🚨Discovery of a New Ketone Body Metabolite that Suppresses Appetite

1/5)🧵This thread will review new data, and suggest one reason why some people might lose more weight on #ketodiet than others

The research, publish in @CellCellPress, documents the discovery of a byproduct of ketone body, beta hydroxybutyrate (BHB), metabolism: The BHB-Amino Acids.

At a high level:

👉The enzyme carnosine dipeptidase 2 (CNDP2) combines the ketone body, BHB, with amino acids to make BHB-amino acids.

👉This pathway appears conserved in mice and humans.

👉BHB-amino acids levels increase in response to ketogenic diets, fasting, or exogenous ketones.

👉BHB-amino acids activate different brain regions to reduce food intake and promote weight loss.

Now… for some more details… 2/5) Background

The enzyme, CNDP2, is primary expressed in the kidney and gut cells and was previously known as the enzyme that generated the appetite suppressing compound Lac-Phe, a combination of lactate and the amino acid, Phenylalanine, that is thought to mediate the appetite suppressing effects of #exercise the drug #metformin on weight loss.

But this CNDP2 enzyme is “multipurpose,” i.e. it not only combines lactate with amino acids but can also only combines the ketone body, BHB, with amino acids, as shown in the paper, the most prevalent of which is BHB-Phe.

The researchers show that ketogenic diets, fasting and exogenous ketones (ester) each increase levels of BHB-Phe.

(Aside: different ketogenic interventions appear to increase BHB-Phe to different degrees, i.e. the relationship between BHB and BHB-Phe levels may vary depending on 'how' ketosis is induced.)

1/4) New Research (Yesterday) in @Nature on the Memory of Your Fat Cells: “Adipose tissue retains an epigenetic memory of obesity after weight loss”

Let’s break it down…

You’re probably aware of the “yo-yo” effect, whereby people who lose excess weight are prone to gain it back.

But is this purely behavioral, or are there deeper metabolic mechanisms at play?

In this study, researchers took cell samples from human patients who were always lean versus those who had a history of obesity but who had lost weight after bariatric surgery, and measured gene expression profiles* from their fat at the time of surgery and 2 years later after substantial weight loss.

🧬They found significant changes in fat cells (adipocytes), as well as their precursors and also in other cell types, like the endothelial cells that line blood vessels.

Overall:
⚡️Fat cells from individuals with a history of obesity showed down-regulation (less expression of) genes relates to metabolic functions
🔥And up-regulation (more expression of) genes relates to inflammation functions

Thus, in the authors’ words, “These results indicate that obesity induces cellular and transcriptional (obesogenic) changes in the [fat cells], which are not resolved following significant weight loss."

Ref. Hinte et al. Nature Nov 18, 2024, doi: 10.1038/s41586-024-08165-7 2/4) To get more granular, they did a similar experiment in mice where they fattened some mice using a high-sugar high-fat obesogenic diet, and then normalized their weight through dietary restriction and compared these to mice who never had obesity.

They found, consistent with the human data, persistently gene expression changes, including downregulation of metabolic pathways, such as fatty acid oxidation, mitochondrial signaling, etc., and upregulation of inflammatory pathways.

🔧How it works🔧

I’ll explain how this works at a high level through an analogy.

Your genetic code is like a book… even though all cells in your body contain your full genetic code they are different.

Why?

Because in different cells different pages are opened or shut. This determines the fat or function of cells.

What’s more, cells can “bookmark” or dogear pages for easy access. In the cell these are “epigenetic” changes, where tags are put on to DNA or the protein complexes around which DNA is wound.

This makes it easier (or harder) to access certain pages (certain genes), changing their expression profiles.

Hopefully that makes sense?
And that’s how cells develop a “memory” of past events, including the memory “I was once an ‘obese’ fat cell.” If it’s not too dark to say, think of it like PTSD for fat cells.

🚨Vegan Diet Increased My Cholesterol!🚨

1/5) Since there is talk about Keto and #LMHR, I thought I’d give people something to talk about.

I went from:
🥩Animal-based #carnivore-ish ketogenic diet to a
🌱#Vegan keto diet

And my LDL cholesterol INCREASED! (👀Read On...) 2/5) For this N = 1 experiment, my macro breakdowns were as shown below.

As you can see, despite eating over 4X LESS saturated fat, more fiber, ZERO cholesterol (and more PUFA), my LDL-C increased by 14%.

How could this be?! ...

1/5) The hot talk of the week is this new paper in the prestigious journal Science that shows early life exposure to sugar, including including in utero and in the first years of life, can seriously and causally impact a child’s risk of developing diabetes, high blood pressure and obesity later in life.

I’ll have a long-form YouTube video produced in this shortly. But in the meantime, I thought you deserved a breakdown.

First, let me explain what’s special about this study.

Usually, to demonstrate causality for effects that take decades to manifest you can’t do a randomized trial, so you need to rely on animal data and standard observational epidemiological studies, which are riddled with confounders.

However, now and again, real-world circumstances impose a natural experiment. And, in the United Kingdom rationing of Sugar continued post-World War II era, until September 1953.

Cc @ChrisPalmerMD @hubermanlab @foundmyfitness @BenBikmanPhD @RobertLustigMD @FitFounder @DaveEDanna 2/5) And after Sugar rationing ended, sugar intake doubled almost immediately – and selectively, with intake of other food stuffs like fats, produce and proteins remaining rather constant.

This presents a natural quasi-experiment, because what you can do is follow cohorts of children – 60,183 children in this study – through their life course, comparing those born just before rationing ended – these are the “rationed babies” – to those conceived and born just after rationing ended – these are the “un-rationed babies” or “sugar babies,” because they were exposed to sugar.

That’s exactly what they did in this study.

And it’s a cool design because it takes advantage of a historical event to control for variables through a sort of ‘randomization’ in time, in a way that would be impossible to control for otherwise.

3 SAD and Hilarious Anti- “Animal Based Diet” Studies
🥩🥓🥜🍝

1/4) On request, I just posted a video interrogating the claim that plant-based proteins are better for longevity than animal-based proteins. In thevideo (link at the end), we’ll delve into the nuances. For X, here are three examples of how the methods, data and literature can be misleading...

Ex 1. The “Beef” Diet

This “beef” diet included a breakfast of English muffin with peanut butter and an apple, low fat milk and spaghetti and salad with Italian dressing with lunch, bread rolls, peanuts and beans and fruit with dinner, and chips, hummus and almonds as a snack 2/4) Ex. 2 Lasagna = Steak?

Not much new here, other than to point out studies that use Food Frequency Questionnaires often cluster foods inappropriately.

Here, for example, “meats” can be delivered as a steak or slab of lasagna. They’re the same to the survey, and this isn’t immediately apparent until you do some digging… in this case back to a form from 11 years before I was born.

🔑How Ketosis Really Works!🔥

1/4) This is cool! New Science in @Nature Explains HOW the body triggers ketosis.

AND, I'm going to tell you how I get my ketone levels to the equivalent of a 6 day fast in < 1 day.

⚠️BUT - be warned ⚠️ I will shock you with some SEED OIL talk... & it's not what you expect.

Listen up...

Specifically, these data reveal how fatty acids change the body's metabolism to boost ketone levels and fat burning... pay attention...
#Ketosis #FattyAcids #Metabolism #eIF4E #AMPK #Fasting #KetoScience #MetabolicHealth #CancerResearch 2/4) A new study in @Nature recently characterized the role of a key protein, eIF4E, in the feeding-fasting metabolic transition.

👉What is eIF4E?

eIF4E is already a known player in the “central dogma” of molecular biology, where your DNA 🧬is transcribed into messenger RNA, which are then translated into proteins. Then, the proteins do the work in the body.

The efficiency of these steps determines the overall balance of the >100,000 proteins in the body, and across tissues and organs and overtime. And eIF4E influences the efficiency of translation of specific proteins... thus, eIF4E is a key node in your body’s metabolic network.

👉The Pathway: Fats as Signaling Molecules

Fasting or a ketogenic diet causes a rise in the fatty acids circulating around in the blood go to the liver where they activate an enzyme called AMPK.

Yes, fatty acids can bind directly to AMPK like hormones in their own right. AMPK then acts on a protein called MNK which acts on eIF4E.

If this went over your head a bit, don’t fret.

The punch line is that fatty acids, which are the primary fuel when you’re fasting on keto, are not just fuel but signaling molecules that can bind to pockets on enzymes, setting in motion a cascade of events leading to the change in proteins that “adapts” the body to fat burning mode.🔥

👉In the authors’ words, “Our findings reveal a new signaling property of fatty acids” which are released during fasting or on ketogenic diets.

The 720 Egg Stunt Worked. But it was never about Eggs or Cholesterol...

1/7) 🧵As a PhD scientist, active clinical researcher, MD student, and ex-chronic disease sufferer with a passion for metabolic health & scientific communication, I appreciate the complex social dynamics that challenge the progress of metabolic health science & prevent the cultural shifts we need to see if we are going to turn the tide of the metabolic disease epidemics. I believe N = 1 and citizen science is the future. Let's break down WHY 2/7) Traditional research and medicine emphasizes a one-size-fits-all model. “What is lost is specificity and individuality.”

This issue is particularly evident in metabolic health.

“N=1 is the future” - Michael Snyder, leading genetics professor at @Stanford Medicine

Instead of drawing conclusions from large groups, N=1 studies focus on the individual, allowing people to directly test how specific interventions affect their unique health profiles."

🥓I Ate 600 Strips of Bacon 🥓
🫀Here’s What Happened to My Cholesterol🫀

1/4) In an N =1 experiment modeled on the #720Eggs Eggperiment, I dropped my LDL by 22% while eating 600 strips of bacon over 20 days.

That’s 21,000 Calories from bacon while eating ~300 grams of fat per day, and buckets of saturated fat, and I was able to drop my cholesterol.

Here’s what you need to know… 2/4) LDL cholesterol can rise and fall for a variety of reasons. And knowing the reason really matters!

🚫By analogy, just like all BMIs of 30 kg/m2 are not the same (you could be overfat or The Rock), not all high cholesterols are the same.

💪And it’s common for lean, fit, insulin-sensitive people on low-carb to see increases in LDL cholesterol likely because of an adaptive shift in metabolic state from carb burning to fat burning explained by the Lipid Energy Model (references at the end)

🏆And when we pit the Lipid Energy Model against conventional models, the Lipid Energy Model wins the day again and again

#LEM @realDaveFeldman @AdrianSotoMota

1/5) In the Metabolic Health Army, is there Space for Sweets?

🤔A "Case Study" on Brownies! 🍫🧈

🏆Opportunity to "win" a prize (3 winners) for a loved one, if you read to the end and Quote RT thoughtfully 👇

I’m not a sweets guy… anymore. But before I adopted a #ketodiet for treatment of my IBD, I LOVED 💕sweets, especially brownies! And if, pre-keto, you’d told me I needed to give up Brownies for life, I would have tossed marmite in your face!

So, I get that some people feel sweet treats will enhance their life and aren’t ready to give them up. That’s not a judgement, it’s pragmatism.

Consider this: Even if you don’t “do” sweet, do you have a loved one who you wish would take a step towards reducing sugar in their diet?

💔Don’t you want a “foot in the door” for their metabolic health?

I know I have many people like this in my life… which is why I’m a fan of tools -- like the “brownie” I’m going to use as a case study -- that can act like “lifestyle transformation springboards” …

… NOT because I need them myself at this stage of my journey, but because I know people who can and do use these to start/maintain their personal metabolic health journey.

But if you’ve been following me, you know I don’t do empty sales pitches.

I like providing people options and tools, but all I want to buy with my words is your curiosity. #StayCurious

In this thread, I promise:

👉 To Use Brownies as hook to speak to interesting metabolism and physiology

👉 To Emphasize my “why”: why I think there is room for brownies in the ammunition pack of our metabolic health army.

👉 To offer you a tool, either for yourself or a loved one, to consider, and opportunity to win a tool for them.

Let’s start with some DATA and SCIENCE…

cc colleagues @DominicDAgosti2 @BenBikmanPhD @AKoutnik 2/5) “Other” Sweeteners

When it comes to low-carb desserts, the first question that comes to my mind is:

🍩What’s the sweetener?

Sweeteners are a heterogenous group of molecules, and the research on them is fascinating.

Here are two astonishing facts about common artificial sweeteners: Sucralose and Aspartame.

🍩Sucralose has been shown, in human randomized controlled trials, do induce insulin resistance and changes in dopamine activity in the brain when consumed even at low-moderate doses in the context of a mixed macronutrient diet.

The effects are quite profound. So profound, in fact, one sub-study in teenagers needed to be prematurely terminated because of the massive jump in HOMA-IR that occurred with sucralose intake, again when consumed with carbohydrates – as in many common foodstuffs like ‘lower sugar’ yogurts (Cell Metabolism, 2020; PMID: 32130881).



🍩Aspartame is another problem child in the metabolism story.

One of the most fascinating studies, to me, on aspartame showed that aspartame dosed at the mouse equivalent of 2-4 Diet Coke per day not only caused an anxiety phenotype in the mice but also led to trans-generational inherence of this anxiety phenotype for up to 2 generations – even when the children and grandchildren of the mice hadn’t been exposed to aspartame themselves (PNAS, 2022; PMID: 36459641).

🧬There are human data on aspartame and anxiety, irritability and mood changes as well. But I think the ‘transgenerational anxiety’ phenomenon is particularly thought provoking. Not only does it give one pause to think about the metabolic consequences of some “considered safe” ingredients, but it does so framed by the reality that these are data we will never have for humans.

So, we must each ask, what is our risk tolerance and what are we risking when we drink that Diet Coke?

🥩Steaking a Claim: Is Haem Iron the Hidden Culprit in Diabetes?

🧵1/5) A new study asserts “Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk.”

It concludes, “These findings have important public health implications in shaping guidelines to prevent diabetes by limiting the daily consumption of foods rich in haem iron, particularly red meat.”

Methods
The primary analysis was conducted on 204,615 participants from the Nurses’ Health Study (NHS), Nurses’ Health Study II (NHS2) and the Health Professionals Follow-up Study (HPFS).

The researchers quantified associations between total, haem, and non-haem iron and T2D risk & between iron intake and established metabolic biomarkers.

High-level Questions to Consider
👉 Are there confounders? What are they?

👉 What are the metabolic associations and how can we use these to filter these data for relevance at the individual level?

👉 Is the AI cover image for this 🧵 fun or garish? 😂 2/5) Basic Confounders

Participants with greater haem iron intake were generally less physically active, more likely to smoke and had at least trending higher BMI.

Furthermore, haem iron intake was positively correlated with a Western style-diet, which includes more “sweets and desserts, french fries, and refined grains,” here quoting from reference 31 where Western diet score is characterized.

To their credit, the authors of the current paper note that the association between dietary patterns and T2D risk could “also be partly due to… high added sugar in the Western diet…” seems plausible...

1/4) This Thread proceed in 3 Parts:

i) A History
ii) A Social Analysis
iii) A Challenge and Opportunity for @BioLayne to help himself

It will have an unavoidable aura of (mindful) “Functional Drama,” i.e. I will present accusations and accountability statements. They will not be vague, but specific – with examples.

Furthermore, I’ll lead my 3 rules for “Fighting” 🥊

i) It Must Add Value, e.g. correcting misinformation or holding bullies to account

ii) Efforts at Bridge Building Failed.

iii) I Must be Ready for Relationship Repair, turning “Foe to Friend,” provided the other party is willing to meet me with authenticity and good will…

Note: This is a clip a video that May or May Not be released. That will depend on Layne Norton @BioLayne (he’s blocked me, so someone may want to notify him).

And to @hubermanlab. I apologize for bringing drama to your doorstep. If you decide to review the contents of this thread, I think you'll find it purposeful. As I know you to be a man of integrity with a devotion to open dialogue, I think you will appreciate it far more that you would be off-put by it. 2/4) The History.

Layne’s considers himself a “BS Crusher” (in bio) and prides himself on being evidence based. He’s an aggressor. That’s no secret and – honestly – it’s worked for him from a marketing perspective.

No shade. There’s pragmatism there.

However, he often fails to hold himself to a high standard of evidence and reason. And, when he missteps on the data or physiology, he has a pattern of failing to correct the record.

I did promise specifics:

>> In his review of our work, @BioLayne selectively ignores RCT-level evidence. Given the degree to which he professes to love “THE HUMAN RANDOMIZED CONTROLLED TRIAL" I found this 'odd.' This was despite being aware of this work, consuming my time and that of colleagues @AdrianSotoMota @realDaveFeldman @Lipoprotein asking question about our meta-analysis of RCTs, and being given ample opportunity to engage in a public dialogue on the matter on his platform or hosted by a third party.

>> In his review of our work, Layne also misrepresents the physiology. He claims certain data refute the Lipid Energy Model #LEM, where they are consistent with the model. Moreover, this was clarified to him in peer-reviewed text and direct messages prior to his coverage. (

>> When these and other elements of error and hypocrisy were raised by well-meaning third parties, Layne was defensive. Rather than engage on an intellectual level, he tossed around vulgarities, like “Sit down, you’re a fucking eye doctor. Sit down”

There are more examples of his pattern of defensive posturing and frank bullying in the full video linked at the end.

And, for those who haven’t caught on yet, I have a 0-tolerance policy for bullying. ZERO TOLERANCE.

>> Layne failure to correct the record when he’s made errors is a pattern. Recently, @theProof corrected Layne on his analysis of a Protein study. Layne hasn’t defended himself, nor clarified the matter to his large following. He has simply ghosted the (polite and fair) correction.

The below is a short clip from a prior response video to Layne. Forgive the stethoscope… I was in a shirt lunch break at the hospital. Again, links at the end.

1/6) Do you want to learn to address the root cause of metabolic syndrome and insulin-resistance disorders?

Of course you do! (links at the end)

🤯And these New Data will Blow your Mind! 🤯

Background
First, for some relevant background: You’ve certainly heard of Ozempic and related obesity medications in the GLP-1 agonist class. This means these drugs mimic a natural hormone (GLP-1) produced by cells in the intestines.

What you may not know is that metabolic syndrome and insulin-resistance disorders, including obesity, diabetes, etc. are associated with a deficiency in natural GLP-1.

So – high-level – “replacing” what’s missing makes sense. BUT, we should also ask “WHY?”

THE QUESTION: Why is there a GLP-1 deficiency in insulin-resistance disorders? 2/6) There have been some hand-wavy answers for a time, e.g. that ‘inflammation’ damages the cells that make GLP-1 in the gut, or that specific inflammatory immune cells “mop up” GLP-1.

But these new data get more specific, more targeted, and provide inroads for practical innovation.

Too Cool for Stool! 🧵A Nerdy💩 Thread🧵

1/6) While multiple lines of evidence support a “metabolic advantage” for #ketodiet #lowcarb diets for treatment of #obesity and weight loss, the exact mechanisms remain a mystery

New research in @NatMetabolism shows how #Ketodiets can cause POOPING OF MORE CALORIES. And, surprise (!), the mediating molecules are NOT ketones… but something else…

In this thread & associated video, I'll take about human data, animal model data proving a fascinating causal pathway, and provide practical take-aways 2/6) The causal pathways the researchers dissect in this paper is as follows:

Ketogenic diets alter the #microbiome to decrease levels of certain gut bugs (BSH-enzyme coding bacteria) that modify bile acids, leading to a rise in a subset of taurine-conjugated bile acids.

Two of these, TDCA and TUDCA, proved to be causal for weight loss & improved glucose homeostasis.

🧵1/5): Artificial Sweeteners are Sold Simply as “Sweet without the Calories.”

🤔But while your tongue may get confused, your “Gut Sense” is harder to deceive!

Brilliant work from Diego Bohorquez featured on @hubermanlab shows HOW your body Outsmarts Sweet!

In this thread (please watch vids!), I will walk you through data from a landmark paper that I found awesome – truly, a moment when I say back and went “WOW, our bodies are AMAZING!”

At the end, find the link to the @hubermanlab episode, paper, and FULL VIDEO (11.5 min) breakdown.

cc @R_Mohr @scicommedia @gutbrains 2/5) In this study, the researchers identify “neuropod cells,” which are gastrointestinal cells with nerve-like properties that can sense sweet in the intestines with specific receptors (we will get to what these are in a moment), and then transmit the signal to the brain via the Vagus nerve. (👇jump to 0:56 if you're impatient, like me)

1/9) 7 Facts About Muscle & Protein 💪

EVERYONE WILL LEARN, even @drgabriellelyon

This thread is going to ‘wade in,’ drawing inspiration from @hubermanlab w/ @drgabriellelyon + extra information, including NEW 2024 data

🚶‍♂️The First 3 Will be your Warmup
🏋️‍♀️Then the Main Set

If you genuinely learn nothing, I’ll buy you a Wagyu Steak.

If you learn at least 3 things, consider a RT of the thread or your most ‘mind-blown’ learning 2/9) #1) We Don’t Know How Much Muscle is Optimal.

At the beginning of the podcast @drgabriellelyon points out a simple but important truth: we don’t know the ideal amount of muscle for a given individual.

Certainly, there’s heterogeneity, but how do we quantify “optimal?”

Optimal for longevity (more on that in #5) Performance? What Type and What Distribution, and how do these impact the endocrine functions of muscles?

There are many unanswered questions with respect to “Muscle-Centric Medicine,” which – I think – makes the field EXCITING!

P.S. Random fact about me, and if you wanted to see what I looked like at 13... and yet I've never been able to bump my BMI above ~22 at max... little boi. Maybe @drgabriellelyon can help, lol:

1/10) 🚨NEW! #Keto for Anorexia🚨

We report on 3 patients who achieved remission from treatment-resistant anorexia using animal-based keto diet 🥩🍳

👉BMIs 10 - 13 kg/m2

👉Each gained ≥20kg

👉+Dramatic improvements in mental health

insulinresistance.org/index.php/jir/…

Read & Share🧵🙏 twitter.com/i/web/status/1… 2/10) Background 👇

Anorexia is a devastating condition that increases risk of death >5X and is associated w/ high rates of relapse

There is desperate need for more effective treatment options

1/ NEW RCT shows that Fat-Sugar mix

👉 Alters reward circuits in human brain

👉⬇️ preference for lower fat-sugar food and ⬆️ response to milkshake

👉These changes were independent of changes in body weight or metabolic health

... A thread🧵
cell.com/action/showPdf… 2/ In this study, normal-weight participants were exposed to EITHER a high-fat/high-sugar snack OR a low-fat/low-sugar snack for 8 weeks in addition to their regular diet. The snacks were to be consumed 2x per day and were isocaloric.

1/ As time has passed and positions have evolved, I’d like to do another thread 🧵 on Satiety Per Calorie (SPC) covering:

👉 Utility vs. Limitations

👉 Issues w/ messaging, “evolutionarily normal” “open-minded”

👉 And to get at sense of prevailing opinions (Poll!) 2/ First, I’d like to say I’m not against SPC as a HEURISTIC and ABSTRACT concept

Reflecting on what food nourishes and satisfies you is a good exercise, in line with mindful eating. That’s the utility!

🚨Carbohydrate insulin model “dead,” OR is it misunderstood again? 🤥

1/ Doctor Tweeted “that the carbohydrate-insulin theory is completely dead” ☠️⚰️

I recently watch the interview with that doctor, and it was surprising the degree to which s/he got the facts wrong… 2/ The CIM does posit that a high glycemic load diet drives high insulin to glucagon ratio state… as a result energy available in the bloodstream is driven downwards in the late postprandial phase leading to “hormonal, hunger” & overeating…

1/ How to poo 💩! Was listening to the new @hubermanlab with @DrGottfried this AM (at 3:37) on hormones and #constipation & was inspired to do a little thread on my top #6 tips for dealing with constipation ... hopefully this thread helps at least 1 silent sufferer 2/ This is a topic I'm interested in is bc as someone with a hx of proctitis + cecal patch (form of ulcerative colitis strongly linked to constipation), it's something I've struggled w/ at times. It's not fun & a far more prevalent problem than people realize 4 obvious reasons

1/4) “Satiety score” score suggest macadamia nuts are more likely to promote weight gain and prevent weight loss than cheesecake?! (higher = more satiety) 🧐

Macadamia = 17
Cheesecake = 19

Battered fried shrimp = 35
Apple juice = 32
Fried zucchini fritters 27

#satiety 2/4) First, lest address the science. Do macadamia nuts cause weight gain?

In a 4 week interventional trial in which people were instructed to eat 40-90 grams of macadamia there was actually a net weight loss.

Try getting those results with cheesecake…