Post

More from @nicknorwitz

Nick Norwitz

@nicknorwitz

Nov 23

Layne Norton @BioLayne “Cracked” 🍳… Let’s Break it Down and describe why his recent thread 🧵 is about MUCH more than eggs 🍳(links at the end)

1/8) Layne Norton recently went on a Twitter diatribe about eggs. I quote it because he’s blocked me.

🍳But why eggs, why now?🍳

Answer: Little Ol’ Me.

He’s thread was clearly targeted – referring to headlines about “some Harvard Medical Student.”

Wonder who that could be?

Again, we ask, “why?”

Well, like Layne’s thread, let’s start with a history...

2/8) Over the past couple of years, colleagues and I have been conducting research on a metabolic phenomenon – lean mass hyper-responders – and the physiology that explains it.

This research is of massive importance and has the potential to reveal the mechanistic “why” behind the diversity of lipid/cholesterol changes in the context of low-carbohydrate and ketogenic diets.

And, in so doing, this line of research may help address an obstacle to the clinical implementation of this powerful metabolic therapy for a broad range of chronic diseases: Autoimmune and inflammatory conditions, Neurological disorders, Mental health disorders, and so on.

Layne is aware of this work.

In fact, he’s engaged with us privately around the research, including our Meta-analysis of Human Randomized Controlled Trials.

And – for those who know Layne – we know how much he “loves” the “Human Randomized Controlled Trials.”

We engaged cordially with Layne, answered his questions, provided him with open data and code ht/ @AdrianSotoMota @realDaveFeldman, and gave him the benefit of the doubt that, if he covered the topic, he’d do so with a mind to platform nuance and represent the science he professes to value.

(To be clear, the below/right is from a Layne Norton clip… he’s the one who photoshopped himself onto a rocket yelling about Randomized Controlled Trials, not me.)

3/8) In the end, Layne @BioLayne decided to:

(i) Reject our invitations to have an open public discussion (on his or third party platforms)

(ii) Entirely ignore the meta-analysis of randomized trials. (Hypocritical?)

(iii) And, on top of that, screw up when representing the physiological explanations of the phenomenon described in the published literature, despite having it explained to him directly multiple times.

Then, to put salt in his own wound, (iv) he aggressively and defensively attacked and bullied well-meaning individuals for asking questions.

Read 8 tweets

Nick Norwitz

@nicknorwitz

Nov 20

🚨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.)

3/5) Although BHB-amino acids are made in humans and present in human blood, to demonstrate causality it’s helpful to use mouse models.

🚨Direct administration of a ketone supplement or BHB-Phe decreased food intake and prevented weight gain.

🚨However – and importantly – mice who had been modified to have the CNDP2 gene knocked out, and thus could not generate BHB-Phe, did not respond to ketone supplementation with appetite suppression.

To reinforce the point, ketone supplementation AND/OR a ketogenic contributed to relative weight loss in animals with functional CNDP2 that could make BHB-Phe. But when this ability to make BHB-Phe was eliminated, so too were the appetite-reducing anti-obesogenic effects of ketones.

This suggests that ketogenic interventions reduce appetite, at least in part, through the generation of BHB-Phe.

Read 5 tweets

Nick Norwitz

@nicknorwitz

Nov 19

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.

3/4) Now, are these changes functionally meaningful with respect to weight regain?

It would appear so. Human observational and clinical data suggest those who have lost weight are more prone to put weight back on.

Although, of course, in free living humans it’s hard to disentangle the effects of behavioral and constitutional (inborn) differences from those imposed from true epigenetic changes brought about by a history of obesity.

However, carefully controlled mouse experiments – which in this case should probably generalize to humans – do indeed strongly suggest that a history of obesity (red vs blue [control]) predisposes fat cells to take up sugar more readily, build up fat stores in response to insulin more quickly, and develop fatty liver more easily.

Read 4 tweets

Nick Norwitz

@nicknorwitz

Nov 9

🚨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?! ...

3/5) The explanation is the Lipid Energy Model. In a nutshell (a macadamia nutshell, in this case, which are very hard to crack):

When Lean Insulin Sensitive People go on Very Low Carb Keto Diets, LDL-C increases as part of a lipid triad of:
☝️HIGH LDL-C
☝️HIGH HDL-C
👇LOW Triglycerides
That is the result of shifting from carb burning to fat burning.

The levers that drive how high LDL increases are leanness and activity level.

Thus, when I went to my vegan keto diet, despite the drop in saturated fat and cholesterol and increase in fiber and PUFA, the restrictive (large, acute calorie drop) nature of the vegan keto diet vs the carnivore-ish keto diet drove UP my LDL.

The importance of these factors, especially leanness in determining LDL-C on low-carb diets, is documented in the literature, including our meta-analysis of 41 human RCTs cc @AdrianSotoMota @realDaveFeldman
PMID: 38237807

Read 5 tweets

Nick Norwitz

@nicknorwitz

Nov 5

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.

3/5) The researchers found a dose-dependent effect whereby less exposure to sugar during early life led to lower risk of type 2 diabetes, lower risk of hypertension, and lower risk of obesity later in life, particularly starting around age 50.

(Caption: Black is un-rationed (Sugar Babies). Green is rationed in utero. Blue is fully rationed during early life.)

When I say “dose-dependent,” in this case I mean in time, whereby there was a protective effect of not being exposure to as much sugar in utero for kids born just before the end of rationing (e.g. around New Years 1953), and an even stronger effect if the sugar ration included the first year of life because the kids were conceived one year earlier, and even stronger still if rationing included the first two years of life.

Read 5 tweets

Nick Norwitz

@nicknorwitz

Nov 4

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.

3/4) Ex. 3 Soy is Animal-Based Now?

This was my favorite!

One of the big holes in the plant-based proteins for longevity argument relates to biological plausibility.

What’s the mechanism?

In a recent study, it’s mentioned in the discussion that animal-based proteins increase IGF-1 relative to plant-based proteins, which is the suggested mechanism… but if you look and their own reference, vegetarians didn’t have lower IGF-1 and … get this … soy protein is clustered with animal proteins because the effect seems to be due to essential amino acids, not the animal/plant nature of the protein.

And if the way you want to craft a narrative around plant > animal protein requires you to call Tofu = “Meat” … well, I’m not sold.

You do you, but I remain unconvinced that tofu and legumes are the thing that will keep my kicking into the 2100s.