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...
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...
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 :).
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The Peptide Proven to Cut Visceral Fat (In RCTs) 🧵
1/6) There is a peptide proven in multiple double-blinded, placebo-controlled randomized controlled trials to reduce visceral fat.
It’s called tesamorelin. (link at the end)
2/6) Tesamorelin is an analog of growth hormone–releasing hormone, a hormone released by the brain that signals the pituitary to release growth hormone.
Its main advantage over growth hormone is that it stimulates the body’s natural release of growth hormone, rather than adding a non-physiologic dose that doesn’t align with biological rhythms.
3/6) To give you just a taste of data: in a landmark 2007 New England Journal of Medicine study, patients with HIV on antiretroviral therapy and excess abdominal fat were given 2 mg of tesamorelin or placebo for 26 weeks.
Visceral fat decreased by ~15% in the tesamorelin group, while it increased in the placebo group. Subcutaneous fat did not change, and there was no loss in lean mass.
*Nuance note: Historically, the patient population studied has been patients with HIV taking antiretroviral therapy. Why? These therapies can cause visceral fat gain. So these patients aren’t biologically unique to HIV—they’re just a particularly vulnerable population in which these drugs have been assessed and FDA-approved.
After 7 Years, I Changed My Mind on Cholesterol Meds (Or Did I?)
🚨You'll want to read this one all the way though. Link at the end🚨
1/7) After seven years of living with astronomically high cholesterol, I’ve decided to start two medications. Not statins, but ezetimibe and bempedoic acid.
But that’s NOT the real story. The real story is WHY… and it has nothing to do with cholesterol🤨🤔...
Quick preface: “cholesterol-lowering drugs” are named for one effect, not their full biological impact.
Molecules don’t respect our labels. These drugs can influence multiple systems, including metabolism and brain health.
And in this case, they likely do.
2/7) Take ezetimibe. Beyond lowering LDL, evidence suggests it crosses into the brain and influences neurobiology.
Specifically, is disrupts the interaction between 14-3-3 and hexokinase, reducing protein aggregation.
Full video:
3/7) That means less amyloid, less tau, and even improved autophagy.
Even more interesting: retrospective analyses have found up to an ~8x lower risk of Alzheimer’s in patients on ezetimibe.
Not causal. Not definitive. But a signal worth paying attention to—especially in the right context.
1/5) Here are four things statins do in your body.
First: A human controlled trial found statins reduced GLP-1 levels by 50% in 16 weeks.
The clinical implications aren’t fully clear—but the fact this isn’t discussed is a disservice to science and to patients.
2/5) Statins disrupt mitochondrial function.
They reduce CoQ10 synthesis (a key electron carrier) and directly inhibit Complex IV in the electron transport chain. These are biochemical effects—but they matter for informed decisions. staycuriousmetabolism.substack.com/p/the-mitochon…
3/5) Statins are sexist. Women face higher risk of muscle pain, potential muscle loss, and statin-induced diabetes.
Eating 1000 Sardines Gave Me THIS Superpower
(New 2026 Findings!)
1/8) I ran a self-experiment where I ate 1000 sardines in a month.
Sure, it made me stink—but it also gave me one epic superpower. Let me explain. 🧵 (link at the end)
We all know sardines make your breath stink and that they’re nutrient-dense.
That’s basic.
But eating that many sardines changed me. It gave me a “superpower” that had my inner Marvel nerd activated—and my scientist brain scrambling to explain it.
Eventually, I found those data.
2/8) It was new paper in a top journal turned confusion into clarity and left me in awe of how much we’re still uncovering about human physiology.
1/5) One meta-analysis of controlled human trials found that citrus bergamot extract lowers triglycerides, increases HDL, and lowers LDL — to a substantial degree.
But that’s not all... (link at the end)
2/5) More interestingly, one trial showed that while bergamot decreased small dense LDL, it increased‘large, fluffy’ LDL.
This shift towards a preponderance of large LDL vs small LDL is a metabolic fingerprint of improved metabolic health.
3/5) So how does citrus bergamot work?
Citrus bergamot isn’t a single nutrient — it’s a cocktail of polyphenolic compounds that influence multiple metabolic enzymes.
For example, the bergamot polyphenols inhibit the enzyme ACAT, contributing to downstream increase LDL receptor expression.