Category Archives: Bromocriptine

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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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’

calories proper

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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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Dopamine

“When we block the D2 receptor in humans, it is expected they will develop glucose intolerance, obesity, and sedentary behavior.” -Jane Plain, in her series on The physiology of body fat regulation.  It’s probably true.

Randomized pilot study of cabergoline, a dopamine receptor agonist: effects on body weight and glucose tolerance in obese adults (Gibson et al., 2012)

Cabergoline is primarily used to treat prolinactinoma, or prolactin-secreting tumors.  In women (& men apparently), prolactin stimulates milk production; in men, it is associated with the refractory period after orgasm.  In both genders, dopamine inhibits prolactin secretion.  Cabergoline targets the D2 receptor, but it’s a dirty drug.  It’s used off-label for gyno and to improve sexy times (Kruger et al., 2003 <– yes, that was actually tested).

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