by the brain, and the “food-entrainable oscillator (FEO),” which is reflected in just about every tissue in the body – and is differentially regulated in most tissues. In this case, the zeitgeber is FOOD.

In brief (2):  Bright light in the morning starts the LEO, and one readout is “dim-light melatonin onset (DLMO),” or melatonin secretion in the evening. Note the importance of timing (bright light *in the morning*) – if bright light occurs later in the day, DLMO is blunted: no bueno.

Morning bright light and breakfast (FEO) kickstart peripheral circadian rhythms, and one readout is diurnal regulation of known circadian genes in the periphery.  This happens differently (almost predictably) in different tissues: liver, a tissue which is highly involved in the processing of food, is rapidly entrained by food intake, whereas lung is slower.

Starting the central pacemarker with bright light in the morning but skimping on the peripheral pacemaker by skipping breakfast represents a circadian mismatch: Afternoon Diabetes? Central and peripheral circadian rhythms work together.  Bright light and breakfast in the morning.

 

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Circadian phase: role of diet

Circadian phase advance: going to bed earlier, waking up earlier.  Blue blockers at sunset, bright light at sunrise.  Flying east.  Autumn.

Circadian phase delay: staying up late, sleeping in.  Flying west.  Spring.  Using smart phones, tablets, and iPads in bed at night.  Light pollution.

Relative to adolescents, infants and children are circadian phase advanced.  This is part of what is fueling the movement to delay high school start times.  Kids are mentally better prepared to work later in the day.  With early school start times, performance is down in the morning, but they kill it on video games after school.  Delaying start time by an hour won’t totally fix this, but could help.

Edit: it seems like a similar movement is happening for adults, too – ie, starting work an hour later.

I’m not saying everything healthwise deteriorates with age, but the gradual circadian phase delay that occurs with aging and overusing blue light-emitting devices at night might not be a good thing.  If a particular diet can promote phase advance, why not? (at least it’d be countering the phase delay).

 

 

Possible role of diet

In the top half of the figure below, it’s mice fed a “normal diet (ND) (high carbohydrate)” (Oishi et al., 2012).  During normal “light dark (LD)” conditions, movement and feeding is concentrated in the active phase.  When the lights are permanently turned off in “dark dark (DD)” conditions, the free-running circadian clock begins to shift slightly forward (phase advance), but nothing drastic.

 

Phase advance high protein diet

 

In the bottom half of the figure, during normal LD conditions the mice are switched to a low carb, high protein diet.  Note how activity shifts leftward (phase advance) during the LD condition.  When low carb, high protein-fed mice are then switched to DD, we can see a clear circadian phase advance.

 

High protein metabolism

 

Low carb, high protein-fed mice ate more but didn’t get fat; physical activity and body temperature were unchanged.  But this post isn’t about that.  Gene expression of key circadian transcription factors in liver and kidney exhibited phase advances.

The next figure is study to the one above, although instead of switching to a low carb, high protein diet, the mice were switched to a low carb, high fat diet (Oishi et al., 2009).

Note the similarity of control (high carb diet) mice: gradual phase advance when switched to DD:

 

Ketogenic circadian phase

 

The phase advance is markedly enhanced in low carb, high fat-fed mice.

The circadian regulation of activity is similarly affected by low carb, high protein, and low carb, high fat diets.  What do those two diets have in common?

A bit of a stretch? carbohydrate restriction mimics some aspects of avoiding artificial light at night and being young: phase advance.  Whether the carbs are replaced with protein or fat doesn’t seem to matter in this aspect.

 

Wanna know what else can do this?  FOOD.  The food-entrainable oscillator (FEO) kickstarts circadian rhythms.  Rodent studies have shown that timed feeding, regardless of the actual time, consistently realigns the circadian expression of numerous genes (eg, Polidarova et al., 2011 and Sherman et al., 2012).

So what’s the hack?  Food: do more of it, earlier in the day.  Phase advance.  Kind of like avoiding artificial light at night or being young.

 

Oh, and mice exposed to dim light at night (who are pretty much metabolically screwed)? phase DELAYED (Fonken et al., 2010).

 

Dim light at night phase delay

 

 

 

calories proper

 

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Circadian Mismatch and Chronopharmacology

Part I: Circadian Mismatch

1. Artificial light at night suppresses melatonin (Lewy et al., 1980); induces “circadian mismatch.”

2. Circadian mismatch is associated with and/or predisposes to breast cancer (eg, He et al., 2014 and Yang et al., 2014).

3. In this epic study, human breast cancer xenografts were exposed to blood taken from healthy, pre-menopausal women during the day (melatonin-depleted), at night (high melatonin), or at night after light exposure (melatonin-depleted) (Blask et al., 2005). They showed that tumors exposed to melatonin-depleted blood exhibited higher proliferative activity than those exposed to melatonin-repleted blood. This has been deemed one of the most “ethical” studies to demonstrate a causal link between circadian mismatch and cancer.

4. And to make matters worse, circadian mismatch also reduces the efficacy of cancer drug therapy (Dauchy et al., 2014).  This study showed that, in a rodent model of breast cancer, exposure to light at night (circadian mismatch) enhanced tumor development and induced tamoxifen-resistance, and this was abolished by melatonin replacement.

melatonin

They also suggested a mechanism: tumors metabolize linoleate into the mitogen 13-HODE.  Melatonin suppresses linoleate uptake.

linoleate 13-HODE

 

 

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