Social jet lag is basically a general term that refers to circadian arrhythmia. Sort of like insulin resistance, it’s rampantly abundant — some have estimated a prevalence of up to 75%! Social jet lag can be induced by shift work, East/West travel, late meal timing, artificial light at night, sleeping late, not enough sunlight in the morning, etc., etc. And while any of the above insults, by themselves, may not really screw up your circadian rhythms, you can see how easy it is for one person to fall prey to nearly of them:
Eat a late dinner, stay up late using artificial light (eg, computer, smart phone, etc.), sleep late the following day so you skip breakfast and don’t get any sunlight in the morning.
CIRCADIAN MISMATCH ACCOMPLISHED
This increases your risk for a wide variety of ailments, ranging from cancer to diabetes to bipolar disorder: no bueno.
One key mediator of the effects of LIGHT is melatonin. Artificial light at night suppresses melatonin. Sunlight in the morning can blunt the impact of this! It all ties in together. Gravitas.
I came across a recent study on a mouse model of Angelman Syndrome (an epigenetic disorder), and wasn’t surprised to learn there’s a strong circadian component to it. Epigenetics are one of the main ways circadian rhythms are programmed.
In this case, the circadian connection is more direct.
Angelman Syndrome (AS): you inherit 2 pairs of each gene, one from Mom and one from Dad. In some cases, one of the copies is silenced via epigenetics and you’re basically just hoping the other one is in good shape. In the genetically relevant region in AS, the paternal copy is silenced and the maternal copy does all the heavy lifting, but in AS, the maternal copy is mutated or absent, so none of the genes in this region are expressed.
Interestingly, scientists found that one of the genes, Ube3a (an ubiquitin ligase), is involved in regulating Bmal1, a core circadian gene (Shi et al., 2015) . And mice with a silenced paternal Ube3a and mutant maternal Ube3a exhibit many of the same circadian symptoms of children with AS. They don’t mimic all of the symptoms as there are many other genes in this region. But both show circadian abnormalities.
Prader-Willi Syndrome (PWS) is the epigenetic opposite: same region of DNA, but silenced maternal copy and mutant or absent paternal copy. This disorder is characterized by massive obesity and low muscle mass (among other things).
While reading about this disorder, I was taken aback with how the obesity was explained.
“Insatiable appetite” (Laurance et al., 1981), although from what I can gather, these children would develop massive obesity even if they were fed cardboard. Some studies even showed no change in food intake and/or energy expenditure (eg, Schoeller et al., 1988), which led some researchers to publish entire papers about how these children must be lying and/or stealing food (eg, Page et al., 1983) .
Further, other researchers even explained their obesity was due to an inability to vomit (Butler et al., 2007).
THEY’RE OBESE BECAUSE THEY’RE NOT BULEMIC.
AYFKM?
When these kids gain weight, it’s nearly all fat mass; when they lose weight, it’s nearly all muscle [shoulda been a BIG hint]… this even led some researchers (who detected no change in fat mass after significant weight loss) to conclude that their techniques to assess body composition must not be valid in this population because: surely, they must’ve lost some fat mass like normal people do.
THEY FAILED TO CONSIDER THIS IS AN EXTREME CIRCADIAN MISMATCH DISORDER IN NUTRIENT PARTITIONING
It was actually painful to read: these kids are being accused of stealing food and not vomiting because that’s the only way to explain it.
NO IT’S NOT, SCIENCE.
They can be forced into losing fat while maintaining some muscle with an extreme protein-sparing modified fast (eg, Bistrian et al., 1977)…
A few research groups have considered the possibility it’s a hormonal disorder, and some fairly long-term studies with GH replacement have shown promising results (eg, Carrel et al., 1999).
Prader-Willi Food Pyramid. Wait, wut? O_o
Some have even speculated involvement of leptin (eg, Cento et al., 1999), although this hasn’t been followed-up on.
Disclaimer: I don’t know the cure or best treatment modality for Prader-Willi, although given the strong circadian component in its sister condition, Angelman’s Syndrome, I strongly believe this avenue should be explored (in combination with the seemingly necessary hormonal corrections, which have been the only successful interventions yet). “Diet” doesn’t work; these kids aren’t obese because they’re stealing food or failing to vomit. Interventions strictly targeting CICO have massively failed this population.
Side note: in the Angelman Syndrome mouse model, *unsilencing* the paternal copy worked… maybe the same could work in PWS (and/or other forms of obesity)…?
Evidence supporting potential circadian-related treatment modalities for PWS:
A Prader-Willi locus IncRNA cloud modulates diurnal genes and energy expenditure (Powell et al., 2013)
Magel2, a Prader-Willi syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells (Devos et al., 2011)
Circadian fluctuation of plasma melatonin in Prader-Willi’s syndrome and obesity (Willig et al., 1986)
And the connection with LIGHT:
Artificial light at night: melatonin as a mediator between the environment and the epigenome (Haim and Zubidat, 2015)
Circadian behavior is light re-programmed by plastic DNA methylation (Azzi et al., 2014)
PWS is much worse than just nutrient partitioning (seriously, just spend a few minutes on any Prader-Willi support forum or this; maybe it is an appetite disorder, but given the data on weight gain [mostly fat mass] and weight loss [mostly muscle mass], it seems far more likely a circadian disorder of nutrient partitioning),
but that component jumped out at me; more specifically, despite the only positive results coming from non-dietary interventions, researchers were still all “#CICO.”
“Lean meat, sugar-free Jello, and skim milk”
FFS
Circadian biology, hormone replacement [where appropriate], and figure out if any specific diets help. PMSF/CR doesn’t work unless “refrigerators and cabinet pantries are locked shut.”
Maybe this applies to other forms of obesity, too.
Maybe.
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Many pre-diabetic, diabetic, and insulin resistant people have used the low carbohydrate diet to successfully manage their blood glucose levels. It just plain works. FACT (P<0.05).
However, a small subset of this population fails to achieve normal fasting glucose. This is likely due, in part, to a type of circadian mismatch induced by aberrant meal timing and excess exposure to artificial light at night. For an extensive list of citations supporting the former, see “Afternoon Diabetes;” stay tuned for evidence of the latter. In brief, a combination of delaying food intake for as long as possible after waking in the morning (“skipping breakfast”) and consuming most calories at night = no bueno. These behaviors can also promote a circadian mismatch and phase delay. Hint: eat when the sun is up; sleep when it is down.
SUNLIGHT entrains circadian rhythms. It gives us vitamin D and melanin; it can give us a sunburn, but some evidence suggests that it does NOT cause skin cancer.
Anecdotally (or so I’ve heard), skin cancer frequently develops in places not regularly exposed to sunlight. If true, this flies in the face of the dogma which goes something like this (Tl;dr): ultraviolet light from the sun penetrates into the nuclei of skin cells and damages DNA; if the right [wrong] genes are altered/mutated and the mutated cells proliferate, it can develop into a tumor (gross oversimplification).
So, what might explain the discord?
LIGHT entrains the circadian clock; this includes regulating cell cycle genes. Aberrant cell cycling may lead to out-of-control proliferation in the wrong context, aka cancer. Interestingly, some evidence suggests that part of the circadian regulation of cell cycle genes includes turning down proliferation when exposure to UV light is expected to be high (daytime); so DNA repair machinery has more time to fix any cell cycle genes that are mutated by UV light before the cell proliferates (Geyfman and Andersen, 2009) = lower chance of creating and propagating a potentially cancerous skin cell.
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.
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.
The mission of the International Dark-Sky Association is “to preserve and protect the night time environment and our heritage of dark skies through quality outdoor lighting.” They’re all about stressing the importance of lighting on health, light pollution, and some really interesting stuff.
…just read that huge disasters, ranging from Exxon Valdez to Chernobyl, may have been due, in part, to ignorance of basic principles of circadian rhythms. Gravitas.
More on why breakfast in the morning, with light onset is important to avoid circadian desynchrony.
FOOD is excellent at entraining peripheral circadian clocks: if you restrict animals to one meal per day, their peripheral circadian clocks rapidly become entrained to this, regardless of when the meal is administered (Hirao et al., 2010):
ZT0 = “zeitgeber time 0,” or “lights on.” pZT indicates a phase shift coinciding almost exactly with meal timing. Mice normally eat at night, but this doesn’t stop their peripheral clocks from entraining to the day time if that’s when their fed.
This study took it to the next level: they fed 2 meals per day, varying in size, time of day, and duration between meals in almost every conceivable combination. Actually, it was a quite epic study… some poor grad students working, literally, around the clock, for months…
“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.
Is it possible to improve the amplitude and resiliency of your circadian rhythms? Is this desirable? Yes and yes, I think.
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.
(an epigenetic disorder), and wasn’t surprised to learn there’s a strong circadian component to it. Epigenetics are one of the main ways circadian rhythms are programmed.
(PWS) is the epigenetic opposite: same region of DNA, but silenced maternal copy and mutant or absent paternal copy. This disorder is characterized by massive obesity and low muscle mass (among other things).
.
