Category Archives: Uncategorized

Protein is the last thing that will make you gain weight

A randomized 3-way crossover study indicates that high-protein feeding induces de novo lipogenesis in healthy humans (Charidemou et al., 2019)

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First it was protein will kill your kidneys and bone, then it kicked you out of ketosis or was converted straight to glucose. Now, not only does it stimulate de novo lipogenesis (DNL), but it is the amino acids themselves that are literally converted to fat.

Do the biochemical pathways exist? Sure. More so on paper because I doubt very much of the fat stored in your body literally came from protein. I can see if you increased protein enough to drive a big energy surplus, then some more dietary fat would get stored as body fat and you might see increased DNL, but even some older protein overfeeding studies show this doesn’t really happen that much*

*it’s tricky to define the magnitude of a surplus if expenditure keeps going up; with protein, the surplus on paper is usually overestimated

Which brings us to today’s study. Great study design (3-way crossover), single meal prepared & provided to the participants. Small sample size. Weird nutritional controls, although I suspect this decision was more practical than scientific. The high fat diet was very high fat and the high protein diet was… higher than control, but if I were designing this study trying to show ‘protein -> DNL -> fat,’ I’d’ve gone with more than 40g.

I don’t even care that the added protein came from soy, which is high in glutamate, similar to beef, and slightly less insulinogenic than whey.

Indeed, this study was very nuanced…


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Circadian rhythms and exercise — re-setting the clock in metabolic disease

Maybe the title isn’t as clever as “Watch the clock, not the scale” or “Clocking in, working out” but this review was pretty good (Gabriel and Zierath, 2019).

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1- I’m a big fan of activity. Walking, hiking, frequent breaks from sitting, and lifting weights are among the things I do daily (and advocate).

2- The elephant in the room (for me at least): exercise timing and the diurnal variation in human performance.

Remember back when researchers would put people on a ketogenic diet for a few days, take some measurements of physical performance, then conclude keto sucks for athletes? But then we learned about ketoadaptation and now know that 3 weeks is the minimum.

It’s happening again, but this time with exercise timing. Take two random people — athletes, old or young, male or female (it’s been tested in all of these populations) — and take some measurements of physical performance in the morning or afternoon, wait a couple days, then measure in the reverse condition.

Same thing every time: performance is greater in the afternoon.

BUT if you train a group consistently in the morning, performance in the morning improves and there’s no longer a diurnal difference. Interestingly, this doesn’t happen to a group that’s trained in the afternoon; they’ll still perform worse in the morning (eg, Chtourou and Souissi, 2012).

There are many implications, nuances, and caveats to this…

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Palmitoylethanolamide. What now?

Palmitoylethanolamide (PEA, not to be confused with phenylethylamine).

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It does all the things in mice (alleviates pain, inflammation, anxiety, etc.), but now that it is widely available in supplement form, what is the evidence in humans?

It’s specific targets are largely unknown. PPARa? Endocannabinoid system? CB1? Others?

[doesn’t look like much, does it]

A few case studies and a clinic that pushes it HERE. Most start with 300 – 600 mg once or twice a day.

Histamine intolerance?

Remember when people used to joke about marijuana for eye health? Well, that might be partially true and argues for either: 1) a common endocannabinoid target of PEA and something in marijuana; or 2) cannabis has an extensive & complicated profile of bioactive compounds and PEA has nothing to do with the cannabinoid system (Costagliola et al., 2014 & Pescosolido et al., 2011).

More studies have been published on pain & inflammation (below)

Is anyone gonna try PEA? Let me know.

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Cannabinoids and sleep

I was not looking forward to writing this, in part, due to my love-hate relationship with cannabinoids: on one hand, they show potential in many difficult-to-treat conditions; on the other hand, some psychiatric risks and this (CB receptor activation is diabetogenic).

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Further, don’t underestimate the complexity of cannabis plants and the endocannabinoid signaling system.

The cannabinoids (Babson et al., 2017):

-THC, the main psychoactive component of cannabis (also in drug form as Nabilone)

-CBD, a non-psychoactive component of cannabis

-Dronabinol, a highly purified synthetic (-)-trans-D9-THC. It’s actually 2-3x weaker than Nabilone (which is a further testament to the complexity of this system, imo).

Nabiximols (Sativex), a roughly 1:1 combination of THC & CBD.

To be clear, the main therapeutic use of cannabinoids is anti-emetic (prevents vomiting) & appetite-stimulation in some conditions (eg, cancer, HIV). The more interesting part, imo, is some of the human studies (discussed below) on people with difficult-to-treat conditions, who also sleep poorly, where any improvement in sleep quality inevitably improves their condition.

This article is specifically on sleep. I’ll do follow-ups on anxiety and maybe inflammation if you’re interested. Let me know!

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If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else

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Circadian rhythms, time-restricted feeding, and healthy aging

Circadian rhythms optimize physiology and health by temporally coordinating cellular function, tissue function, and behavior” (Manoogian & Panda, 2017).

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These rhythms dampen with age and metabolic dysfunction. Part of the age factor is caused by a natural decline in eyesight as we age and that deteriorates our ability to entrain the master clock with light.

Light/dark & feeding/fasting (and even exercise [before 4pm]) are our tools.

Even I’ll admit 2-3 meals a day with no snacking seems optimal for most people and a good pattern for optimizing protein utilization. Want to mix in some intermittent fasting? eTRF seems like the strongest contender but my interpretation of the evidence is somewhat less strict than what appears in the literature — eg, I don’t think you need a kcal % distribution of 50/30/20 or need to have dinner at 3pm. Just shifting away from a late eating pattern seems sufficient.

A lot of things started going downhill after the invention of artificial lighting — we no longer have the automatic light/dark cycle.

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Ketogenic diet: glucose, lipids, and inflammation

Glucose and lipid homeostasis and inflammation in humans following an isocaloric ketogenic diet (Rosenbaum et al., 2019)

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-Rosenbaum & Leibel come out of retirement? These scientists did some of great pioneering work on the biology of leptin in weight gain/loss.

-I don’t know how much Kevin Hall contributed to this study but he’s been working HARD lately!

4 weeks of a baseline diet (15% protein, 50% carb, 35% fat) -> no washout? -> 4 weeks of a ketogenic diet (15% protein, 5% carb, 80% fat)

Following each diet period, a ketogenic & conventional meal tolerance was done:

Diet breakdown, sample menu, and my analysis below:

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A bigger dinner decreases parasympathetic activity leading to less restorative sleep

Clunky title, I know. The study was comparing two different kcal distributions on autonomic nervous system activity and sleep (Tada et al., 2018).

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There were two conditions in this randomized crossover trial: breakfast/lunch/dinner calories either as 1:2:1 (the low-energy dinner group [LED] or 1:1:2 (the high-energy dinner group [HED]).

Then they were monitored overnight to assess autonomic nervous system activity and sleep.

What was the point of this study? The next step in the scientific method! Researchers have noticed correlations between dietary intake (meal size, not timing) and restorative/non-restorative sleep. So now they want to test if meal size directly influences sleep.

The authors extended the conclusions slightly beyond what the study was designed to test, imo. They previously noticed bigger dinners & poorer sleep during the luteal phase in women and this correlated with progesterone. But in this study they didn’t include the right controls to test that: luteal phase vs. follicular phase [and optionally, vs. men or postmenopausal women].

That said, I’m sure sex hormones definitely play a role here, it just wasn’t clearly teased out in this study.

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Breakfast: a multidisciplinary approach… eTRF in disguise :-)

I say “breakfast” to indicate the first meal of the day, shortly after waking up. Not “breaking the fast.”

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Other definitions of breakfast from this awesome paper:

  • socio-anthropologists: breakfast is the first post-nocturnal meal of the day
  • biochemists & doctors: the biodynamic aspects of a meal after prolonged resting/fasting.
  • scholars of social sciences: the first meal after a physiological break with consciousness during the need.

Besides those philosophical takes on breakfast, this article also reviews the evidence showing breakfast improves cognitive function, memory, attention span, concentration, and academic performance.

Of the cultures reviewed, meat, cheese, fruit, and wine came up a lot. Some had coffee & chocolate 🙂

It was sometimes eaten outside and finished before it got too hot (this is seasonal/geographical, of course, but interesting). And similar to our ancestors (by some accounts), it was done prior to heading out for the day.

It wasn’t really until artificial lighting came along when people started eating their main meal late at night. Side note: that is a highly interesting observation.

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The ‘biome, insomnia, circadian biology, & depression. Yes, they’re all connected.

One of the most direct ways is via metabolites secreted from the ‘biome: GABA, norepinephrine, acetylcholine, serotonin, dopamine, etc. (Jacka 2018).

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Germ-free mice (ie, no ‘biome) have all sorts of behavioral abnormalities: pronounced changes in their stress responses, brain plasticity, immune function, neurotransmitters, etc.

And most interestingly, fecal transfers from humans with depression to germ-free mice induces a depressive phenotype in the latter (Kelly et al., 2016).

Over 50% of people with irritable bowel syndrome (constipation, diarrhea, or alternating) have depression, anxiety, or sleep problems (Li et al., 2018).

In my experience, people have multiple complaints at once but with enough discussions and trial & error, we can pinpoint the lowest hanging fruit and it usually turns out to be just one of those factors controlling the rest. Get that sorted and many aspects of health improve.

For personalized health consulting services: drlagakos@gmail.com.

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Easy prospects for circadian treatment of mood disorders

Interesting review showing many ways how circadian desynchronization can lead to mood disorders and some steps to fix ’em (Huhne et al., 2018)

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Circadian arrhythmia is strongly associated with a variety of mood disorders. It is known.

The authors of this manuscript break it down into 4 potential cause-effect links:

  1. loss of synchronization to environmental 24-hour rhythms
  2. internal desynchronization among body clocks
  3. low rhythm amplitude
  4. changes in sleep architecture


And as suggested in the title, each of these factors have specific remedies.

Disruption of the sleep-wake cycle is a characteristic feature of mood disorders, one of the core symptoms that define them, and many think there’s a causal link. Regardless of that latter point, these people strongly benefit from “chronotherapies” targeting the circadian system. Some keen docs already know this and try it prior to prescribing drugs. Good on them.

It is known that shift work and seasonal changes in photoperiod can induce mood disorders in some people. There are also a number of genetic polymorphisms in core circadian genes that substantially increase the risk of certain mood disorders. Of course, there is also a bidirectional relationship such that pre-existing mood disorders may contribute to circadian disruptions, but there’s a large body of evidence (including both human & animal studies) supporting a causal relationship.

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20% off some delish stocks and broths from Kettle and Fire HERE

If you want the benefits of  ‘shrooms but don’t like eating them, Real Mushrooms makes great extracts. 10% off with coupon code LAGAKOS. I recommend Lion’s Mane for the brain and Reishi for everything else

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