Share this page!

Enter URL or ID to Unroll

You can paste full URL like: https://x.com/threadreaderapp/status/1644127596119195649
or just the ID like: 1644127596119195649

How to get URL link on X (Twitter) App

  1. On the Twitter thread, click on or icon on the bottom
  2. Click again on or Share Via icon
  3. Click on Copy Link to Tweet
  4. Paste it above and click "Unroll Thread"!
  5. More info at Twitter Help
Nick Norwitz MD PhD Profile picture
@nicknorwitz
Jul 6, 2021 • 10 tweets • 4 min read • Read on X
The #ketone body, acetoacetate (AcAc) regulates lipid metabolism through receptor GPR43
pnas.org/content/116/47…

Cool study .@DaveKeto and I were discussing...

AcAc binds to the GPR43/FFAR2 receptor to promote Lipoprotein Lipase activity and help burn fat.

Some more details...
2/ Short-chain fatty acids (SCFAs) in the gut r known to modulate energy homeostatis. Butyrate, acetate, proprionate all have recptors. The acetate receptor is GPR43.

The ketone BhB is all well studied as a signaling molecule, and binds HCAR2 etc., but AcAc is less well studied.
3/ This paper provides good evidence that, during fasting and ketogenic conditions, its AcAc that helps promote fat burning (lypolysis) throughout the body (except in the gut, more on that in a bit). Again, AcAc binds GPR43 and promotes Lipoprotein lipase (LPL activity)...
4/ The researchers were able to demonstrate this phenomenon using mice that didn't express GPR43, this lead to decreased LPL in their fat cells, elevated Trig levels, decrease energy expenditure, and less weight loss... ImageImage
5/ Interestingly, they also found that the AcAc-->GRP43 --> LPL signaling axis, while increasing LPL expression, decreased ANGPLT4 expression - with ANGPLT4 being a protein that inhibits LPL activity. The reason I mean to highlight this is...
6/ ... is loss of function in LPL and gain of function in ANGPLT4 are each linked to decreased turnover of Trig-rich lipoproteins that are now the subject of scrutinity in terms of development of CVD....
nature.com/articles/s4158…
7/ They also observed GPR43 signaling was important to regulate energy homeostasisunder ketogenic conditions. GPR43-/- mice actually gained weight (body fat) when fed a ketogenic diet... Image
8/ But while fasting and #keto increase AcAc to increase GPR43-mediated LPL activity in fat cells around the body, fasting also decreases acetate production in the gut (of course, because you're not eating). In the gut, acetate remains the main GPR43 ligand. Therefore...
9/ The AcAc / acetate-->GPR43-->LPL axis actualy helps w the choreography of energy homeostasis when fasting

Fat burning is upregulated around the body to supply energy, while LPL activity is decreased in gut to prevent wasting energy on the digetive track

Pretty logical to me
10/ I just thought this was a cool one because we don't often talk about acetoacetate signaling. Also LPL dysfunction may be a common feature in metabolic diseases leading to lipid abnormalities. See where I'm going with this train of thought...
Cool stuff :).

• • •

Missing some Tweet in this thread? You can try to force a refresh
　

Keep Current with Nick Norwitz MD PhD

Nick Norwitz MD PhD Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!

PDF

Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @nicknorwitz

Nick Norwitz MD PhD Profile picture
Dec 19
How a $1 Trillion Drug Got it Wrong

1/6) Today’s video on statins (linked below) dives into several key studies you need to understand, along with some provocative demonstrations that will definitely stick in your brain.

But in this short thread, let’s quickly review a few major takeaways...
2/6) Take Away 1: Across the board—whether you're looking at the 4S trial or more recent datasets involving cardiac imaging—a consistent pattern emerges:

People with good metabolic health and/or a zero-calcium score may see minimal benefit from statin therapy or LDL reduction.

Now, of course, there are nuances.

But broadly speaking, if your coronary artery calcium (CAC) score is zero, there's little to no reduction in cardiovascular events from lowering LDL.Image
3/6) And even if there is a tiny marginal benefit on subclinical progression at a population level (being generous)... does it outweigh the risks?
Statins are often treated as benign. They are not.

Side effects include—and go beyond—muscle pain:
↑ Insulin resistance
↓ GLP-1 levels (Shown, Atorvastatin vs Control)
↑ Risk of diabetes
Potential long-term muscle loss
Variable brain effects

This isn’t to say statins don’t have a place. It’s to say: the risk-benefit analysis must include actual risks.Image
Image
Read 6 tweets
Nick Norwitz MD PhD Profile picture
Dec 15
Have High Lp(a)? You Need to See Today's Video covering a new 2025 study on Lp(a) and waist-to-hip ratio

1/5) Here's a quick breakdown...

The goal of this new study was to determine whether a measure of adiposity—waist-to-hip ratio—modifies the relationship between Lp(a) and cardiovascular disease risk.Image
2/5) To explore this, researchers analyzed data from 4,652 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), following them over a median of 17.4 years.

The study stratified individuals based on Lp(a) levels defined as >50 mg/dL and investigated how this risk interacted with waist-to-hip ratio as a marker of central adiposity and visceral fat

*Lp(a) (nmol/L) = Lp(a) (mg/dL) x 2.15Image
3/5) And—remarkably—in individuals with a ↓ waist-to-hip ratio, Lp(a) levels were not significantly associated with increased cardiovascular risk…

Full video: Image
Read 5 tweets
Nick Norwitz MD PhD Profile picture
Dec 13
New Study: Person Study Finds Statin Use Associated Decline in Muscle Mass

1/6) A colleague of mine—a medical doctor—texted me recently: “I’m stopping my statin.”

The new paper referenced concludes: “Continuous statin use is associated with a decline in muscle function and mass over time (25% decline in grip strength and 73% decline in appendicular lean mass compared to never-­ users).”

Let’s discuss. (links in 5/6 and 6/6)Image
2/6) We’ll break this up by discussing the cross-sectional (single time point) and longitudinal (over time) results.

Cross-sectional analysis: In the fully adjusted model, adjusting for age, sex, education, smoking, BMI, activity score, diet quality score, high blood pressure, diabetes, and so on, statin use was associated with lower grip strength and lower appendicular lean mass.
3/6) Longitudinal Analysis: Statin Use Associated with Steeper Muscle Decline

Echoing the prior analysis, continuous statin use was significantly associated with accelerated declining grip strength and lean mass.

*Nuance note: For those with keen eyes, we discuss the y-intercept in the full letter

TL;DR: Statins use is linked to fasting muscular decline.Image
Read 6 tweets
Nick Norwitz MD PhD Profile picture
Dec 11
Sardines Accidentally Supercharged my Metabolism?(link in 8/8)

1/8) Now, I want to follow-up on one of the strangest findings from the Sardine Diet Experiment...

I became cold-resistant.

Taking off my shirt on an icy Boston winter day felt almost like a cool, soothing summer breeze.

It felt weird. It was unexpected. But it also makes sense... Let's discuss...Image
2/8) As a quick recap, I recently did a self-experiment that can be summarized in just two words: Sardine Diet. After a couple weeks on this extremely high omega-3 diet, I became conspicuously cold-resistant.

This was weird.

And I wanted to understand what might be happening. So, I dug into the literature.Image
3/8) Here's what could be happening...

Metabolically active brown fat can convert omega-3 fatty acids into a hormone called 12-HEPE.

12-HEPE stimulates thermogenesis in brown fat and ramps up glucose uptake into muscle as well.

This ultimately promotes heat production, cold adaptation, and energy expenditure.

Now, let’s get into some data…Image
Read 8 tweets
Nick Norwitz MD PhD Profile picture
Dec 9
The Best form of Omega-3 Matters (🔗 in 8/8)

(1/8) Alzheimer’s disease is personal for me. In my early 20s, I discovered I carry the ApoE4/4 genotype—placing me at the highest genetic risk. I was terrified. But over time, that fear shifted to a realization:
👉A genetic predisposition is a vulnerability, not a destiny.
👉 Our choices shape our health trajectory more than our genes ever could.

Today, I want to share a piece of that puzzle: The Omega-3 Paradox.

👉The Signal: Data clearly shows eating fatty fish lowers Alzheimer’s rates and boosts cognitive longevity.
👉The Failure: Yet, large clinical trials using Omega-3 supplements often fail to protect the brain.
👉The Question: Why?

One answer lies in a specific delivery mechanism most people—and many researchers—overlook.

Here is the science of getting Omega-3s into the brain. 🧵👇Image
(2/8) So, why do supplements often miss the mark? The answer is likely the form in which the Omega-3s are packaged.

When you eat seafood, you ingest Omega-3s in diverse forms, including phospholipids. However, most supplements on the shelf provide them in other forms, like triglycerides.

The Form Matters…Image
(3/8) The Form of Omega-3 Matters.

Think of it like this: Consuming DHA as a free fatty acid triglyceride is like mailing a letter with no address. It enters your system, but it doesn't know where to go. It rarely reaches the brain.

But if you have phospholipid-bound DHA? That’s like sending a letter via express courier, straight to the correct neuron. More specifically, the “express courier” form is called Lyso-DHA.

This specific form has special access to the brain through a transporter called MFSD2A.

Without the phospholipid "address," the DHA gets lost in transit.Image
Read 8 tweets
Nick Norwitz MD PhD Profile picture
Dec 7
How Metabolic Disease Feeds Emotional Eating 🧠🍩
(link at the end)

1/8) A brand new study (Dec 10, 2025) reveals how poor metabolic health can drive emotional eating.

Why this is important: There’s a known link between metabolic disease (obesity, diabetes, etc.) and mental health conditions (eating disorders, anxiety, depression).

But the causal relationships remain murky.

In uncovering the “how” we lay the groundwork for innovative solutions.

cc @Metabolic_Mind @janellison @TuitNutrition @ChrisPalmerMD @MitoPsychoBio @WilliamFurness @drjenunwinImage
2/8) The researchers behind the experiments took interest in ImP, which is known to be elevated in patients with metabolic conditions like diabetes (below)—and is linked to cardiometabolic disease.

*ImP levels are elevated in humans with type 2 diabetes (red) vs healthy controls (blue).Image
3/8) Given the link between metabolic diseases and mental health, the researchers set out to test a new hypothesis:

If you increase ImP, does that change the brain and behavior?

To do this, they fitted mice with a tiny pump that continuously delivered ImP at levels designed to mimic what’s seen in people with diabetes.

Afterward, they looked for neural changes and found a large shift in gene-expression programs within neurons tied to the stress response in the hypothalamus.

Those molecular changes lined up with behavior.
Read 8 tweets

Did Thread Reader help you today?

Support us! We are indie developers!

This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Don't want to be a Premium member but still want to support us?

Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal

Or Donate anonymously using crypto!

Ethereum

0xfe58350B80634f60Fa6Dc149a72b4DFbc17D341E copy

Bitcoin

3ATGMxNzCUFzxpMCHL5sWSt4DVtS8UqXpi copy

Thank you for your support!

Follow Us!

Send Email!

:(