Circadian phase delays and metabolism

Remember the “jet lag-resistant” mice?  Guess what: screw with circadian biology and metabolism pays the price.

In brief, vasopressin was classically thought of as an anti-hypotensive hormone.  The vasopressin analog Desmopressin is used to treat bed-wetting.  But vasopressin biology is much more interesting than that: mice lacking both vasopressin receptors require very little time adapting to large circadian phase changes.  And as with many fundamental concepts in chronobiology, this is intimately linked with metabolism.

People with certain polymorphisms of the vasopressin receptor, V1A, exhibit elevated blood glucose levels and are at greater risk for diabetes (Enhorning et al., 2009):


This risk is strongest in men in the highest quartile of fat intake, and is statistically more significant after adjusting for age and physical activity:

Fat consumption

This study wasn’t designed to be a very powerful indicator of diet-disease relationships, but a little speculation: some think higher fat [and lower carb] intake should be protective against diabetes… which may be true, for people who can tell time.  Alter one nucleotide in the vasopressin 1A receptor gene and the game changes.

Removal of the vasopressin 1A receptor in mice mirrors the human polymorphism.  Hyperglycemia and impaired glucose tolerance (Aoyagi et al., 2007)


Their livers crank out glucose in droves:


Aaaand when given an obesogenic diet, they eat just as much but gain significantly more weight:

eat less, weigh more

Odd, considering they’re fat-burning machines (Hiroyama et al., 2007), but similar to the human condition: mess with chronobiology and the game changes.


Remove V1B receptor, on the other hand, and the mice are “insulin hypersensitive” (Fujiwara et al., 2007):


…which may or may not be due to increased adiposity (Hiroyama et al., 2009):


Remove both receptors, and they don’t simply cancel each other out (Nakamura et al., 2009): these mice eat less, weigh more:


Removal of V1B increases adiposity which preserves insulin sensitivity; this doesn’t happen in the context of V1A deficiency… the double knockouts exhibit impaired glucose tolerance despite increased insulin = robust insulin resistance:




V1A KO: eat same, weigh more.  Insulin resistant.

V1A polymorphism: increased risk of diabetes.

V1B KO: increased adiposity.  “Insulin hypersensitive.”

V1AB KO: eat less, weigh more.  Insulin resistant, yet seemingly impervious to circadian phase changes ->

Mice genetically deficient in vasopressin V1A and V1B receptors are resistant to jet lag (Yamaguchi et al., 2013)  

In the figure below, the black marks reflect activity.  Mice are normally more active in the dark phase.  Shift the dark phase 8 hours earlier (“jet lag”), and normal mice take about a week or so to adjust their circadian activity behavior (see red circle on left).  However, V1AB KO’s adjust practically instantaneously (see red circle on right):

phase delay

However, in contrast to the diverging effects on insulin sensitivity, both single knockouts appear slightly better at reentraining:


V1A KO: insulin resistant, pretty good at reentraining

V1B KO: insulin sensitive, a little better at reentraining

V1AB KO: insulin resistant, very good at reentraining

In each of these models, superior response to jet lag correlates with poor nutrient partitioning.  Cause-effect?  Maybe it’s supposed to take a while to adjust to jet lag, and we’re doing more harm than good by expediting adaptation to circadian phase changes via blue blockers, bright light therapy, etc… or we’re just not meant to fly long distances.

Alternatively, maybe it’s not “superior response to jet lag,” but rather these mice just have a “loose” clock: they can easily adapt to circadian phase changes because they’re not strongly tied into their current circadian phase, but by the same mechanism, nutrient partitioning is impaired.  Or nutrient partitioning pays the price.

calories proper


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  • Tuck

    OK, that’s fascinating.

    How common is this Arginine vasopressin receptor 1A
    polymorphism? Do we know?

    • William Lagakos

      CC: 30.4%

      CT: 49.2%
      TT: 20.4%

  • William Lagakos

    VIP also appears to be involved in “loosening” the clock, but not in a good way…? V1AB double knockouts exhibit a strong circadian rhythm and expedited reentrainment. VIP knockouts reentrain quickly, but have disrupted basal rhythmicity.

    “VIP is thought to play a role in both the synchronization between SCN cells when the organism is in the dark and the entrainment of the SCN when the organism is exposed to a light cycle.”

  • William Lagakos

    “Jet Lag Cure for Mice Illuminates Inner Workings of Circadian Clocks… the hormone vasopressin could be key to unlocking the treatment of jet lag, says new study.”

  • rs711

    You SUMMARY section

    “V1A KO: eat same, weigh more. Insulin resistant.
    V1A polymorphism: increased risk of diabetes.
    V1B KO: increased adiposity. “Insulin hypersensitive.”
    V1AB KO: eat less, weigh more. Insulin resistant, yet seemingly impervious to circadian phase changes ->”

    reminds me of additive/threshold effects seen in mitochondrial disorders where tissue-specific energy requirements (partially) dictate the order of tissues in which we’d predict such disorders to manifest first (cardio, neuronal etc.).

    I’m assuming (correct me if not) these studies here reflect plasma (body) insulin resistance & don’t look at insulin resistance in the brain, specifically, under ‘jet lag’ conditions. I raise the “insulin-body/brain” distinction because light/dark cycles are so closely tied to foraging behavior that it seem crucial for organisms to manage rapid insulin modulation in order to appropriately adapt to new light patterns…while respecting ’tissue hierarchy’ energy demands.

    ‘Switching’ pathways has an opportunity cost in biological systems. Silly analogy: fast-forward a music track & it’ll sound bad (opportunity cost) but at least you get to where you wanted to faster (adaptation/new equilibrium).

    Per your explanation I’m getting that VIA/B et al. appear to function as ‘additive switches’ (fast-forwards) in this scenario, bringing about significant opportunity costs (increased adiposity).

    Maybe looking for tissue-specific changes in VIA/B et al. gene expression levels might tell us which tissues are prioritized. This in turn, could hint as to how our body actually goes about adapting to light patterns on a cellular level.

    Shoot me down if I make no sense.

    • William Lagakos

      this all seems very reasonable. I’d only add that “V1A/B et al. gene expression levels” may be misleading… need a good marker of vasopressin signaling, bc receptor is regulated in a tissue-specific manner; also ?receptor =/= ?signaling if ??ligand…

      also nice to know if other receptors for vasopressin, and other ligands of V1A/B…

      • rs711

        Good point [auto head-slap!]: gene expression levels aren’t of much use if we don’t known what this means in terms combined activity with receptor density (+ other variables).

  • This Old Housewife

    Maybe this is another of Hubby’s problems, but I installed the f.lux to train him to get sleepy and go to bed at a decent hour, plus I wanted to see if it helped cut down his migraines caused by glare.

    Now if I could only get him to install it at work…or not, after reading this.

    • William Lagakos

      “Now if I could only get him to install it at work…or not, after reading this.”

      I think “yes.” These findings may only be relevant, specifically, during actual jet lag. Blue blocking in general is wise after sunset.

  • Tuck

    So this sounds like a random mutation that would have been harmless (maybe beneficial) in our ancestral environment, but harmful in the modern one…

    • William Lagakos

      Interesting. The “jet lag” aspect would be irrelevant, because East-West travel wasn’t fast enough to disrupt circadian rhythms; slow travel speed = enough time to adapt; no clear benefit of improved reentrainment.

      But yeah, combining a “loose” clock with staying up late at night with blue lights blazing, working indoors all day, etc. doesn’t seem like it’d end well…

  • William Lagakos
  • Jack Kruse

    Bill the link is undeniable at this point. Let me ask you a question…… long will it take ancestral health to realize that food is not the key issue when circadian signaling is off? Do they not realize that technology is the source of this things?

  • William Lagakos

    Sleep fragmentation seen in AD patients is specifically correlated with the loss of vasopressin-expressing cells in the SCN.