Epigenetics & Circadian Biology: Prader-Willi

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).

 

Prader-Willi

 

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

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)

Symptoms of Prader-Willi associated with interference in circadian, metabolic genes.

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.

 

calories proper

 

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  • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

    Theres no question PWS is likely a failure to develop, or an age-onset loss of the normal CNS (hypothalamic) regions that wt/growth regulating hormones act upon. Its more than leptin as the PWS phenotype seems more severe than simple leptin deficiency. Its as if the part of the brain where ALL metabolic hormones signal is null.

    IMO there is no question their brain can’t perceive leptin. IN addition to the IGF1 failure (which is consistent with leptin deficiency) pts also have a short stature, cannot enter puberty, and have thyroid problems. This is more or less standard issue congental leptin deficiency, but PWS seems to have particularly severe metabolic conservation so likely its just hypothalamus-wide deletion / non function of all metabolic regulating hormone receptors.

    I lean toward the PWS patients gradually destroying this part of the hypothalamus vs congenital agenesis.

    I was surprised to learn the growth of fat and pathological eating does not onset until about 3-4 yrs old. This is the phase where GH helps. The GH compensates for failure to induct igf1 normally from likely region specific hypothalamic deletion/damage. It must be age progressive in severity because what starts as simple growth retardation only later progresses into a severe, dysregulated starvation phenotype. Ironically, when this occurs, they are not candidates for the (expensive) GH therapy as their weight catches up to height.

    It would b interesting to compare age of onset of obesity with congenital leptin deficiency VS PWS. That might be illuminating as to pathophys.

    Also, angelman’s syndrome is very fascinating. As soon as i heard a description of the children (“Happy all the time, sleep problems”) I knew it was very likely they had a circadian rythm disorder, developmental failure.

    http://www.angelmantoday.com/angelman-syndrome-and-sleep-disorders/

    I very much related to the child in this story. The mother was doing everything I do pretty much. (I always felt i have inherited a circadian defect…)

    The kids sleep disturbances are much more severe than this lets on. They have to be kept in cribs because they will wander at night, like dementia patients. (I keep meaning to write my blog entry that many cases of dementia are a circadian rhythm failure , that circadian dysruption of modernity is likely crucial in triggering dementia. )

    I too found it ABHORENT how the PWS pts are treated. They are starved on 1000 calorie diets, and accused of stealing food . So you have it , an obese fat mother, restricts food from her PWS child. I dont know how they can do this, how can you be so fat and withhold food from your much slimmer son, who feels as if he is starving and would eat garbage from a dumpster?

    TBH PWS is one of the most cruel disorders there is. Imagine how it must feel to have painful starvation, that never terminates, for life? Furthermore, one lacks the mental ability to advocate for yourself and resist the abuse from caregivers because you are mentally handicapped? Its just like, a caricature of cruelty.

    Few people have felt starvation. Its very, very painful. I’ve starved.

    If i had a PWS child i would let nature take its course. Its just too painful to make someone go through life like this.
    In the PWS doco i was watching, the father even said as such. “She’s happier away from us, and if she’s fatter, but happier, that’s the price”.

    Perhaps shes not unhappy because of being with you, but she’s unhappy because you are starving her when she is biologically severely fat?

    Just horrible the whole situation.

    Anyway thx for writing, observing biological syndromes of weight disorders are always very educational , illuminating insight for any with the capacity to question , contrast, and think.

    • Kindke

      indeed PWS displays a lot of the leptin deficiency symptoms.

      A defect of NE sympathetic tone into adipose tissue allows that adipose tissue depot to grow, since NE also inhibits pre-adipocyte differentiation.

      once you get pre-adipocytes maturing your gonna get fat regardless of anything else.

      also the low lean mass to fat mass ratio, that is again clear leptin deficiency signature. The epigenetic switch in PWS must surely be interfering with leptin signal somewhere?

      • http://www.caloriesproper.com/ Bill Lagakos

        “The epigenetic switch in PWS must surely be interfering with leptin signal somewhere?”

        yes, most likely: http://www.ncbi.nlm.nih.gov/pubmed/10368796

        http://www.ncbi.nlm.nih.gov/pubmed/25926624

        • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

          Thsi is a peeve of mine, the idea that the CNS negative regulates leptin so high leptin = leptin resistance.

          High leptin does usually indicate fatness, but its mostly via ADIPOCYTE ENVIRONMENT that synthesize great levels of leptin because they grow so easily and so totally listen to insulin.

          High leptin = very very high insulin OR very very insulin sensitive adiopcytes. One or other.

          It says not much about CNS leptin sensitivity because there is no direct route from leptin sensitivity of brain -> peripheral level. Leptin is NOT like insulin where you can approximate insulin resistance based on circulating insulin responses to a glucose challenge.

          It is entirely possible to have very high leptin but SOMETHING ELSE is broke. E.g. thyroid pts have high leptin, which is an expected result of the effects of T3/TSH to induce adipocyte growth.

          http://www.ncbi.nlm.nih.gov/pubmed/23684667

          I am really tired of stupid researchers seeing a high leptin level and concluding “leptin resistance” . Such terrible system understanding and reasoning.

          All high leptin means is growing FAT. Thats all.

          We know PWS almost CERTAINLY have a brain level defect that induces peripheral defects to grow fat, so it is entirely expect their leptin levels would be very high.

          Now it is ALSO likely their brain is not listening to leptin properly either, but the true cause of the high leptin is the adipocyte defect (reactive 2 brain defect) to induce abnormal growth, abnormal insulin stimulated fat synthesis that translates into leptin synthesis.

          The key is isolating these concepts because another type of obesity: hyperinsulinemic, IR, may not really feature a CNS leptin defect but their leptin will be very high because their adipocytes are on BLAST, inflammatory, distended, from bathing in extreme insulin . The primary defect HERE is an insulin resistance syndrome, which itself has a myriad of causes.

          TL;DR

          Soooo tired of reading “high leptin leptin resistance” there is ZERO concrete relationship here.

  • Nicolás Flamel

    Oh, a very interesting post, thanks for share! :-)

  • Danny J Albers

    This disorder goes far beyond obesity having watched a family member grow up with it. Seizures, facial ticks, weird tongue movements and odd facial expressions. A gait that seems to be like a marionette caused it to fist be called Happy Puppet syndrome. My cousin had over 65 large seizures in his first 2 years of life and now in his 30s has the mind of a 2 year old and is under full time care just like a 2 year old.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1791803/

    • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

      Hi danny it seems you are describing angelman’s syndrome. These kids are usually lean. Its PWS that has obesity. Sorry to hear about your relative with AS.

  • http://davebridges.github.com/ Dave Bridges

    There was a times article earlier this year on PWS, showing how devastating it can be to the kids suffering from it:

    http://www.nytimes.com/2015/01/25/magazine/food-is-a-death-sentence-to-these-kids.html?_r=0

    • http://www.caloriesproper.com/ Bill Lagakos

      Thanks, Dave.

  • Cody Fyler

    Bill, interesting about this applying to other forms of obesity. I can only lose weight using a PSMF. I’ve done regular low carb and I don’t lose weight. I never feel truly sated, even after pounds of fatty meat. I’ve even tried a fat fast and didn’t lose one pound over a week. And that was nothing but butter and cream cheese. I also tend to be a night owl.

    • http://www.caloriesproper.com/ Bill Lagakos

      “I also tend to be a night owl”

      ^^^this might be part of the problem

      • Cody Fyler

        So how do I make myself not be a night owl? I feel more awake and more energetic at night. My mother is the same way.

        Do I just take melatonin at 9 and turn off all the lights and try to force myself to sleep?

        • weilasmith

          my daughter and husband have ADHD and my husband also has Tourette’s. They both can’t help but fall asleep late. My daughter takes melatonin, but it doesn’t consistently help. One thing that does help my daughter is if I give her a massage. I would love to find a good massage chair with good home repair service. Also, in my mom’s last years when she had trouble sleeping, being out in the sun most of the day helped her have a better night sleep. I make it a point to walk outside during my lunch time at least. i sleep well the first 5 hours, but after that hot flashes keep me up. i need gabapentin to sleep well on certain days of my cycle.

          • Cody Fyler

            I’ve been taking Melatonin and l-ornithine to help me sleep. I tend to have a lot of anxiety and racing thoughts at bedtime. The ornithine seems to really make that go away.

            But that’s a good reminder on the sun exposure. Being November in Iowa, I think using really bright light first thing in the morning might help. I have a 250 watt Halogen garage light that is quite intense in brightness. I’ll have to dig it out and try it again.

          • Jack Kruse

            Halogen will make you gain weight because of the high color temperature and the melanopsin window 435-465nm. This is what everyone misses in obesity and leptin signaling.

          • weilasmith

            you can buy a sun/light box. i have a verilux brand one that wasn’t expensive.

          • http://www.caloriesproper.com/ Bill Lagakos

            “being out in the sun most of the day helped her have a better night sleep”

            this is big.

            Light exposure (daytime) and meal timing (more food earlier in the day) are two powerful ways to entrain circadian rhythms.

        • http://www.caloriesproper.com/ Bill Lagakos

          a couple tips to try:

          Bedroom should be pitch black at night, and no smart phones, computers, etc.
          Temperature should be a bit cooler.

          Shift eating pattern to earlier in the day (eg, big breakfast, medium lunch, small dinner).

          Early sun or bright light exposure.

          Hope this helps!

      • weilasmith

        i do know of obese people who have breakfast, are up bright and early and stay outside for much of the day, and do a lot of hard physical labor. my father and brother are both farmers. my brother is obese even though he does hard physical labor and eats breakfast, is up early, and is outside a lot. my father used to be heavy, but when he found out he had diabetes, he cut down on carbs and lost weight. low carb might help my brother too, he just doesn’t want to do it i guess. so in their case light exposure and meal timing are not factors in their obesity.

  • This Old Housewife

    I always wondered if the people suffering from Prader-Willi and pica could benefit from a HFLC diet, as the fat might solve the constant hunger (or inappropriate hunger) dilemma.

    Seeing the photo of a PW patient, now I’m wondering if dyslipidemia is somehow involved.

    • George

      Here’s a LCHF Prader-Willi study.
      It didn’t work amazingly at controlling blood sugars here, but it did seem to give the woman some autonomy and calorie control, reading between the lines that’s why her family recommended it when she became an adult.
      The SLGT2 inhibitor caused the ketoacidosis, there was no reason to bring LCHF into it.

      http://onlinelibrary.wiley.com/doi/10.1111/jdi.12330/pdf

  • rs711

    great post bill

    • http://www.caloriesproper.com/ Bill Lagakos

      thanks!

  • alan2102

    Bill writes: “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).”

    The abstract to which you linked describes the use of 125 mgs of testosterone PER MONTH. For testosterone replacement, 125 mgs is closer to a 3-day dose than a 30-day dose! 125 mgs per month is a scant 4 mgs per day — barely even a significant supplementary quantity, let alone a replacement amount (or pharmacological support amount). Giving that dose of T and calling it “replacement” is like giving 200 grams of carbs a day and calling it “low carb”.

    What is amazing is that even that tiny dose of testosterone was sufficient to reduce body fat from 47% to 39% in 2 years! That’s a huge change relative to the piddling intervention. What if those guys were put on a real replacement dose, like 2-400 mgs/week, sufficient to bring their T into the healthy normal young-person zone upwards of 600 ng/dl? Or preferably upwards of 800 ng/dl. (That would be up from their abysmal starting levels of under 100 ng/dl.) Would they be fully cured, or only half-cured? Who knows? One thing is for sure: there would be a lot less interest in hypothalami, “complex genetic” etiology, leptin, and all the rest!

    Testosterone is a powerful and under-appreciated factor in body fat regulation. But the prejudice against it runs so deep, over so many years, that it will be another decade or two at least before this is recognized.

    I note also, in a brief dig about the PWS literature, that growth hormone treatment appears not to be nearly as effective as testosterone.