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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Mushrooms are awesome (P<0.05)

“Without leaves, without buds, without flowers;
Yet they form fruit.
As a Food, as a tonic, as a medicine;
The entire creation is precious.”

-weird mushroom poem of sketchy origin

 

Mushrooms: They have B12! When exposed to UV light, they make vitamin D2.  Protein, fibre, and selenium.  Shall I go on?

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Vitamin D, Fiat Lux, and Circadian Rhythms

Vitamin D synthesis is TEAMWORK!

Skin: 7-dehydrocholesterol + UVB = previtamin D3.
Liver: Previtamin D3 –> 25(OH)-Vitamin D3.
Kidney: 25(OH)-Vitamin D3 –> 1,25(OH)2-Vitamin D3 if you need it or 24,25(OH)2-Vitamin D3 if you don’t.

N.B. one of the major regulatory pathways occurs in skin: if you’re getting a lot of sunlight, then skin darkens to block this step.  Supplemental and dietary Vitamin D3 bypass this… but the dietary Vitamin D supply rarely produces toxicity because it’s not very abundant.  In other words, sunlight Vitamin D never reaches toxic levels.  Supps could (rare, but possible).

Disclaimer: I’m not against Vit D supps, but prefer sunlight whenever possible.

The other major regulatory step is in the kidney.  Production of 1,25(OH)2-Vitamin D3 is tightly regulated — so blood levels don’t decline until your very deficient… so 25(OH)-Vitamin D3 is a better indicator of skin production and dietary intake.

Disclaimer #2: this post is not about any of the pleiotropic effects of Vitamin D or D supps, which range in value from worthless to helpful to possibly harmful.

For some of that stuff, see:

Vitamin D: still a scam, still immunosuppressive… by Jane Plain

The Vitamin D seminar by Ivor Cummins

Vitamin D 101 by Kris Gunnars

The Vitamin D Debacle with Ivor Cummins and Sam Feltham

all of the above are more pro-D supps than me, which I find perfectly OK.

 

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OmniCarb

Why Low Carb?

OmniCarb (Sacks et al., 2014)

Study design & results in a nutshell:

5 weeks, low(ish) vs. high carb (40 vs. 58%) with the calorie difference split between protein (23 vs. 16%) and fat (37 vs. 27%).  In other words, the low(ish) carb diet was higher in protein and fat.  And there was 2 versions of each diet —  a high and low glycemic index.  Lots of crossing over; all in all, weak intervention but decent study design & execution.

Aaaand nothing drastic happened.  Goal was insulin sensitivity, not weight loss.

 

glucose and insulin

 

Important points:

1) The participants were relatively healthy at baseline.  Anyone on meds was excluded.  Average BMI 32.  Mostly educated non-smokers.  This population is expected to respond reasonably well to any diet (wrt body weight… see next point).

2) “Calorie intake was adjusted to maintain initial body weight.”

^^^this really knocks the wind out of low carb. One of the big benefits of cutting carbs is spontaneous appetite suppression –- two points here: 1) this effect is most prominent in obese IR; and 2) it is more relevant to weight loss.  By not targeting insulin resistant and/or type 2 diabetics, and feeding specifically to prevent weight loss, I ask you this: Why Low Carb?

3) the biggest difference between the two diets was carbs (45% higher in low[ish] fat group), but the biggest difference from baseline, was protein in the LC group (53% increase).  In other words, the Low Carb group had their carbs decreased from 50 to 40% of calories. *meh*

4) Body composition wasn’t assessed; so even if LCHP induced nutrient partitioning and improved body comp, we wouldn’t know it.

5) Everyone was eating cereal or oatmeal for breakfast, bread with most meals, and pasta or rice for dinner.  What did you expect?  Really?

REALLY?

Prior posts in what seems to be developing into a series of rants:
2 New Diet Studies
CICO and rant 

 

calories proper

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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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CICO and rant

“Wait… what?  nutrient partitioning?”

Calories In, Calories Out should not be interpreted as “eat less, move more,” but rather kept in its more meaningless form of: “if you eat less than you expend, you’ll lose weight.”  At least then, it’s correct… meaningless, but correct.  Eating less and moving more is no guarantee of fat loss, in part, because total energy expenditure isn’t constant and there’s that whole thing with nutrient partitioning.

For obese insulin resistant folks, this is Low Carb’s strong suit: it causes “eat less, move more”spontaneously.

For some obese insulin sensitive patients, for whatever reason, their adherence and success is greater with Low Fat.  You might say, “yeah, but those suckers had to count calories.”  To that, I’d counter with: “it doesn’t matter, THEY WERE MORE SUCCESSFUL COUNTING CALORIES ON LOW FAT THAN NOT COUNTING ON LOW CARB.”  The spontaneous reduction in appetite obviously didn’t cut it.  Do not be in denial of these cases.

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Ketone bodies as signaling metabolites

*non sequiter*

One of the ways dietary carbohydrate contributes to liver fat is via ChREBP: “carbohydrate-response element binding protein.”  It responds to a glucose metabolite and activates transcription of lipogenic genes.  Insulin helps.  Ketones do the opposite (Nakagawa et al., 2013), by inhibiting the translocation of ChREBP into the nucleus where it does it’s dirty work:

 

ChREBP

 

More interestingly, ketones are histone deacetylase inhibitors (HDACi)… this leads to more histone acetylation.  Benefits of fasting sans fasting?  Modulating of acetylation is a MAJOR regulator of circadian rhythmicity.

Butyrate is another HDACi, so have some fibrous plant foods with your red wine and dark chocolate.  Anti-aging (mostly worm studies, but still).

 

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Omega-3 Index

“Need” is a funny concept.  You don’t need to eat seafood.  You don’t need an appendix or legs, either.

An article about the Omega-3 Index was published in Whole Foods Magazine.  Scanning through the figures, I noticed a few interesting studies.

For example, Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease (Farzaneh-Far et al., 2010)

Telomere length is believed to be a biomarker of aging: the shorter your telomeres, the faster you’re aging.  In the study, they measured telomere length in white blood cells and EPA+DHA in whole blood at baseline and again 5 years later.

omega-3 intake and telomerase

Quartile 1: EPA+DHA = 2.3% of the fatty acids in whole blood.

Quartile 2: 3.3%

Quartile 3: 4.3%

Quartile 4: 7.3%

Potential confounders: quartile 4 was comprised of educated rich white old non-smokers with low levels of inflammation, but the statisticians assure us those variables were controlled for… so there’s that.

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Because chocolate

To improve a memory, consider chocolate –NYT

Dark chocolate could improve memory by 25%, but you’d have to eat 7 bars a day –PBS

Dietary flavanols reverse age-related memory decline –Columbia University Medical Centre

dark chocolate

 

The actual study: Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults (Brickman et al., 2014)

High flavanol group: 900 mg cocoa flavanols and 138 mg epicatechin (that’d be a LOT of dark chocolate).

Control: 10 mg cocoa flavanols and 2 mg epicatechin

Study duration: 3 months

Funding: NIH & Mars lol

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Sweet’n Low

I didn’t want to blog about the artificial sweetener study; to be honest, I didn’t even want to read it.  I just wanted to report: 1) how many Diet Cokes are we talking about; and 2) when are you going to die.

Artificial sweeteners induce glucose intolerance by altering the gut microbiota (Suez et al., 2014)

Non-caloric artificial sweeteners (NAS) = saccharin, sucralose, and aspartame. Saccharin worked the best (worst) in the mouse study, so they tested it in humans.  This was the part I found most relevant: seven healthy volunteers (5 men & 2 women, aged 28-36) who did not typically consume a lot of sweeteners were recruited and given 120 mg saccharin three times per day.  360 mg saccharin is ~10 packets of Sweet’n Low.

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