Your brain on Ozempic

March 19th, 2024

Written by: Stephen Wisser

Oh, oh, oh, Ozempic! If you’ve watched TV in the last year or been on social media, especially TikTok, there’s a good chance you sang that first sentence in your head. The catchy jingle used to advertise the diabetes drug Ozempic has taken off in mainstream media as the public and celebrities alike marvel at its ability to cause weight loss. Although Ozempic was developed for people with diabetes, in June 2021 the maker of Ozempic gained FDA approval for a more powerful version of Ozempic meant specifically for weight loss, called Wegovy¹. Yet, with all the popularity of these drugs, little attention has been given to how they work. In this post we’ll explore the neuroscience of the active ingredient in these so-called “miracle weight loss drugs”, and their effects, both good and bad, beyond weight loss.

Your Brain on Food Crash Course

To understand how drugs like Wegovy and Ozempic can cause weight loss, we first need to understand a bit about what happens in the brain when we eat. The feelings of hunger and fullness are mainly regulated by an intricate balance of hormones that are produced in the gut, liver, and pancreas². One of these hormones that you might be more familiar with is insulin which causes a decrease in blood sugar and is normally produced by the pancreas after a meal. When the pancreas does not produce enough insulin to tell our cells to soak up the food we just ate, that causes our blood sugar to rise in a condition known as diabetes. Although it is produced in the pancreas, insulin also has effects in the brain. Many brain regions are responsible for controlling appetite, but there are a few specific “hunger regions” that insulin can interact with³ and give you the feeling of fullness⁴. So, in addition to telling cells throughout the body to take up nutrients, insulin also tells our brain that we’re full.

Clearly, insulin is an important part of eating and feeling full, but what causes it to be released from the pancreas in the first place? Here we come to the major player in the story of Ozempic & Wegovy: glucagon-like peptide 1, or GLP-1. After food enters the gut, a hormone known as GLP-1 is produced, which then activates the pancreas to release that important insulin⁵ (Figure 1). Some studies estimate that as much as 70% of the insulin produced from the pancreas is due to GLP-1⁶, so like insulin, GLP-1 is a very important hormone in feeding.

History of GLP-1 drugs: Natural and Man-Made

While GLP-1 serves as the “parent” to insulin by stimulating the pancreas to produce it, GLP-1 also has other effects that decrease the feeling of hunger. For one, GLP-1 has been shown to work in the gut and decrease a phenomenon known as gastric emptying⁵ where food moves out of the stomach to the rest of the digestive system. Simply put, GLP-1 can slow the digestion of food to make the feeling of fullness last longer. Additionally, GLP-1 has actions in the brain’s “hunger regions”^7,8 much like insulin that give the feeling of fullness.

The ability of GLP-1 to cause insulin production made it a very attractive hormone for pharmaceutical companies wanting to make diabetes drugs. But the problem is that natural GLP-1 produced by our bodies doesn’t last very long. So, scientists created synthetic forms of GLP-1 that last longer called liraglutide and semaglutide in hopes that longer lasting forms of GLP-1 would have longer lasting effects – and they did. In a clinical trial involving 75 patients with type-2 diabetes, semaglutide significantly increased insulin production, improved the cells in the pancreas that produce insulin, and caused weight loss.⁹ Thus, semaglutide was deemed an effective GLP-1 synthetic drug to treat diabetes and began to be sold under the brand name Ozempic.

Although there are some differences between liraglutide and semaglutide, they are both longer lasting synthetic forms of GLP-1 and semaglutide is the active ingredient in both Ozempic and Wegovy. However, since liraglutide and semaglutide work similarly, for the rest of this post I’ll collectively refer to them as “GLP-1 drugs” to explain what scientists know about this class of drugs more generally.

Initially, GLP-1 drugs were only investigated for their ability to stimulate the pancreas and increase insulin production. But that’s just one role of GLP-1. As discussed, natural GLP-1 also has effects in the brain and so it would make sense that GLP-1 drugs would also have effects in the brain. Indeed, GLP-1 drugs directly interact with the same neurons in “hunger regions”¹⁰ that natural GLP-1 and insulin bind to, causing fullness.

Side Effects

            While the initial hype around GLP-1 drugs was mostly positive surrounding weight loss, reports of unwanted side effects are now surfacing and gaining more traction. Since scientists are still understanding the basic science of GLP-1 activation in the brain and beyond, side effects vary from person to person. In this excellent podcast episode from The Daily produced by the New York Times, reporters interviewed 2 people with totally different experiences on GLP-1 drugs. One individual noticed they stopped thinking about food the very next day after taking the drug and eventually lost 40lbs¹¹. But the other person felt bloated and nauseated to the point that she had to set reminders to force herself to eat. When she decided to stop taking the medication she gained the weight back,¹¹ a common side effect when one stops taking a GLP-1 drug.

Like this second person interviewed, when someone stops taking GLP-1 drugs, hunger comes back. One study found that after one year off a GLP-1 drug, participants regained an average of two thirds of the weight they had lost¹². This is likely because the GLP-1 telling their brain they are full is gone. However, this resurgence in hunger could also be due to GLP-1 rewiring the brain. One group found that long-term use of a GLP-1 drug did cause weight loss, but increased brain activity in a region that could encourage someone to eat¹³. Sure, GLP-1 drugs decrease feelings of hunger which leads to an initial bout of weight loss, but it seems that eventually the brain rewires and pushes back making it harder to lose even more weight. When someone stops taking a GLP-1 drug, the scale tips toward hungry feelings since the GLP-1 “fullness” signals are gone and you’re left with a rewired brain aimed toward eating…and regaining that weight. This suggests that in order to experience the benefits of GLP-1 drugs long term a person needs to continually take them.

The Unexpected

            In addition to their current use in modifying eating-related thinking and behavior, GLP-1 drugs are also being discussed in the context of other diseases, like decreasing addiction behaviors. Some common and perhaps welcome side effects of GLP-1 drugs are reports of decreased alcohol consumption, smoking, and even online shopping¹⁴. While the discussion so far has been on GLP-1 in the brain’s hunger regions, GLP-1 can act on many other parts of the brain meaning it can have diverse effects. Some other places that natural GLP-1 is known to affect are brain regions responsible for addictive behaviors, so it would make sense that GLP-1 drugs would also work here. In support of this idea, scientists found that GLP-1 drugs decreased binge drinking behaviors in rats by affecting brain activity in the brain’s addiction regions,¹⁵ providing a potential explanation for the reduction in addictive behaviors found in people using GLP-1 drugs.

Conclusion

            GLP-1 drugs like Ozempic and Wegovy are radically changing the discussion of weight management. With all their promise, it is important to consider long-term consequences of a drug that needs to be continually taken for results. Of particular concern are the many side effects of GLP-1 drug use that are being increasingly reported as more people take these drugs. However, as discussed, not all these side effects are necessarily a bad thing which opens many new doors for these drugs to potentially address health concerns beyond obesity. So, if you thought you were hearing a lot about these medicines already, it is safe to say that you’ll probably be hearing about them even more over the coming years.

References

1. Commissioner, O. of the. (2021, June 4). FDA approves new drug treatment for Chronic Weight Management, first since 2014. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
2.  Munekata, P. E., Pérez-Álvarez, J. Á., Pateiro, M., Viuda-Matos, M., Fernández-López, J., & Lorenzo, J. M. (2021). Satiety from healthier and functional foods. Trends in Food Science & Technology, 113, 397-410.
3.  Dodd, G. T., Michael, N. J., Lee-Young, R. S., Mangiafico, S. P., Pryor, J. T., Munder, A. C., … & Tiganis, T. (2018). Insulin regulates POMC neuronal plasticity to control glucose metabolism. Elife, 7, e38704.
4.  Toda, C., Santoro, A., Kim, J. D., & Diano, S. (2017). POMC neurons: from birth to death. Annual review of physiology, 79, 209-236.
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6.  Nauck, M. A., Heimesaat, M. M., Orskov, C., Holst, J. J., Ebert, R., & Creutzfeldt, W. (1993). Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. The Journal of clinical investigation, 91(1), 301-307.
7.  Secher, A., Jelsing, J., Baquero, A. F., Hecksher-Sørensen, J., Cowley, M. A., Dalbøge, L. S., … & Knudsen, L. B. (2014). The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. The Journal of clinical investigation, 124(10), 4473-4488.
8.  Knudsen, L. B., & Lau, J. (2019). The discovery and development of liraglutide and semaglutide. Frontiers in endocrinology, 10, 440904.
9.  Kapitza, C., Dahl, K., Jacobsen, J. B., Axelsen, M. B., & Flint, A. (2017). Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Diabetologia, 60, 1390-1399.
10.  Gabery, S., Salinas, C. G., Paulsen, S. J., Ahnfelt-Rønne, J., Alanentalo, T., Baquero, A. F., … & Knudsen, L. B. (2020). Semaglutide lowers body weight in rodents via distributed neural pathways. JCI insight, 5(6).
11.  Barbaro, M (Host), Blum, D (Reporter). (2023, September 18). The Ozempic Era of Weight Loss [Audio podcast episode]. The Daily. The New York Times. https://www.iheart.com/podcast/326-the-daily-28076606/episode/the-ozempic-era-of-weight-loss-123479067/
12.  Wilding, J. P., Batterham, R. L., Davies, M., Van Gaal, L. F., Kandler, K., Konakli, K., … & STEP 1 Study Group. (2022). Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension. Diabetes, Obesity and Metabolism, 24(8), 1553-1564.
13.  Farr, O. M., Upadhyay, J., Rutagengwa, C., DiPrisco, B., Ranta, Z., Adra, A., … & Mantzoros, C. S. (2019). Longer‐term liraglutide administration at the highest dose approved for obesity increases reward‐related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti‐obesity therapies. Diabetes, Obesity and Metabolism, 21(11), 2459-2464.
14.  Stokes, V. (2023, June 26). Why Some People Are Claiming Life on Ozempic Is ‘Miserable.’ Healthline. https://www.healthline.com/health-news/why-some-people-are-claiming-life-on-ozempic-is-miserable
15.  Chuong, V., Farokhnia, M., Khom, S., Pince, C. L., Elvig, S. K., Vlkolinsky, R., … & Leggio, L. (2023). The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission. JCI insight, 8(12).

Cover photo by Vidmir Raic from Pixabay

Figure 1 made with BioRender.com