Removing Intuition in a GLP-1RA-driven world

New research on GLP-1 RAs and metabolism is trying to reshape the narrative around obesity.

As I have reiterated in many of my prior posts on GLP-1 receptor agonists, we are in a murky era where pharmaceuticals and medicine are overriding our natural, intuitive thoughts on health and nutrition.

This is made pronounced when it comes to Ozempic and similar medications where a new narrative has taken place which suggests that diet and exercise are futile in preventing and treating obesity. You cannot lose weigh through sheer will and effort, but instead must rely on drugs in order to properly address, treat, and prevent the current obesity epidemic that is plaguing the US.

When even Oprah Winfrey says that she could not lose weight through willpower alone, and must turn to these medications to aid her on her weight-loss journey then surely we are in a sad state culturally:

It also doesn’t help that modern social movements have tried to remove any negative connotation regarding obesity, with “fat positivity” and other activist movements further complicating something that was primarily intuitive- watch what you eat, exercise, and you can lose weight and get healthier.

Obviously, such an endeavor is made difficult with how processed and addictive many of our foods have become. That being said, it still doesn’t remove the fact that health is based upon first principles of proper nutrition and being active.

As it goes- keep it simple, stupid!

Now, a new study¹ has come out that claims to even reshape the narrative surrounding these GLP-1 medications, supplanting prior hypotheses in how these drugs work with a new mechanism involving metabolism.

The study itself is a highly simplistic study, in which 30 patients who have obstructive sleep apnea, are obese, but do not have diabetes were randomized into one of 3 groups: a CPAP group'; a GLP-1 group in the form of Liraglutide; and a group provided both. Patient biometric data was evaluated 24 weeks after treatment and compared to their baseline measurements.

On the surface such a study as the one outlined above doesn’t seem like one designed to examine fat metabolism. Indeed, this study was part of the authors’ prior work² evaluating the 3 groups and the effects of such treatment on cardiovascular risk factors. Thus, it seems that the findings in this study are a result of noticing correlative information from their prior work.

In this case the authors examined visceral adipose tissue (VAT) metabolism with the utilization of positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT).

In more simple terms, patients were administered fluorescently labeled glucose molecules. The idea here is that cells utilize glucose at different levels from one another, and this is made more evident in diseased states in which dysfunctional cells may utilize glucose differently than when in a healthy state. For instance, cancer cells are argued to uptake glucose more frequently, and thus PET/CT imaging which recognize concentrated areas of 18F-FDG uptake may be suggestive of tumor growth.

As was utilized by O’Donnel, et al. in their prior study 18F-FDG PET/CT can also be utilized to infer atherosclerosis, as macrophages associated with atherosclerotic plaque show increased glucose uptake and is indicative of vascular inflammation. By providing a radiolabeled molecule a researcher can track where the glucose ends up and to what degree cells in an region of the body utilize the glucose.

Here, the authors noticed that in those who were administered Liraglutide there was a noticeable increase in alleged VAT metabolism as suggested by increased 18F-FDG fluorescence at the 24-week mark relative to baseline measures. This effect wasn’t seen in those who used CPAP machines as they appeared to show a decline in 18F-FDG fluorescence at the 24-week mark. Also, the combination therapy seemed to show an increase in fluorescence, albeit not to the same degree as the Liraglutide only group.

From O’Donnell, et al. Figure 1. Plots representing changes in body weight and alleged metabolism changes across all 3 groups. Those provided Liraglutide showed the greatest amount of weight lost. When it comes to visceral adipose tissue greater uptake of 18F-FDG was seen in those administered Liraglutide as compared to other groups. This is alleged to be related to increased visceral fat metabolism, although the evidence for that remains a point of contention.

Now, this finding coincides with the recognition that those within the Liraglutide and combination group showed higher levels of weight-loss relative to the CPAP group:

Significant weight loss was achieved with liraglutide alone and in combination with CPAP (6.17 [3.57] and 3.67 [4.22] kg, respectively), but not with CPAP as single modality (Figure 1A–C).

Taken together, the authors are alleging that administration of GLP-1 receptor agonists are possibly related to increased metabolism, which would highlight a separate mechanism not generally recognized with these medications:

Here, we demonstrate that upregulation of metabolic activity within VAT occurs in patients treated with GLP-1 analogues. The fact that the degree of upregulation correlates positively with the degree of weight loss supports a contributory role of this pathway in the weight loss effects of GLP-1. Furthermore, lower baseline levels of VAT metabolic activity were associated with greater weight loss in response to GLP-1 therapy, suggesting that individuals with lower VAT metabolic activity may benefit most from the dual impact of GLP-1 on reduction of energy intake and increased metabolic activity.

This would at least be the case if one were to entertain headlines from media outlets regarding this study:

From Newsweek

From The Independent

Funny that these headlines mention Ozempic- the study never used Ozempic which has the active agent Semaglutide. Liraglutide, which the authors used in their study, goes by the name Victoza or Saxenda. So much for journalists being accurate in their reporting.

That aside, there’s quite a few problems with this study that is not being reported on.

For instance, what’s worth criticizing is that the authors never provide any explanation for how they know that the increased fluorescence is indicative of increased metabolism.

Remember that mechanism is being assumed due to the correlation in VAT fluorescence and weight-loss in the participants, and nothing else.

Also, note that the authors’ prior work utilizing 18F-FDG PET/CT was to examine vascular inflammation, and within this context they noticed a reduced fluorescence score in those who used a CPAP machine.

I don’t have access to the full study, but here is what is reported in the Abstract (therefore, take this information with a grain of salt; emphasis mine):

Both Lir and combination treatment led to significant weight loss, but only CPAP alone resulted in significant decrease in vascular inflammation (aortic wall target-to-background ratio from 2.03 ± 0.34 to 1.84 ± 0.43; P = 0.010), associated with an improvement in endothelial function and a decrease in C-reactive protein.

Again, within the context of the prior study a lower score relative to baseline is suggestive of reduced inflammation, likely related to reduced macrophage activity as mentioned above when discussing 18F-FDG PET/CT utilization.

It’s interesting that the authors don’t make any comment regarding the fact that the CPAP group also appeared to have a lower score at the 24-week mark, although this may be due to the decreasing score not meeting statistical significance.

Nonetheless, all of this emphasizes that the fluorescent scores here may not directly infer increased metabolism because we don’t know why the cells are utilizing more glucose. Is it due to increased metabolism, increased inflammation, or for some other reason?

In that sense, it seems like a stretch to go so far as to state that this is a sign that Liraglutide increases metabolism from this limited information. Bear in mind that the authors’ prior work on GLP-1 therapy and metabolism did not utilize 18F-FDG PET/CT, and instead examined the effect of GLP-1 on activating a class of immune cells called invariant natural killer T (iNKT) cells, which appear to be involved in thermogenesis. Activation of these immune cells by way of Liraglutide seems to increase thermogenesis and thus weight loss.

Again, the intent here is not to say that Liraglutide is not associated with increased metabolism, but that the data provided by the authors in this specific study is hardly enough to warrant such an alleged mechanism. No additional work is provided to further associate these two variables, and it certainly doesn’t provide any association with their prior work and the cells involved there.

So here we are left with a study with very limited methodology that is alleging a new mechanism of action for these medications. This alone would be worth scrutinizing on the basis that more concrete evidence would be needed, but like with many studies that get published there is a narrative that must be associated with the study.

In this case the authors suggest that these findings allege that the old adage of “eat less, move more” is not the way to treat obesity:

Further targeted studies comparing GLP-1 with other weight-loss modalities need to be undertaken to define the relative contribution of this pathway to the overall reduction in body weight. Such studies will improve our understanding of energy homeostasis and move us away from the narrative that the treatment of obesity is eat less, move more.

And this is emphasized further in the Newsweek piece with the excerpt below:

"It always seemed oversimplistic to me that these new treatments were just making people eat less," said research lead Professor Donal O'Shea in a statement. "So, this study is an exciting step forward in our understanding of how these new medicines for obesity work."

"The findings also provide science to support the fact that the treatment of obesity is not simply to eat less and move more—that's the prevention piece. The treatment is more complex than that."

It’s a rather striking declaration to make, and it further pushes to confuse obesity by takings out of an individual person’s control- something that many fat activists have proclaimed in recent years where they have tried to undermine the role of eating right and exercising by stating that obesity is related to genetics and slow metabolism.

It’s not your fault that you are obese- it’s your genetics and slow metabolism, which can clearly be treated with medications with unknown side effects!

There’s an irony in this subversive narrative, especially given the fact that people with lower metabolisms would inherently have to eat less- they require fewer calories due to their slower metabolism, after all. These things kind of go hand-in-hand…

It also works against current evidence which suggests that exercise can have a multitude of changes on the body’s metabolic processes, including alterations in brown/white fat composition.³,⁴,⁵

In that sense, exercise seems to be critical in improving metabolism. If Liraglutide is alleged to improve metabolism, then is it wrong to claim that “moving more” is necessary for weight-loss?

There’s currently far too much confusion regarding obesity, and it doesn’t help that matters are made more complicated in order to remove any sense of personal accountability, responsibility, and autonomy.

Yes, obesity is a complex issue, but one doesn’t need complex solutions to approach such problems. Do what you can with great effort before relying on drugs which may cause more harm than good in the long run. Don’t let new-age narratives dissuade you from eating better and exercising more.

There’s far too little of that going on anyways…

---

If you enjoyed this post and other works please consider supporting me through a paid Substack subscription or through my Ko-fi. Any bit helps, and it encourages independent creators and journalists such as myself to provide work outside of the mainstream narrative.

Click on the image above or visit the website at https://ko-fi.com/moderndiscontent

1. O'Donnell, C., Ryan, O., Hogan, A. E., Killick, D., Crilly, S., Dodd, J. D., Murphy, D. J., Ryan, S., & O'Shea, D. (2024). GLP-1 therapy increases visceral adipose tissue metabolic activity: lessons from a randomized controlled trial in obstructive sleep apnea. Obesity (Silver Spring, Md.), 10.1002/oby.24126. Advance online publication. https://doi.org/10.1002/oby.24126

2. O'Donnell, C., Crilly, S., O'Mahony, A., O'Riordan, B., Traynor, M., Gitau, R., McDonald, K., Ledwidge, M., O'Shea, D., Murphy, D. J., Dodd, J. D., & Ryan, S. (2024). Continuous Positive Airway Pressure but Not GLP1-mediated Weight Loss Improves Early Cardiovascular Disease in Obstructive Sleep Apnea: A Randomized Proof-of-Concept Study. Annals of the American Thoracic Society, 21(3), 464–473. https://doi.org/10.1513/AnnalsATS.202309-821OC

3. Brandão, B. B., Madsen, S., Rabiee, A., Oliverio, M., Ruiz, G. P., Ferrucci, D. L., Branquinho, J. L., Razolli, D., Pinto, S., Nielsen, T. S., Festuccia, W. T., Martins, A. S., Guerra, B. A., Knittel, T. L., Søgaard, D., Larsen, S., Helge, J. W., Brandauer, J., Velloso, L. A., Emanuelli, B., … Mori, M. A. (2020). Dynamic changes in DICER levels in adipose tissue control metabolic adaptations to exercise. Proceedings of the National Academy of Sciences of the United States of America, 117(38), 23932–23941. https://doi.org/10.1073/pnas.2011243117

4. Stanford, K. I., Middelbeek, R. J., & Goodyear, L. J. (2015). Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations. Diabetes, 64(7), 2361–2368. https://doi.org/10.2337/db15-0227

5. Lehnig, A. C., & Stanford, K. I. (2018). Exercise-induced adaptations to white and brown adipose tissue. The Journal of experimental biology, 221(Pt Suppl 1), jeb161570. https://doi.org/10.1242/jeb.161570