GLP-1s: The Weight Loss Drug That’s NOT Just About Weight

We will discuss new literature in Science & Cell Metabolism about GLP-1 receptor agonists, inflammation, the brain and overall health. Get ready for nuance...

1 year ago, I thought if I said “GLP-1” or “GLP-1 receptor agonist” your average non-medical person would have no idea what’s I’m talking about. Oh, how that’s changed.

This family of weight loss drug has taken the obesity and metabolism world by storm, with mixed opinions.

Some people think they’re God’s Gift to Modern Medicine, a secular scientific miracle.

Others are skeptical, given the history of weight loss drugs in medicine is – well – not so great and riddled with missteps.

What if GLP-1 receptor agonists are different?

What if they’re not weight loss drugs? … Or at least not only weight loss drugs?

There’s now a YouTube video covering this content. If you prefer to watch, click below. If you prefer to read, skip onward.

Caveat

But – first – a caveat. I’m NOT here to place judgement on the clinical use of these medications. That is not my place. I’m here to talk science.

But because it’s relevant to my audience, I’ll just say my opinion on these medications is they are powerful tools that should be used in the right patients, like many medications.

However, at a societal level, I am concerned about adopting a wide-spread cultural position that injections and drugs are “THE” answer to the obesity epidemic to the point that we lose sight of the fact that obesity is a disease of lifestyle and environment, and that we must improve the way we live if we are to truly succeed in forcing obesity towards extinction.

Pharmacotherapy will not be enough.

(Note: That’s my hypothesis. As a scientist, I wouldn’t mind being proven wrong if it meant a population without obesity and metabolic disease.)

Anyway, onto the science…

GLP-1, Beyond Weight Loss: Inflammation

A recent review article published in Science discussed the many applications of GLP-1 medications, including cardiovascular disease, liver disease, mental health and neurological disorders, and so on. (If you want to follow the author, Professor

It makes the point that the benefits of GLP-1s are not just related to weight loss but also that a “potentially unifying mechanism of action for GLP-1R agonism is the reduction of inflammation.”

This led me to another paper, published in Cell Metabolism, where they showed that the action of GLP-1 on the brain causes a decrease in inflammation in the body.

In this study, they treated mice with a substance that causes inflammation, Lipopolysaccharide (LPS), which can be measured as increases in an inflammatory signaling molecule, TNF-α.

They also treated some mice with GLP-1 receptor agonists and observed this reduced inflammation in the mice. But then… they did something else.

They did the same experiment, treating mice with the inflammatory substance (LPS) and trying to dampen the inflammation with a GLP-1 receptor agonist, BUT in mice missing the receptor for GLP-1 in various tissues and organs…

• Deleting GLP-1 Receptor in Bloods Cells and Blood Vessels (A): In one experiment, they deleted the GLP-1 receptor from various blood cells and cells that line blood vessels. Interestingly, GLP-1 receptor agonism COULD still reduce inflammation in these mice (note in blue, how the GLP-1 drug, Exendin-4, decreases TNF-α relative to vehicle control).

• Deleting GLP-1 Receptor in the Brain (C): In another experiment, they deleted the GLP-1 receptor from the brain. In these mice, GLP-1 COULD NOT reduce inflammation in these mice. (note in purple, how the GLP-1 drug, Exendin-4, did not decrease TNF-α relative to vehicle control). And they even verified this was the case in another mouse model lacking GLP-1 receptors in the brain.

I’ve modified the labels on the figure to make it easier for you to interpret, e.g. replaced terms like Glp1rTie2-/- and Glp1rWnt-/-.

Takeaway: This suggests that it’s the action of GLP-1 on the brain that mediates the systemic, whole body anti-inflammatory effects of GLP-1 drugs.

Quick Aside on Tirzepatide?

Well, they tested the GLP-1 + GIP receptor agonist, Tirzepatide, on mice with GLP-1 deleted from the brain, it was able to reduce inflammation where the GLP-1 agonist (Semaglutide) could not. This suggests the combination agonist is acting through additional pathways to reduce inflammation. For more on Tirzepatide, click HERE.

What About Humans?

Well, you can’t delete GLP-1 receptors from various organs in humans.

However, there are signs that benefits of GLP-1s can be independent of weight loss.

• For example, “in the SELECT cardiovascular outcome trial studying people with obesity, the extent of weight loss did not correlate with the effects of the drug to reduce heart attack, stroke, and cardiovascular death.”

• Also, “another long-acting GLP-1 therapy, albiglutide, [was] withdrawn from the market owing to modest efficacy for reduction of glucose and body weight in people with T2D; [however], it reduced the rates of major adverse cardiovascular events by 22%.”

Point being, GLP-1s in humans almost certainly have benefits beyond weight loss. In part, this might be due to reduced inflammation.

GLP-1s and Metabolic Disease

So, here’s the core truth I want to communicate in this video: metabolic health isn’t simply about weight.

Duh, right?

But – more importantly – good metabolic health causes a healthy weight, not the other way around.

As applies to obesity, one could reframe this as eating in a way that promotes high blood sugar, high insulin and inflammation – and overall throws your body into metabolic disarray – causes obesity.

This contrasts with the simplistic “calorie balance” or “energy surplus” mindset that still plagues society, like a mind virus.

For more the nuances of Calories and Obesity, see these two videos:

And this contrast (Calories-first vs. Metabolic Health-first) is critical to acknowledge, since we are living in a world where Calories are Still King from a mechanistic point of view, but where we’re leaning into drugs to solve the problem, and then inappropriately attributing their benefits to simply, “less hunger” and fewer calories eaten – when the effects of these GLP-1s area clearly more metabolic and complex.

And that brings me to the intervention that’s better than GLP-1, albeit harder to implement: living a healthier lifestyle.

Okay, I’ll give you a moment to finish your eye roll or groan, but here me out.

The “lifestyle” line has a taint because it’s often seen as victim blaming, in the camp of eat less move more advice. But that’s NOT what I’m suggesting.

I’m suggesting that, as a society, we have lifestyle and environmental creep, whereby being more sedentary and eating worse (I said “worse,” not “more) is facilitated by changes in our social norms and physical environments. I could provide examples, but I know you know what I’m talking about.

So, the solution – as I see it – needs to be talking about these norms and constructing environmental change.

I want to see a world where there aren’t junk food filled vending machines in hospitals, where it’s not normalized to have 10 teaspoons of sugar in your coffee, where supermarkets aisles aren’t themselves obese with colorful sugary breakfast cereals targeting innocent children for profit.

And that doesn’t mean that GLP-1 aren’t a useful tool… but they’re not enough.

Let’s not lose sight of the metabolic forest for one (very financially fruitful) tree.

More on GLP-1 Science

For more on GLP-1 science, here are several prior videos.

1. Defeat Your Culinary Kryptonite! New Science of GLP-1 and Satiety

2. Teach Your Doctor: 4 Facts about GLP-1 Based on New Data

3. Make your Fat Flexible: This Can Do what Ozempic Never Could

4. Could GLP-1 Be the Missing Link in PCOS Therapy?