How Your Brain is Weighing You Down

Chapters
0:00 – Intro, Leptin Basics
1:56 – Mechanism of Leptin Resistance
3:46 – HDAC6 inhibitor treatment
4:30 – Whoops! Molecular Mystery!?

#neuroscience #obesitymedicine #brainhealth

Like my shirt? Many more designs here, thanks to my friend Andrew D.

[gerrywaneck]

I'm a 75 y.o. retired research professor of medicine. I have a saying taught to my trainees, "Science moves forward not through experiments that work, but by troubleshooting those that don't." Similar to your dad's saying. "Not working" means "unexpected results." Happened to me more than once, and generated two NIH grants.

[DrJonesDC]

Have you done your follow up video on a update to your journey towards better understanding? I’m super excited to see it!

[alexfox]

Super cool of you, to not just overload us with whole bunch of information like the rest of the internet does but instead try to foster some curiosity

[LVArturs]

I'm not sold on keto over Mediterranean, nor do I feel particularly excited about being proven wrong. But the depth of knowledge, strict adherence to scientific principles and good-willed fact checking definitely make this channel worth subscribing to and the videos worth watching.

[docgl]

Oh oh, Mark Twain quote: "It ain't what you don't know that gets you into trouble. It's what you know for sure that just ain't so".

[johntatman]

"Profoundly confused" that's great I love it. It's funny in life when you think you have something figured out and it all falls apart. It's exciting and perplexing at the same time.

[Jonura]

Besides this, leptin has been found in the joints of leptin-resistant patients. Its true that leptin is a hormone primarily produced by adipose tissue, known for regulating appetite and metabolism. But aditionally, its role extends beyond these functions, impacting various tissues and systems, including the joints.
In leptin-resistant individuals, the body's response to leptin is impaired, often leading to elevated levels of this hormone. These elevated leptin levels are also present in the synovial fluid and tissue of the joints, where they contribute to inflammation and cartilage degradation. This association suggests that leptin resistance could increase the risk or severity of joint diseases like osteoarthritis, highlighting the complex interplay between metabolic health and joint health.

[Heatherleianne]

Thanks for the great analysis. I’m an LMHR, keto for over a year. The list of health issues that keto resolved is too long to list. It’s so interesting how keto just turns off that feeling of hunger that eating carbs creates. I think it’s the BHB that inhibits hunger? I love your channel and your content! Keep it up!

[homomorphic]

In software engineering, when trying to solve a complex bug, I always look to test all my assumptions about what should happen with various inputs and this process always plays out as a lot of uneventful confirmations of assumptions and then one invalidation of an assumption and every time that invalidated assumption is what leads directly to identification of the defect.

Biochemical systems are just very complex software problems; in fact biochemistry is just different hardware for implementation of software.

[tnthomas]

You’re the best. As a 70-year-old retired patent attorney, I sometimes think that I should learn more about nutrition science so that I can better evaluate the arguments and implications. Then reality sinks in.

[SortaPredictable]

I know this is a late comment, but, I imagine from an evolutionary context, inhibition of HDAC-6 in ketosis would potentially be detrimental for survival of any animal. For example, if you don't know where your next meal is coming from, the cycle of ketosis inhibiting HDAC-6 would make it difficult to "overeat" (in the modern perspective) when food is available. This would result in a cycle where if such a pathway were possible, it would be quickly selected out of the gene pool. Obviously, evolution doesn't necessarily reward those with the best metabolism or brain function, it simply rewards biological configurations which survive.

[verticalhorizon]

It makes sense that HDAC6 remains high on a ketogenic diet. Ketones are normally produced during a fasting state – which should induce you to increase your food intake.

[Adrian-yqhg]

I suspect it's because humans were frequently in fasted states as hunter gathers, and we know ketones sky-rocket when you fast, more so than when consuming a ketogenic diet. So if ketones inhibited HDAC 6 then we would expend too much energy and also not have a strong urge to eat. Which would reduce our survivability in certain environments where food is scarce. So I think nature decoupled this betahydroybutyrate /HDAC 6 interaction to improve fasting survivability

[OvahZealous]

First, Andrew Huberman today now you. Leptin must be the topic of the day.

[northerncowboy]

HDAC6 inhibits leptin sensitivity. So, inhibit the inhibitor. What else will inhibiting HDAC6 do in the body? Why is HDAC6 as active as it is? What is the mechanism behind HDAC "overworking?" Maybe being in ketosis doesn't impact HDAC6 *directly* but impacts whatever is at the root of whyHDAC6 is overactive?

[petermadany]

I really appreciate the latter part of this episode.

[mikeward]

I agree. However, it kinda makes sense (hypothesis) that HDAC6 is not inhibited by BHOB, but instead resensitizes the leptin overload! Just imagine when ketones are highest (long fasts). Evolutionarily (channelling Bret Weinstein here), you do not want to inhibit eating behaviors while you are starving.

[EmblazNOR]

Great video and thanks for sparking such an interesting discussion.

Ketogenic diets influence several metabolic pathways beyond just increasing ketone levels. Keto can alter insulin sensitivity, reduce inflammation, and change the expression of genes related to metabolism and fat storage, which could collectively contribute to improved leptin sensitivity.

Ketogenic diets also alter the gut microbiome, which can influence metabolic health and inflammation levels.

Proposed Mechanisms:

Insulin Sensitivity: Improved insulin sensitivity reduces the negative impact of insulin resistance on leptin signaling.
Inflammation: Reduced inflammation alleviates disruptions in leptin receptor function.
Fat Oxidation: Increased fat oxidation and energy expenditure enhance overall metabolic health, improving leptin sensitivity.
Behavioral Changes: Reduced caloric intake and weight loss improve leptin dynamics and sensitivity.

Patently waiting for your thoughts!

Stay curious,
Chris

[steventurner]

I believe that not allowing b hydroxybutyrate from inhibiting HDAC6 is a protective mechanism, Say for instance that b hydroxybutyrate did inhibit HDAC 6 and allowed the up regulation of Leptin, well during times of Ketosis the body would burn body fat for fuel but due to b hydroxybutyrate inhibiting HDAC6 the body would be flooded with Leptin so you would not want to eat so you would not go out to find new sources of food. The body would carry on breaking down fat until all that was left was protein and them the body will start to break that down, it makes no sense from an involution standpoint for the body to continually stopping the body not wanting to eat

[MC]

Leptin is really fascinating to me as well.
Initially, i was presented with the idea that high leptin levels in obese patients indicate that this person developed leptin resistance, and this in turn would "prove" that this person experiences a lot of hunger and consumes too much food. Even tho high leptin in itself should do the opposite and actually make a person less hungry (unless resistance develops)
However, interestingly if you reverse the question "what about very lean people ?" you ll find that actually they too have very high leptin levels. Its observed in recovering anorexic patients, who do have low leptin levels while on starvation but upon re-feeding their leptin increases to a point where they constantly under-eat and yet feel full.

So what i wonder is, what is with people who constantly struggle with weight and go on diets? Do they have a resistance to leptin by purposefully ignoring their hunger cues?
Because if adipose tissue creates leptin, and leptin resistance can be developed, then it seems also plausible to assume if one has adipose tissue but ignores hunger cues, the body would produce more leptin to signal hunger and get "noticed"?

I find this worth noting because of course its tempting to conclude that high leptin levels equate overeating, but because a body will try to perseve homeostasis its worth wondering if the diets and other restrictive behaviours screwed with the leptin pathways (which are still not fully understood i take). For example ignoring hunger, and hence creating leptin resistance.
I feel that given the medical importance of eating disorders and obesity, too many doctors do look at leptin as a parameter, yet dont really know how to logically conclude from it. Yet alone properly understand all the pathways involved to treat ideally.