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.

 

dysglycemia

 

It would take further analyses of beta-cell function or a hyperinsulinemic-euglycemic clamp to know for sure, but this suggests these mice can’t shut down hepatic glucose production after a bolus dietary carbs (if beta cell function is normal), and they can’t increase hepatic glucose production when jabbed with insulin.  Bmal1, in a broad sense, may be necessary for “euglycemia.”

Another interesting phenotype of these mice is complete ablation of circadian activity patterns – it’s like they sleep walk and frequently nap (McDearmon et al., 2006).  And not surprisingly, this doesn’t bode well – lifespan is significantly reduced; only about 30% are still alive after a year, compared to 100% of normal mice.  No bueno.

Mice that lack Bmal1 selectively in liver exhibit virtually none of these effects, suggesting Bmal1 is important, just not in liver…? with the exception that these mice tend to be slightly hypoglycemic, so perhaps liver Bmal1 is a positive regulator of hepatic glucose production – this could explain the apparently improved insulin sensitivity – which would imply a pancreatic or skeletal muscle defect to explain the impaired glucose tolerance.

If you take the global Bmal1 knockout mice and transgenically express Bmal1 in brain, the mice are lean and slightly less active, but still lack normal circadian activity patterns.  And they live slightly longer than global Bmal1 knockouts (75% are alive at 1 year).

If the same experiment is done but Bmal1 is rescued in muscle instead of brain, body weight and total activity is normalized, still no circadian activity; however, the lifespan is restored.

 

activity

 

The observation that neither of these transgenic models could recover circadian activity suggests Bmal1 somewhere other than brain and muscle is responsible for this phenotype (I think).

As mentioned above, Clock and Bmal1 are considered ‘positive’ regulators of circadian gene expression; deletion of either in liver drives a tendency toward hypoglycemia.  Deletion of a negative regulator, Cry, does the opposite (Ramsey and Bass, 2011).  It doesn’t always work out this way, but it’s much easier when it does.

here’s where it starts to get interesting

Deletion of Bmal1 in adipose disrupts circadian feeding patterns, induces obesity, and improves the efficiency of physical activity.  That is, they burn fewer calories to do the same amount of work, similar to the weight-reduced state (Paschos et al., 2012).

 

efficiency

 

And if the negative regulator Cry is deleted globally, the mice develop obesity despite hypophagia (Barclay et al., 2013).  Increased adipose tissue insulin sensitivity.

Circadian rhythms: 1
CICO: 0

Mice lacking Clock globally are obese and fasting-intolerant; they fail to maintain body temperature and exhibit reduced free fatty acids (the two are probably related) (Shostak et al., 2013).  But more interestingly, they’re manic!  Less sleep, less depression-like behaviors and anxiety, hyperactivity… and all of this reversed with lithium (Roybal et al., 2007).

Admittedly, some of these experiments are, well, not entirely straight forward; eg, one way to assess “depression” in mice is to drop ‘em into a bucket of water and see how long it takes until they realize they float.  Technically, when they stop swimming, some researchers think this reflects helplessness or “despair;” and depressed mice “give up” sooner.  The Clock knockouts just kept on truckin’.    And they spent waaay more time in the center of an open field – theoretically indicative of less anxiety.  (the meaning of these experiments are highly debated; they definitely measure something, it’s just not exactly clear what.)

They’re also more sensitive to the behavioral effects of psychostimulants (cocaine, in this case) (McClung et al., 2005).

 

bipolar

 

Since these mice only seem to exhibit the manic side of bipolar, it would be interesting to see how altering the light-dark cycle would effect them – say, for example, dimming the lights…  this might at least help to normalize their enhanced dopaminergic activity.

Oddly enough, deletion of Clock specifically in one part of the brain (midbrain VTA neurons – of the notorious dopamine reward pathway), mimics the manic phenotype of global Clock deletion, but also induces depressive-like behaviors (Mukherjee et al., 2010)… I think this means that VTA Clock is anti-manic and anti-depressant; and Clock somewhere else is more depressant… however, i’m a little unclear about this part.

Circadian dysregulation in the amygdala or HPA axis may play a role in mediating the depressive aspect, although no clever mouse experiments have been done to tease this out [yet].  Maybe Jane Plain can weigh in here…

 

 

Deleting a bona fide circadian gene wreaks havoc, but mice without vasopressin receptors are immune to jet lag… who would’ve guessed!

Circadian rhythms are finely tuned, under-explored, and fascinating. Unpredictable.  Don’t mess with ‘em.  Lights out!

calories proper

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  • Jack Kruse

    I’m glad your finally seeing what I been saying. It is not about food like paleo land thinks. It is all about the signals we get and how we handle those signals correctly or incorrectly. I chuckled when I saw your really interesting point on adipose tissue. That is why the no exercise rule is present in my leptin Rx. Once you recover your redox potential in your adipose tissue then you can proceed. Good Stuff Bill. Have some Malbec and cocoa.

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

      Thanks, Jack.

      “That is why the no exercise rule is present in my leptin Rx.”

      This is definitely one of the parts I found more interesting – when timing is off, exercise is simply less effective…

      • Wenchypoo

        I find this interesting too in light of the spate of “why your workout isn’t working” articles that came out this morning.

    • http://cristivlad.com Chris

      Jack, I was sending this to you on FB today. not sure if you got it! Are you aware of Mick Dodge, the guy who lives in the forest for 20 years and talks about his amazing barefoot experience?

      https://www.youtube.com/watch?v=7o7UzYDQtmM

      • Jack Kruse

        Yes my wife introduced me to him. Interesting guy. He is instinctively aware of things I am talking about. He is running from the modern world because he realizes in pushing other species to extinction with our modern behaviors and beliefs, humanity is busy sawing off the limb on which it perches upon the tree of life.

  • Jack Kruse

    The logic behind how circadian biology is the result of the quotient of quantum mechanism of the amount of electrons and protons from our environment is simple to understand in our species: Our brain’s frontal lobes gives us the freedom from the constraints of evolution. Humans nevertheless remain dependent on the earth’s electromagnetic, biological, and geochemical systems. It amazes me how those CICO and paleo land people just breeze by this huge obstacle in most of their dogma. Just by disrupting these systems, clothing, with simplified diets, modern technology, fake light, cutting down tropical rainforests, altering the composition of the atmosphere, acidifying the oceans— we’re putting our own survival in danger. The proof is in all the new emergent disease that have cropped up in the last 60 years. It is obvious……..if you are looking at science critically. Few are.

    • Jack Kruse

      Right now in 2014, in the amazing moment that to us counts as “our present”, we are deciding, without quite meaning to, which evolutionary pathways will remain open and which will forever be closed to our epigenome. No other life form has ever managed this, and it will, unfortunately, be our most enduring legacy on this planet.

    • Tiffany Chantel

      Jack, I know you don’t know me from Adam, but I am beyond desperate for some answers. In short – I developed binge eating disorder after a traumatic incident. At the same time, I was working a job at a bar that had me not getting to bed until 3-5 am several nights a week. I would binge on high-sugar foods at 4am, and gained 20-25 lbs. in about 8 weeks. I was also doing hardcore spinning for exercise, but when it didn’t help, I stopped. I haven’t been able to lose the weight. I just quit my job, and am moving to Colorado to try to recover from this year of hell. Did I destroy my body and system for good? I fear I’ll never get back to my normal self again.

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

        Tiffany, just my two cents: the weight gain was: 1) recent; and 2) relatively quick. Those two things suggest it’s not likely “true obesity.”
        I suspect once you get back into your routine and sleeping normally, health and body weight will improve.

        • Tiffany Chantel

          Would you still say that, even if I told you that the weight gain happened back in March through May? It’s not that recent…however, I’ve still been eating excess sugar on a regular basis, and was working nights a few days a week up until this past week, so I’m assuming that has affected everything as well? Yeah, I really hope that once I get back to a normal routine, and try to stop the binging and calorie counting, that my body will work itself back to normal…I can’t live like this. I don’t recognize myself in the mirror, I can’t wear any of my clothes, and it’s one of the most unbearably painful things I’ve ever gone through.

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

            “Would you still say that, even if I told you that the weight gain happened back in March through May?”

            yes. Ie, compare your situation to someone who has been obese for their entire life, since childhood.

            “I’ve still been eating excess sugar on a regular basis”

            Gotta cut this out!

            I still think that a lot of things will improve when you get back to your normal routine and no more night shift.

  • http://ashsimmonds.com/ Ash Simmonds

    Clock mice…

    • Wenchypoo

      Hickory Dickery Dock?

  • Kindke

    because physiology isnt already complicated enough

    ITS STILL all about calories though, CICO. !!

    btw I wonder if Paschos et al., 2012 would therefore recommend a diet high in PUFA for shift workers? :?

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

    Very interesting Bill. You are one of the only LC or paleo bloggers giving proper emphasis to non food factors in relation to health.

    Any psychiatrist who is not an idiot can affirm that bipolar patients have evidence of a total body illness. Even before medication they are obese/overweight/diabetic relative to healthy people. This is unlike other mental illnesses without a profound mood/cycling circadian component. Diabetes can trigger bipolar disorder in several ways (high blood sugar, immune insults, cortisol; these also independently cause diabetes and mood problems) but more significantly the weight/blood sugar dysregulation likely represents some kind of insult to their circadian clock.

    I think when psychiatry is abolished for the psuedoscience/plastic surgery like discipline it is, and mental illnesses are properly conceptualized as the genetic, neurologic, immunologic problems they really are, we will discover that manic depression is caused by some kind of defect in circadian clock (which is well known to be targeted by lithium).

    I also think lower grade “bipolar like” illnesses which are not bipolar will also turn out to be circadian defects although with less severe/life disrupting presentation as manic depression. For example, bipolar II/atypical depression that cycles, will likely be similar, although more of a depressive vs manic risk from circadian dysregulation. These patients are, like manic depressives, overweight/obese/diabetic (and again, the latter set of problems can directly induce, as well as being symptoms of).

    Bipolar disorder is a mood problem, if parkinsons is a trembling problem. No one calls parkinsons a “tremor disorder” because it’s obviously caused by autoimmune to the dopamine producing neurons int he brain, tremor is like 1/100th of the problem. Ironically changes in movement are the first symptom of bipolar episodes; before mood or behavior the patient experiences change in movement. The body is first, mood is a later symptom.

    • Jack Kruse

      Jane sooner or later you will relent…….bipolar disease is an electron steal syndrome……..Peter is heading there and when he gets there you will have your epiphany and I will just chuckle…….we’re all on the same team and y’all have no clue……..that this is reality.

      • http://ashsimmonds.com/ Ash Simmonds

        >bipolar disease is an electron steal syndrome

        Pacman: #1 cause of bipolar since 1980.

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

      Thanks, Jane.

      Yeah, I think “non food factors” are pretty big.

      “Ironically changes in movement are the first symptom of bipolar episodes; before mood or behavior the patient experiences change in movement. The body is first, mood is a later symptom.”

      Interesting. is this like: high energy running around -> euphoria/irritability -> hypomania/mania ?

    • PC

      This is on the verge of happening already. Saw an article in New Scientist about rebooting psychiatry in this way recently. Of course it was all focused on creating new drugs for various brain areas :(

  • Jack Kruse

    I’d also point out this gem: If gene matter so much why is it that most, not all, circadian gene regulation is post transcriptional? This is a huge problem for neo Darwinians. Why? A post transcriptional protein is non functional for life. So how could life’s stage be gene based?

    • Jack Kruse

      Unexpectedly the most pervasive circadian regulation observed on a genome scale are rhythms in RNAPII recruitment and initiation, H3K4me3, H3K9ac, and H3K27ac, which occur at thousands of expressed genes whether or not RNA cycling was detectable. What accounts for these genome-wide circadian rhythms in RNAPII occupancy and histone modifications? Examination of the correlation between circadian transcription factor occupancy and gene expression shows that about 90% of genes bound by these factors are expressed whereas only 1 to 5% of unexpressed genes are similarly bound. These results demonstrate that gene expression per se, rather than rhythmicity of gene expression, is tightly correlated with circadian transcription factor binding. Rhythmic circadian transcription factor occupancy in turn could then be responsible for RNAPII recruitment and initiation on a genome-wide basis, which would then lead to the global rhythmic histone modifications seen here. Thus, circadian transcriptional regulators appear to be involved in the initial stages of RNAPII recruitment and initiation and the histone modifications associated with these events to set the stage for gene expression on a global scale, but additional control steps must then determine the ultimate transcriptional outputs from these sites. http://211.144.68.84:9998/91keshi/Public/File/41/338-6105/pdf/Science-2012-Koike-349-54.pdf

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

      #epigenetics