Category Archives: Dopamine

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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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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Angiotensin: more than just blood pressure.

Pathologically low blood pressure can lead to shock & death.  Angiotensin II is there to prevent that, but it does much more.  A bit non-sequiter, perhaps.

This is what I call teamwork: low blood pressure detected by kidneys –> secretes renin.  Angiotensinogen (liver) is cleaved by renin to Angiotensin I.  Angiotensin Converting Enzyme (lungs [among other tissues]) cleaves angiotensin I into angiotensin II.

RAAS

Angiotensin II increases blood volume and restores blood pressure.  Good if you’ve lost a ton of blood fighting a wild beast; not good if you’re an overweight pen pusher on potato chips.  ACE inhibitors reduce angiotensin II, lowering blood pressure.  ACE is present in lungs probably because it deactivates bradykinin.  ACE inhibitors prevent this which might contribute to one of their side effects, a persistent dry cough which makes these drugs intolerable for many.  One alternative is angiotensin II receptor 1 blockers, or “ARBs.”


If anyone in pharma reads my blog (doubtful, unless they are monitoring for people to polonium-laced blow-dart), this will be their favorite post because I think ARBs are an interesting class of drugs.

If diet and weight loss are inadequate, telmisartan might be the next best thing to manage hypertension in diabetics:  Telmisartan for the reduction of cardiovascular morbidity and mortality (Verdecchia et al., 2011) –> effective at reducing mortality in patients with diabetes.

Efficacy of RAS blockers on cardiovascular and renal outcomes in NIDDM (Cae & Cooper 2012)  –> reduces morbidity and slows progression of renal disease (both hypertension and diabetes contribute to [irreversible] kidney damage, and frequently occur together, which makes this endpoint particularly relevant).  Hyperglycemia should be managed via diet, of course, and ARBs would need to be tested in people following something other than a Western diet (although said people may not even need treatment in the first place) (just thinking out loud here.  Or typing/whatever.)

But enough about blood pressure (<– boring); on to the more interesting stuff:

It started here: Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice (Duchemin et al., 2013)

Then: Candesartan prevents impairment of recall caused by repeated stress in rats (Braszko et al., 2012)

And: Anti-stress and anxiolytic effects of [candesartan] (Saavedra et al., 2005)

[Candesartan] prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding (Saavedra et al., 2006)

[Candesartan] ameliorates brain inflammation (Benicky et al., 2011)   brain inflammation induced by chronic exposure to artificial lights causes depression-like symptoms (in mice) (probably humans, too)

Finally, a human study: Candesartan and cognitive decline in older patients with hypertension (Saxby et al., 2008)

And then there’s this: Angiotensin receptor blockers for bipolar disorder (de Gois et al., 2013)


No mechanistic stuff because, well, I have no idea how it works.  On one hand, it might seem obvious that stress & anxiety can raise blood pressure, so something that lowers stress & anxiety could lower blood pressure.  Candesartan appears to do both (cause <–> effect?).  There are two unique properties of candesartan to note: 1) it gets into the brain; and 2) it leads to increased levels of angiotensin II (which presumably can’t do much because candesartan blocks the receptor for angiotensin II).  Perhaps angiotensin II targets a different receptor?  ARBs might blunt angiotensin II-induced CRH secretion, leading to anxiolysis, stress-tolerance, and pro-cognitive effects (that speculation was made possible by a thread on Avant Labs’ Forum and a few posts by Jane Plain on CRH [eg, here & here]).

Oh yeah, ARBs also prevent cafeteria diet-induced weight gain, insulin resistance, and ovulatory dysfunction [in rats] (Sagae et al., 2013).  And are sympatholytic like bromocriptine (Kishi & Hirooka 2013).

“The Angiotensin-melatonin axis” (Campos et al., 2013).

just sayin’

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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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Does junk food make you lazy?

From Times LIVE: “Does junk food make you lazy?” 

“A diet rich in processed foods and fat – and the extra weight that comes along with it – may actually cause fatigue, a lack of motivation and decreased performance, according to a recent study involving lab rats… excessive consumption of processed and fat-rich foods affects our motivation as well as our overall health.”

(this is categorically false as both diets used in the study being discussed were very low in fat.)

And from Psych Central: “Rat study shows junk food can make you lazy

The theory itself isn’t too far-fetched: a crap diet can cause weight gain and reduced energy expenditure, or a tendency to minimize any kind of physical activity… instead of: “’laziness’ causes obesity.”  And whether or not it’s true, unlike what some would have you believe, this wasn’t the study to prove it.

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It’s paleo: Hypothyroidism impairs reproductive success in bitches.

Kisspeptin was discovered in Hershey, Pennsylvania, and was named after Hershey’s Kisses.  It has 776 pubmed citations going back to 2001, and may (or may not) play a key part integrating circannual reproduction patterns and seasonal thyroid function.

Kisspeptin was originally identified as a protein that inhibited breast cancer and melanoma.  This might also provide insight into the WHO’s recent declaration of shift work as a “probable” carcinogen.

Exhibit A. TSH restores a summer phenotype in photoinhibited mammals via the RF-amides RFRP3 and kisspeptin (Klosen 2013)

In this study, TSH infusion in short-day adapted hamsters (who are in winter non-breeding mode) induced summer phenotype & kisspeptin.  It also fattened them up a bit.  These TSH secreting neurons express melatonin receptors, but not those for TRH or T3 (Klosen 2002), so it is said to go something like this:Kisspeptin feedback diagram

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Paleo breeding: mating in the wild.

I’ve adapted much of this chart from Howell-Skalla (2002)  and Tsubota (1998).

Canadian polar bears: bona fide seasonal breeders.circannual hormones

The light cycle increases until June, then decreases until December.  Melatonin goes in the exact opposite direction. Testosterone peaks around the onset of breeding season (springtime, April/May), coinciding with LH (as expected). There is also a lot of bear-on-bear violence at this time due to: 1) testosterone-induced aggression; and 2) the high female:male ratio –-> females rear their cubs and are thus out of the game for about 3 years, but males like to breed every year.

Females followed a similar pattern, with estrogen peaking around breeding season and prolactin following the light cycle.

The authors mentioned that prolactin levels mirrored day length, and according to Wiley this would be the prolactin peak that normally occurs when you’re sleeping, but has spilled over into the daytime due to short sleep / long light cycle… not total prolactin levels (24h AUC?), which should be highest in winter (see below).

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The incredible camping experiment, circadian proper

Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle (Wright et al., 2013)

Abstract (edited): The electric light is one of the most important human inventions. Sleep and other daily rhythms in physiology and behavior, however, evolved in the natural light-dark cycle, and electrical lighting is thought to have disrupted these rhythms. Yet how much the age of electrical lighting has altered the human circadian clock is unknown. Here we show that electrical lighting and the constructed environment is associated with reduced exposure to sunlight during the day, increased light exposure after sunset, and a delayed timing of the circadian clock as compared to a summer natural 14 hr 40 min:9 hr 20 min light-dark cycle camping. Furthermore, we find that after exposure to only natural light, the internal circadian clock synchronizes to solar time such that the beginning of the internal biological night occurs at sunset and the end of the internal biological night occurs before wake time just after sunrise

In other words, they compared circadian events during 2 weeks of normal life to 2 weeks of 100% camping.  And camping won.

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Summer is fattening. Don’t do it in winter.

Seasonal eating proper

More from T.S. Wiley and Dr. Kruse on seasonal eating in what appears to be the primary model for its justification for use in humans – hibernating mammals.

How it goes, or so they say: in summer, hibernators massively overeat, including carb-rich foods, in order to generate muscle and liver insulin resistance, so as to promote body fat growth.  The long light cycle reduces evening melatonin, which pushes back the usual nighttime peak in prolactin, which causes an abnormal resistance to leptin, which induces hypothalamic NPY and subsequent carbohydrate craving.  Ergo, summer is fattening.  In today’s day, increased artificial lights guarantee year-round pseudo-summer; and we no longer experience the benefits of the short light cycle: longer sleep times (akin to hibernation) and fasting – either complete fasting as in hibernation, or pseudo-fasting, ie, a ketogenic diet.

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Lights Out! Get your melatonin.

From T.S. Wiley’s website:
“People spent summers, before electric lights, sleeping less & eating heavily in preparation for winter because the light triggered the hunger for carbohydrates. Now, light is available 24 hours a day. Heating and air-conditioning climate control our hormonal responses to consume carbohydrates now available year round. This is the scenario for obesity, Type II diabetes, and depression… In Wiley’s opinion, sleep is the best medicine.”

And Wikipedia:
“Wiley’s main thesis in Lights Out is that light is a physiological trigger that controls dopamine and hormones like cortisol. Wiley posits that with the extension of the natural day through artificial lighting, rest at the hormonal level is rarely adequate for optimum biological needs of the body. In her view, this results in both fatigue and unnatural appetite, which leads to weight gain, exhaustion, and disease. Wiley theorizes that the body’s responses are cyclical, reflecting the seasons of the year, and that the body’s needs vary seasonally. According to Wiley, during the winter months the body needs more sleep, and carbohydrates should be restricted as they would have been naturally during hunter-gatherer times.”

melatonin

Most of the first third of Wiley’s book “Lights Out: Sleep, Sugar, and Survival” centers around light exposure, melatonin, and the many, many effects of a screwed up circadian cycle.  Jane Plain and Jack Kruse have written volumes on the subject, please see their websites for more in-depth analyses and practical applications…

Much of this blog post is my take on that first third (I couldn’t wait to finish it before writing about it), plus a little input from Google, Pubmed, et al; some commentary & pseudo-fact-checking as well.  I’m going to finish the book, and hopefully it will inspire a few more blog posts as opposed to a tin foil hat.  Most of the stuff in Lights Out makes incredibly good sense, but: 1) that doesn’t mean it’s true; and 2) the strings of logic are far too long to do a proper fact-check.  But really it’s how well it makes sense (mostly) that has me intrigued.

divide and conquer

Melatonin is a sleep-inducing hormone controlled by the light-dark cycle.  It is known.  On the day-to-day, melatonin increases at night and decreases during the daytime.  From Wiley: on a seasonal level, longer days during the summer meant less melatonin overall during these months.  Since melatonin suppresses sex hormones (inconsistent? Eg, Smith et al., 2013), summer is supposed to be breeding time, so the baby is born in spring when food is plenty (I’m OK with this now, but will certainly disagree come December).  Melatonin also suppresses metabolic rate, so the decreased daylight and thus increased melatonin during the winter months helped to survive on less food (supported by Marrin et al., 2013).

Disruptions in circadian rhythms royally screws us up.  According to Wikipedia, fireplaces/candles and incandescent bulbs produce less of the melatonin-suppressive blue lights… use these at night in winter?


Antidepressant and circadian phase-shifting effects of light. (Lewy et al., 1987)
Abstract: Bright light can suppress nighttime melatonin production in humans, but ordinary indoor light does not have this effect. This finding suggested that bright light may have other chronobiologic effects in humans as well. Eight patients who regularly became depressed in the winter (as day length shortens) significantly improved after 1 week of exposure to bright light in the morning (but not after 1 week of bright light in the evening). The antidepressant response to morning light was accompanied by an advance (shift to an earlier time) in the onset of nighttime melatonin production. These results suggest that timing may be critical for the antidepressant effects of bright light.

Next:  Prolactin inhibits sex hormones, and melatonin stimulates prolactin (supported by Gill-Sharma 2009Campino et al., 2008).  Thus, less melatonin in summer means less prolactin = more sex & fertility.  She also says day sex is more likely to result in conception compared to night sex for this reason (couldn’t find a reference for or against this).

Dopamine inhibits prolactin, whereas TRH & melatonin stimulate it.  Melatonin also blunts ACTH-induced cortisol secretion (supported by Torres-Farfan 2003Campino 2008).  Winter = high melatonin, prolactin, and low cortisol & dopamine.  Summer = high dopamine & cortisol, and low melatonin & prolactin.  Prolactin is supposed to be high in winter, during pregnancy; low dopamine would support this.

Circadian rhythm

Dopamine is a summer hormone?  Lu et al. (2006) showed high dopaminergic activity was associated with light and wakefulness (ie, summertime).  However, Venero (2002) showed melatonin stimulated dopamine synthesis in specific brain regions, and Eisenberg (2010) showed increased dopamine synthesis in fall & winter relative to spring and summer.  Two  possible confounding factors come to mind: 1) Location, location, location!  Some of these discrepancies may be due to brain region-specific dopamine metabolism… actually, Lu is the only odd-man out, so perhaps dopamine is a winter hormone?  And 2) Wiley’s main premise is that we pwned the light… epigenetics and the like mean that we, including the people in those studies, have deeply screwed up light/dark summer/winter metabolic programs on an epigenetic level, so it’s possible those studies are riddles with artefacts.  However, Wiley also says that people get sick because they live in perpetual summer (lights on all the time = high dopamine), and Markianos (2013) showed elevated dopamine metabolites in overweight patients; in my experience these studies usually continuously enroll patients, year-round.


I’m really just blazing through abstracts here – this is why I call it “pseudo-fact-checking;” not to be confused with any degree of academic rigor.

To be continued… (no tin foil hats, I promise) (not yet at least)

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