Category Archives: Leptin

The carb/insulin model of obesity was tested again, and it fared better this time.

Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial (Ebbeling et al., 2018)

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This is another NuSi study designed to evaluate certain aspects of the carb/insulin model of obesity. Understanding the design of this study is critical to being able to properly evaluate the results.

Very important:


1. All food was provided, all the diets were healthy, and most people complied.

2. This was a very expensive study. They used great methods.

Study design: during the “Run-in diet,” everyone followed the same diet (C/F/P: 45%/30%/25%) at 40% caloric restriction in order to lose about 10% of their initial body weight.

Importantly, insulin sensitivity was assessed and this may have influenced what happened next, in the weight maintenance phase. I used to put a lot of weight on this theory — eg, the top 25% most insulin sensitive people will do better on low fat whereas the bottom 25% insulin sensitive people (the most insulin resistant, ie) will do better on low carb — this theory has fared better or worse depending on which study you look at. In this study, it did pretty well.



In the end, we had 38 people in the entering into the high carb arm of the weight maintenance phase and 43 on low carb.

Remember, they all lost weight on the same diet. Now they’re being fed enough to maintain body weight (low carb, moderate carb, or high carb) and we’re measuring things.

Really exciting stuff!

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calories proper




Mutual influence of sleep and circadian clocks on physiology and cognition

“The 24-hour sleep-wake cycle is one of the most prominent outputs of the circadian clock systems (Heyde et al., 2018)”

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Sleep disruption and circadian arrhythmia induce metabolic, cognitive, and immunological impairments. Is it causal? YES.



Sleep is highly conserved across the animal kingdom, since the dawn of time.

Interesting comparison: unlike hibernation or a coma, sleep is highly reversible. Lots of rebound regulation: lots of wakefulness makes you tired; lots of sleep leads to increased wakefulness.

Studies have shown improved memory performance after naps and extended sleep durations. Imo, you don’t need to go from 6 to 9.5 hours overnight, but keep that “9.5” on your radar.

Diet is easy, just eat like an adult. You can go 10 days without even eating! Try that with sleep. No, don’t try that. Most definitely incompatible with survival. Sleep deprivation impairs cognitive functions.

As a marker of health: cognitive function >>> how many reps you can do at the gym.

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It STARTS with Sleep.


What or When to Eat

Artificial light at night, crappy sleep, and skipping breakfast are major contributors to poor circadian rhythms.  Some bro’s insist WHAT you eat is infinitely more important than WHEN you eat.  I beg to differ, at least in part – nix the refined & processed foods and it doesn’t really matter if you prefer low fat or low carb (P<0.05).  Evidence: Hunger-free diet(s).


Exhibit A.  On the other hand, feed two people identical diets but induce circadian disruption in one and whammo – big difference in outcome.



Significantly less fat loss and more muscle loss in the circadian disrupted group.

Interindividual variability? Yes.  Statistical significance? YES.


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HANGRY! (part deux)

Effects of diet composition on postprandial energy availability during weight loss maintenance (Walsh et al., 2013)

Now, we’re getting somewhere!

3 diets (carbs 10%, 40% or 60%; protein was higher in the lowest carb group). Four weeks. CROSSOVER.

Then a test meal which approximated the diet assignment. Total “energy availability” in the blood was approximated by measuring the calories in blood glucose, free fatty acids, and ketones.


energy availability and metabolic rate

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Circadian rhythms and prostate cancer


Incidence of prostate cancer is higher among pilots, flight attendants, and rotating shift workers than the general population (RR as high as 3.0 in some cases!).

Circadian rhythms of androgens is absent & clock genes are disrupted in prostate cancer; the latter of which is reversible with melatonin which also suppresses prostate cancer progression.

Interestingly, radiation treatment is significantly more effective before 5pm than after.  I don’t know why this is; could be a spurious correlation.  Or not.


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Gypped by GIP

Dr. Johnson’s recent paper is nothing short of a monster.  They did a TON of experiments.  Here, I only want to focus on one aspect.

The insulin-obesity hypothesis in a nutshell (very oversimplified): more insulin = more fat mass and vice versa.

I know I know, it was mice fed standard rodent chow, but also included models relevant to human biology like reduced insulin and caloric restriction, which may reflect certain aspects of ketogenic diets and intermittent fasting… and some of the results actually do reflect what happens to humans.  Some.


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LIGHT timing for circadian entrainment

Basically, this much is pretty obvious now: LIGHT and food in the morning + darkness after sunset = proper circadian entrainment.  But the how is pretty cool; LIGHT affects different biochemical pathways at different times of the day, which is how it can either advance or delay your circadian phase.

LIGHT entering the eyes is perceived by ipRGCs which then dish out glutamate and PACAP.  These mediators go on to activate receptors in the SCN (the “Master Clock”).

Depending on the time of day, glutamate and PACAP affect different pathways.


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Insulin resistance and obesity

Some people believe insulin resistance (IR) causes obesity, and they are not pleased when I say this is actually a controversial topic in the field…

“Bill isn’t toeing the company line.  Again.”

So I asked a simple question: if IR causes obesity, how?



The Common Response: 1) IR -> 2) hyperinsulinemia -> 3) more insulin = more fat mass.

However, this is flawed.

Easiest rebuttal (somewhat of a strawman, but whatevs): Barbara Corkey and her group has done a lot of work showing that insulin hypersecretion (caused by dietary additives, preservatives, weird chemicals, etc.) may actually precede & causes IR… not enough insulin hypersecretion to induce hypoglycemia, just enough to induce IR.

So that basically breaks the 1st step in the Common Response, but doesn’t really disprove the possibility that IR still causes obesity (or can cause obesity).

In any case, check out Corkey’s 2011 Banting Lecture.  Highly recommended, a lot of food for thought.


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Dopamine and breakfast

T.S. Wiley wrote a lot about the protein-rich breakfast; here’s my understanding of her take on it.

N.B. I highly recommend her book, Lights out: sleep, sugar, and survival.

Quotes are mainly taken from the text. I’ve tracked down some of the cites; the rest are in the back of the book, albeit somewhat unorganized :/

Part 1. We naturally have a cortisol spike first thing in the morning, known as the Cortisol Awakening Response (CAR).  This peak, which can be screwed up by artificial light at night or a big evening dinner, helps support morning light-induced dopamine.


Dopamine is great, but may induce impulsivity if it’s unfettered.

Enter: the protein-rich breakfast. It provides tryptophan and a bit of insulin to promote serotonin synthesis (eg, Manjarrez-Gutierrez et al., 1999).

Not enough serotonin to make you crazy, just enough to balance the dopamine = impulse control.

~ circadian balance achieved ~

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Vasopressin’ me again

I’ve been following the links between blood pressure modulatory hormones and circadian rhythms for a while now — and while it’s a fascinating overall picture, this nut hasn’t been cracked [yet].  A paper published in Science may have brought us one step closer.  (And some potential biohacks.)

Background reading (probably important, because my thoughts on this aren’t very coherent [yet]):

LIGHT, Leptin, and Environmental Mismatch (skip down to Part 2)

Circadian phase delays and metabolism

Circadian biology: jet lag, mood, & potential role of BP regulatory peptides


The new study: Changes in the composition of brain interstitial ions control the sleep-wake cycle (Ding et al., 2016)

It was a study on mouse brain, but the #context is very relevant here.

Tl;dr: they showed that changes in extracellular ions, independent from neuronal activity, can induce sleep or wakefulness.  “Independent from neuronal activity” was accomplished by silencing the neurons with tetrodotoxin.




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