Tag Archives: melatonin

MELATONIN

Posted on January 2, 2017 | 8 comments

There are a lot of mysteries involving melatonin, eg, relative importance of gut vs. pineal-derived melatonin.  Does brain melatonin talk to peripheral MT receptors?  Does gut melatonin talk to brain MT receptors?

What we do know: oral melatonin works in people with circadian-related sleep disorders.  This may suggest that oral/gut melatonin talks to brain MT receptors OR that oral/gut melatonin corrects circadian sleep problems by acting in the periphery.  OR a major target of brain melatonin is peripheral MT receptors.  I don’t know.

And as a further testament that melatonin supps aren’t sleeping pills is that they’re non-addictive and can at least temporarily “fix” circadian sleep problems: after prolonged treatment, people report no withdrawal symptoms and still sleep better even up to two weeks after discontinuation (Lemoine et al., 2011)!

 

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Posted in angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, Dopamine, melatonin, Sun, vasopressin, Vitamin D

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LIGHT is a drug

Posted on December 14, 2016 | 13 comments

Three stories about LIGHT

One

Carbon monoxide (CO): one of the nasty things in car emissions & cigarette smoke.  Also, a byproduct of the ever-important heme.  Heme, as you may recall, activates Rev-erb:

 

“Food for thought: an endogenous ligand of Rev-erb is heme (the iron-binding element in red blood cells).  Heme is degraded into bilirubin.  Elevated levels of bilirubin cause jaundice.  A treatment of neonatal jaundice is exposure to blue light.  Blue light is a major regulator of circadian rhythms and Rev-erb is an executive-level player in this game.  The primary mechanisms of blue light appear unrelated in these two models (melanopsin activation vs. bilirubin photoisomerization), but seem intertwined, because heme activates Rev-erb.  Cool.”

 

News: Disruption of the body’s internal clock causes disruption of metabolic processes

Science: Reciprocal regulation of carbon monoxide and the circadian clock (Klemz et al., 2016)

Tl;dr: heme degradation occurs on a circadian cycle and produces CO.  CO prevents Clock/Bmal1 from binding to DNA. Inhibiting this process throws off numerous other circadian rhythms in the liver.

SUNLIGHT and food in the morning, and let endogenously produced CO rhythmically tune the clock in the evening.

 

 

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Posted in angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, Dopamine, melatonin, Protein, sleep, Sun, vasopressin

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If meat causes cancer…

Posted on December 1, 2016 | 6 comments

Disclaimer: I’m meat-cancer agnostic.  *IF* meat causes cancer (and I don’t think it does), it happens extremely slowly and only at very high levels of intake: to get statistically significant risk ratios, researchers usually look to top vs. bottom quartiles, which is quite a large difference in intake.

Meat-cancer studies Tl;dr: some studies show positive associations, some neutral, and none are negative (ie, it’s unlikely meat prevents cancer).

That said, if meat does cause cancer, here is how it might happen:

1. The “Maybes:” AGEs, leucine/mTOR, methionine, etc., but only in combination with numbers 2 & 3.  Not by themselves.

2. Circadian arrhythmia and cancer: potential mechanisms

3. Most animal foods have a lot of linoleate 18:2n6 or at least a lot more n6 than n3 (grass-fed is usually a little better in this context).  More on this below.

 

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Posted in angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, Dopamine, melatonin, mortality, muscle, Protein, sleep, Sun

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Circadian rhythms and cancer: potential mechanisms

Posted on November 7, 2016 | 10 comments

Humans are incredible omnivorous beasts that can thrive on a great variety of diets, but crumble if you mess with their sleep.

Circadian arrhythmia is thought to be a driving force behind a few types of cancer.  But how, exactly, does seemingly harmless things like artificial light, skipping breakfast, or jet lag actually promote tumorigenesis?  There are many potential mechanisms, and I’d bet different circadian disruptions promote different cancers in different #contexts.

In some cell types, circadian disruptions which dampen amplitude increase proliferation.  This has led to some researchers to believe a robust circadian rhythm per se is tumor-suppressive.  In agreement with this, many tumor suppressors are direct targets of circadian transcription factors.  As was observed in some skin cancers, you may want suppressed proliferation at some times of the day but not others, so the tissue can renew properly.  But you don’t want, for example, skin cells to be proliferating while they’re being exposed to UV light, so this process happens at night (in circadian fashion).

Circadian transcription factors also directly interact with endogenous antioxidant systems.

 

circadian-image

 

Cancer clocks out for lunch: disruption of circadian rhythm and metabolic oscillation in cancer (Altman, 2016)

 

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Posted in angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, Dopamine, melatonin, sex, sleep, vasopressin, Vitamin D

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Circadian disruption impairs survival in the wild. Again.

Posted on October 2, 2016 | Leave a comment

We evolved on Earth, with regular 24-hour “circadian” cycles; abandoning them is incompatible with survival.  Natural Selection does not look upon this favorably.

Natural selection against a circadian clock gene mutation in mice (Spoelstra et al., 2016)

 

The first time this was discussed, HERE, they ablated the master circadian clock, the SCN, which made the animals arrhythmic with a bollixed circadian period:

 

scn-lesion-activity-image

 

scn-lesion-period-image

resulting in significantly increased predation in the wild:

 

scn-lesion-activity-survival

 




 

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Posted in angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian

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Circadian timing with REV-ERB and PERIOD

Posted on August 15, 2016 | Leave a comment

The circadian proteins Bmal and casein kinase (CK) enhance and degrade Period (PER), respectively, by completely different mechanisms.  Both are necessary, but at different times of day… #context

Gross oversimplification: the Bmal party is kicked off in the morning by LIGHT, and acts to increase PER by night (among many, many other things).  As the day progresses, REV-ERB the Repressor slowly shuts down Bmal, so that peak PER occurs in the evening and doesn’t carry over until the next morning.  GSK3b activates REV-ERB the Repressor.  Lithium puts the system in fast forward, leading to phase advance* and ZZZ’s when timed right, at night… I think

 

Lithium GSK3b image

 

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Posted in angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, diabetes, Dopamine, insulin, melatonin, mortality, Sun, vasopressin, Vitamin D

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LIGHT timing for circadian entrainment

Posted on July 5, 2016 | 13 comments

Basically, this much is pretty obvious now: LIGHT and food in the morning + darkness after sunset = proper circadian entrainment.  But the how is pretty cool; LIGHT affects different biochemical pathways at different times of the day, which is how it can either advance or delay your circadian phase.

LIGHT entering the eyes is perceived by ipRGCs which then dish out glutamate and PACAP.  These mediators go on to activate receptors in the SCN (the “Master Clock”).

Depending on the time of day, glutamate and PACAP affect different pathways.

 

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Posted in Advanced nutrition, angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, Dopamine, Ketosis, Leptin, melatonin, nicotine, Sun, vasopressin, Vitamin D

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Insulin resistance and obesity

Posted on June 25, 2016 | 32 comments

Some people believe insulin resistance (IR) causes obesity, and they are not pleased when I say this is actually a controversial topic in the field…

“Bill isn’t toeing the company line.  Again.”

So I asked a simple question: if IR causes obesity, how?

 

 

The Common Response: 1) IR -> 2) hyperinsulinemia -> 3) more insulin = more fat mass.

However, this is flawed.

Easiest rebuttal (somewhat of a strawman, but whatevs): Barbara Corkey and her group has done a lot of work showing that insulin hypersecretion (caused by dietary additives, preservatives, weird chemicals, etc.) may actually precede & causes IR… not enough insulin hypersecretion to induce hypoglycemia, just enough to induce IR.

So that basically breaks the 1st step in the Common Response, but doesn’t really disprove the possibility that IR still causes obesity (or can cause obesity).

In any case, check out Corkey’s 2011 Banting Lecture.  Highly recommended, a lot of food for thought.

 

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Posted in Advanced nutrition, angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, diabetes, diet, Dietary fat, Dopamine, insulin, Leptin, Protein, TPMC

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Dopamine and breakfast

Posted on June 5, 2016 | 39 comments

T.S. Wiley wrote a lot about the protein-rich breakfast; here’s my understanding of her take on it.

N.B. I highly recommend her book, Lights out: sleep, sugar, and survival.

Quotes are mainly taken from the text. I’ve tracked down some of the cites; the rest are in the back of the book, albeit somewhat unorganized :/

Part 1. We naturally have a cortisol spike first thing in the morning, known as the Cortisol Awakening Response (CAR).  This peak, which can be screwed up by artificial light at night or a big evening dinner, helps support morning light-induced dopamine.

CAR

Dopamine is great, but may induce impulsivity if it’s unfettered.

Enter: the protein-rich breakfast. It provides tryptophan and a bit of insulin to promote serotonin synthesis (eg, Manjarrez-Gutierrez et al., 1999).

Not enough serotonin to make you crazy, just enough to balance the dopamine = impulse control.

~ circadian balance achieved ~

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Posted in Advanced nutrition, angiotensin, Bromocriptine, Cabergoline, chronopharmacology, circadian, diet, Dopamine, fat, Fish, insulin, Leptin, melatonin, Protein, sex, sleep, Sun, TPMC, Vitamin D

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Vasopressin’ me again

Posted on May 25, 2016 | 3 comments

I’ve been following the links between blood pressure modulatory hormones and circadian rhythms for a while now — and while it’s a fascinating overall picture, this nut hasn’t been cracked [yet].  A paper published in Science may have brought us one step closer.  (And some potential biohacks.)

Background reading (probably important, because my thoughts on this aren’t very coherent [yet]):

LIGHT, Leptin, and Environmental Mismatch (skip down to Part 2)

Circadian phase delays and metabolism

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

 

The new study: Changes in the composition of brain interstitial ions control the sleep-wake cycle (Ding et al., 2016)

It was a study on mouse brain, but the #context is very relevant here.

Tl;dr: they showed that changes in extracellular ions, independent from neuronal activity, can induce sleep or wakefulness.  “Independent from neuronal activity” was accomplished by silencing the neurons with tetrodotoxin.

 

Pufferfish

 

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Posted in Advanced nutrition, Bromocriptine, Cabergoline, chronopharmacology, circadian, Dopamine, Leptin, melatonin, Sun

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