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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Vegetable oil fatty acids are not essential. 

They are conditionally essential at best, only if docosahexaenoic acid (DHA) is lacking.  We can’t synthesize omega 3 fatty acids, and indeed they do prevent/cure certain manifestations of “essential fatty acid (EFA) deficiency” (Weise et al., 1958), but DHA can do all that and more.  Not that I recommend this, but a diet completely devoid of 18-carbon vege oil fatty acids will not produce EFA deficiency in the presence of DHA. (“vege,” rhymes with “wedge”)

Essential fatty acid metabolism

 

The “parent essential oils” are linoleic acid (LA) and alpha-linolenic acid (ALA).  The others, which I think are more important and the truly “essential” ones are eicosapentaenoic acid (EPA), arachidonic acid (AA), but mostly just DHA.

The first manifestation of EFA deficiency is dermatitis (Prottey et al., 1975).  Some people say LA is necessary to prevent this, but it would be better phrased as “LA prevents dermatitis;” not “LA is necessary to prevent dermatitis.”  All of the evidence suggesting LA is essential is in the context of DHA deficiency.

Technically, we can convert a bit of ALA to DHA, estrogen helps, testosterone doesn’t (women have better conversion rates)… and I’d speculate that the reverse is probably easier (DHA –> ALA).

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Pharmaceutical-grade circadian enhancement?

Is it possible to improve the amplitude and resiliency of your circadian rhythms?  Is this desirable?  Yes and yes, I think.

Go the fuck to sleep.png

 

Introducing, the aMUPA mice (Froy et al., 2006).  What you need to know about ‘em: they have very robust circadian rhythms.  How is this assessed?  Take some mice acclimated to their normal 12 hour light-dark cycle (LD) and place them in constant darkness (DD).  Then take liver biopsies and measure circadian genes to see how well they still oscillate throughout the dark day; this is also known as the free-running clock, and it craps out differently in different tissues depending on a variety of factors.  Most of the time, however, it’ll run for a few days in the absence of light.  Circadian meal timing also helps to hasten re-entrainment.

Note in the figure below: 1) there are two distinct lines of aMUPA mice; and 2) both exhibit a greater amplitude in circadian oscillations during free-running, or DD conditions.

strong circadian rhythms

 

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Evolution stole this dude’s circadian rhythm

I got a laugh out of this one; not for the actual content, but because of how the authors worded their findings.  They sure love their fishies.

We have two very closely related fish, both Mexican tetra, Astyanax mexicanus, one with eyes who lives on the surface, and another who’s blind and lives in dark caves (“Pachon”).  It’s thought that they were the same species one day; divergent evolution.

 

note: eyeless

note: eyeless

The blind ones are circadian arrhythmic (Moran et al., 2014).  Surface-dwellers are more active during the day than night (blue line, left figure below), and their free-running circadian clock maintains this in the absence of photic input (blue line, right figure).  The blind ones, on the other hand, exhibit no circadian rhythm in the light or dark (orange lines):

 

Circadian rhythm metabolism

 

Cave-dwellers are circadian arrhythmic.  This is both in their natural photoperiod (ie, darkness) and in light-dark conditions (which is technically an environmental mismatch, but since they’re eyeless, it doesn’t really matter).

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“Afternoon diabetes” and nutrient partitioning

Don’t exacerbate afternoon diabetes with afternoon carbs.

Skeletal Muscle
As discussed previously [at length], insulin sensitivity in skeletal muscle follows a circadian pattern: starts out high in the morning and wanes throughout the day.

Diurnal variation in oral glucose tolerance: blood sugar and plasma insulin levels, morning, afternoon and evening (Jarrett et al., 1972)

 

impaired circadian glucose tolerance in the morning

 

Diurnal variation in glucose tolerance and insulin secretion in man (Carroll and Nestel, 1973)

Circadian variation of the blood glucose, plasma insulin and human growth hormone levels in response to an oral glucose load in normal subjects (Aparicio et al., 1974)

Adipose Tissue
And insulin sensitivity of adipose tissue goes in the opposite direction: starts out low, and increases as the day progresses.

Diurnal variations in peripheral insulin resistance and plasma NEFA: a possible link? (Morgan et al., 1999)
The studies were standardized for a period of fasting, pre-test meal, and exercise… Following insulin, NEFA fell more slowly in the morning (149 uM/15 min) than in the evening (491 uM/15 min).

Diurnal variation in glucose tolerance: associated changes in plasma insulin, growth hormone, and non-esterified fatty acids (Zimmet et al., 1974)
Adipose tissue insulin sensitivity is greater in the evening.  FFA are higher, and get shut down more rapidly, after a carb meal in the evening.

Summary: to minimize blood glucose excursions and proclivity for fat storage, eat more calories earlier in the day; this is circadian nutrient timing.  And according to the Alves study, a low-carb protein-rich dinner best preserves lean tissue during weight loss.

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Ketoadaptation and physiological insulin resistance

This is where the magic happens.

Rat pups, fed a flaxseed oil-based ketogenic diet from weaning onward – note the drop-off in ketones after 2 weeks (Likhodii et al., 2002):

flaxseed ketogenic diet

What happened on day 17?

Patient history: these rats have been “low carb” their whole lives.

Side note: flaxseed oil is very ketogenic! (Likhodii et al., 2000):

ketogenic rodent diets

Flaxseed oil-based ketogenic diet produced higher ketones than 48h fasting; the same can’t be said for butter or lard.  PUFAs in general are more ketogenic than saturated fats in humans, too (eg, Fuehrlein et al., 2004):Saturated polyunsaturated ketones

Crisco keto (adult rats) (Rho et al., 1999):

shortening-based ketogenic diet

suspect those two rogue peaks were experiment days…

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2 New Diet Studies

*ugh* journalists

I’m talking to you, Mandy Oaklander!

Regarding the new low carb vs low fat study, she writes: “Popular diets are pretty much the same for weight loss, study finds.

Effects of low-carbohydrate and low-fat diets: a randomized control trial (Bazzano et al., 2014)

Further, “An earlier study in Annals of Internal Medicine did find that low-carb dieters lost slightly more weight than low-fat dieters after one year. The study today reached similar conclusions, but the differences in weight loss were not significant.”

Perhaps Mandy just doesn’t realize there’s a difference between significant, as in “meaningful,” and significant, as in “P<0.05.”  Pro-tip: you can tell them apart relatively easily, because the latter is usually accompanied by a cute little asterisk.  For example, the differences in weight loss were quite statistically significant (P<0.05):

Bazzano BW
She goes on to say “After a year follow-up, some of those pounds crept back for people on both diets…”

To that I say: yeah, but fat mass continued to decline in those on the low carb diet, meaning some of that weight re-gain was muscle:

Bazzano FM

So, between 6 and 12 months, carbs and calories were creeping up in the LC group, yet fat mass was still declining.  Perhaps this way of eating improved their metabolism, or restored the ability to effectively partition nutrients.

***in real-time: at this point, I realize that Mandy was actually talking about the other study, which she was covering accurately.  Sorry, Mandy!***

Bazzano PA

…so maybe the low-carb (LC) diet improved muscle mass because it was also high protein? …perhaps, but 19% vs 24% (71 vs 85 grams) isn’t a very big difference.  Alternatively, since the LC group really just maintained absolute protein intake (86 grams at baseline, 85 at month 12), whereas low-fat (LF) dieters decreased (86 grams at baseline, 71 at 12 months); perhaps this is why LF lost muscle mass..?  Still, those changes in protein intake are small, and I think people can be too quick to chalk up the benefits of LC to “high protein.”

In sum, this is actually one of the more “pro” LC studies.  And it wasn’t even a huge difference in carbs: 198 vs 127 grams/d at month 12 (54% vs 34%).  Big difference in fat mass; and CRP, a marker of inflammation, even declined in the LC group.

Low fat diet advocates have been giving me headaches for years… the low fat diet caused headaches (P<0.05):

Adverse Events 1

 

 

Adverse Events 2

The study Mandy was actually talking about: Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis (Johnston et al., 2014)

It was a meta-analysis, which is just about the only type of study capable of taking down LC.

 

 

…but at least it had this cool chart (modified):

cool chart (modified)

cool chart (modified)

 

*ugh* scientists

crap

The macro’s in “Low fat” overlap with “Moderate,” implying “Low carb” is “EXTREME”  …the authors’ bias is subtle, I’ll give ‘em that, but I’m getting too old for this.

Dear Obesity Researchers,

If you want to design a study showing a low fat diet is as good as low carb for fat loss, here’s your best bet: recruit young, exercise-tolerant overweight patients who aren’t on any meds.  PROOF (see Ebbeling study).  Or find 10 similar ones and write up a pro-LF meta.

If you want to show low carb is better, recruit patients with obesity.

 

calories proper

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Cyclical ketosis, glycogen depletion, and nutrient partitioning

Meal & exercise timing in the contexts of “damage control” and nutrient partitioning are frequent topics on this blog.  I generally opt for a pre-workout meal, but nutrient timing hasn’t panned out very well in the literature.  That’s probably why I’m open to the idea of resistance exercise in the fasted state.  A lot of pseudoscientific arguments can be made for both fed and fasted exercise, and since a few blog posts have already been dedicated to the former, this one will focus on the latter.

The pseudoscience explanation is something like this: since fatty acids are elevated when fasting, exercise in this condition will burn more fat; and chronically doing so will increase mitochondria #.  The lack of dietary carbs might enhance exercise-induced glycogen depletion, which itself would bias more post-workout calories toward glycogen synthesis / supercompensation.  Much of this is actually true, but has really only been validated for endurance training (eg, Stannard 2010, Van Proeyen 2011, & Trabelsi 2012; but not here Paoli 2011)… and the few times it’s been studied in the context of resistance exercise, no effect (eg, Moore 2007 & Trabelsi 2013).  However, there are some pretty interesting tidbits (beyond the pseudoscience) which suggest how/why it might work, in the right context.

Exercising fasted or fed for fat loss?  Influence of food intake on RER and EPOC after a bout of endurance training (Paoli et al., 2011)

John Kiefer, an advocate of resistance exercise in the fasted state, mentioned: “the sympathetic nervous system responds quicker to fasted-exercise. You release adrenaline faster. Your body is more sensitive particularly to the fat burning properties of adrenaline and you get bigger rushes of adrenaline.”

Much of this is spot on.  That is, ketogenic dieting and glycogen depletion increase exercise-induced sympathetic activation and fat oxidation (eg, Jansson 1982, Langfort 1996, & Weltan 1998).

The question is: can this improve nutrient partitioning and physical performance?  Magic 8-Ball says: “Signs point to yes.”  I concur.

Contrary to popular beliefs, glycogen depletion per se doesn’t harm many aspects of physical performance.  A lot of fuel systems are at play; you don’t need a full tank of glycogen.

Effect of low-carbohydrate-ketogenic diet on metabolic and hormonal responses to graded exercise in men (Langfort et al., 1996)

High-intensity exercise performance is not impaired by low intramuscular glycogen (Symons & Jacobs, 1989)

Increased fat oxidation compensates for reduced glycogen at lower exercise intensities (eg, Zderic 2004), and ketoadaptation may do the same at higher intensities.

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Ketosis in an evolutionary context

Humans are unique in their remarkable ability to enter ketosis.  They’re also situated near the top of the food chain.  Coincidence?

During starvation, humans rapidly enter ketosis; they do this better than king penguins, and bears don’t do it at all.

Starvation ketosis

 

Starvation ketosis

Humans maintain a high level of functionality during starvation.  We can still hunt & plan; some would even argue it’s a more finely tuned state, cognitively.  And that’s important, because if we became progressively weaker and slower, chances of acquiring food would rapidly decline.

Perhaps this is why fasting bears just sleep most of the time: no ketones = no bueno..?

Observation: chronic ketosis is relatively rare in nature.  Angelo Coppola interpreted that to mean animals may have evolved a protective mechanism against ketosis (if you were following along, please let me know if this is a misrepresentation).

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Circadian phase delays and metabolism

Remember the “jet lag-resistant” mice?  Guess what: screw with circadian biology and metabolism pays the price.

In brief, vasopressin was classically thought of as an anti-hypotensive hormone.  The vasopressin analog Desmopressin is used to treat bed-wetting.  But vasopressin biology is much more interesting than that: mice lacking both vasopressin receptors require very little time adapting to large circadian phase changes.  And as with many fundamental concepts in chronobiology, this is intimately linked with metabolism.

People with certain polymorphisms of the vasopressin receptor, V1A, exhibit elevated blood glucose levels and are at greater risk for diabetes (Enhorning et al., 2009):

genotype

This risk is strongest in men in the highest quartile of fat intake, and is statistically more significant after adjusting for age and physical activity:

Fat consumption

This study wasn’t designed to be a very powerful indicator of diet-disease relationships, but a little speculation: some think higher fat [and lower carb] intake should be protective against diabetes… which may be true, for people who can tell time.  Alter one nucleotide in the vasopressin 1A receptor gene and the game changes.

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