Your Body´s Built-in Weight Loss System

Wegovy, Ozempic and Mounjaro are weight loss and diabetes drugs that have made quite a splash in health news.¹⁾We Know Where New Weight Loss Drugs Came From, but Not Why They Work. New York Times, August 17, 2023 They target regulatory pathways involved in both obesity and diabetes and are widely considered breakthroughs for weight loss and blood sugar control.²⁾Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab. 2021; 23(Suppl. 3): 5-29. https://doi.org/10.1111/dom.14496

But do these drugs point toward a root cause of metabolic disease? What inspired their development in the first place?³⁾João, A. L., Reis, F., and Fernandes, R. (2016) The incretin system ABCs in obesity and diabetes – novel therapeutic strategies for weight loss and beyond. Obesity Reviews, 17: 553–572. doi: 10.1111/obr.12421.

It turns out your body produces natural versions of these drugs – also known as incretin hormones – in your gut.⁴⁾Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. Diabetes Obes Metab. 2018; 20: 5–21. https://doi.org/10.1111/dom.13129 It may not be surprising that nutrients in food help regulate these hormones.⁵⁾Hira T, Trakooncharoenvit A, Taguchi H, Hara H. Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity. International Journal of Molecular Sciences. 2021; 22(12):6623. https://doi.org/10.3390/ijms22126623 But it may intrigue you to know that the trillions of microbes in your gut are key for orchestrating this process.⁶⁾Damman C. Hangry bacteria in your gut microbiome are linked to chronic disease – feeding them what they need could lead to happier cells and a healthier body. The Conversation, April 10, 2023

I am a gastroenterologist at the University of Washington who studies how food and your gut microbiome affect health and disease. Here’s an inside-out perspective on the role natural gut hormones and healthy food play in metabolism and weight loss.

A broken gut

Specialized bacteria in your lower gut take the components of food you can’t digest like fiber and polyphenols – the elements of plants that are removed in many processed foods – and transforms them into molecules that stimulate hormones to control your appetite and metabolism. These include GLP-1, a natural version of Wegovy and Ozempic.⁷⁾Fu J, Zheng Y, Gao Y, Xu W. Dietary Fiber Intake and Gut Microbiota in Human Health. Microorganisms. 2022; 10(12):2507. https://doi.org/10.3390/microorganisms10122507
Hawi Debelo, Min Li, Mario G Ferruzzi, Processing influences on food polyphenol profiles and biological activity, Current Opinion in Food Science, Volume 32, 2020, Pages 90-102, ISSN 2214-7993, https://doi.org/10.1016/j.cofs.2020.03.001.
Christopher J. Damman, Perspective: Nutrition’s Next Chapter – Bioactive Gaps and the Microbiome–Mitochondria Axis, Advances in Nutrition, Volume 14, Issue 3, 2023, Pages 420-425, ISSN 2161-8313,
https://doi.org/10.1016/j.advnut.2023.03.016.

GLP-1 and other hormones like PYY help regulate blood sugar through the pancreas.⁸⁾Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y and Zhang Y (2021) GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front. Endocrinol. 12:721135. doi: 10.3389/fendo.2021.721135
Karra, E., Chandarana, K. and Batterham, R.L. (2009), The role of peptide YY in appetite regulation and obesity. The Journal of Physiology, 587: 19-25. https://doi.org/10.1113/jphysiol.2008.164269 They also tell your brain that you’ve had enough to eat and your stomach and intestines to slow the movement of food along the digestive tract to allow for digestion. This system even has a name: the colonic brake.⁹⁾Nightingale JM, Kamm MA, van der Sijp JR, et al. Disturbed gastric emptying in the short bowel syndrome. Evidence for a ‘colonic brake’. Gut 1993;34:1171-1176. https://doi.org/10.1136/gut.34.9.1171

Prior to modern processed foods, metabolic regulatory pathways were under the direction of a diverse healthy gut microbiome that used these hormones to naturally regulate your metabolism and appetite.¹⁰⁾Schnorr, S., Candela, M., Rampelli, S. et al. Gut microbiome of the Hadza hunter-gatherers. Nat Commun 5, 3654 (2014). https://doi.org/10.1038/ncomms4654 However, food processing, aimed at improving shelf stability and enhancing taste, removes the bioactive molecules like fiber and polyphenols that help regulate this system.¹¹⁾Martínez Steele, E., Popkin, B.M., Swinburn, B. et al. The share of ultra-processed foods and the overall nutritional quality of diets in the US: evidence from a nationally representative cross-sectional study. Popul Health Metrics 15, 6 (2017). https://doi.org/10.1186/s12963-017-0119-3

Removal of these key food components and the resulting decrease in gut microbiome diversity may be an important factor contributing to the rise in obesity and diabetes.¹²⁾Christopher J. Damman, Perspective: Nutrition’s Next Chapter – Bioactive Gaps and the Microbiome–Mitochondria Axis, Advances in Nutrition, Volume 14, Issue 3, 2023, Pages 420-425, ISSN 2161-8313,
https://doi.org/10.1016/j.advnut.2023.03.016.

A short track to metabolic health

Wegovy and Ozempic reinvigorate the colonic brake downstream of food and microbes with molecules similar to GLP-1. Researchers have demonstrated their effectiveness at weight loss and blood sugar control.¹³⁾Suran M. As Ozempic’s Popularity Soars, Here’s What to Know About Semaglutide and Weight Loss. JAMA. 2023;329(19):1627–1629. doi:10.1001/jama.2023.2438

Mounjaro has gone a step further and combined GLP-1 with a second hormone analogue derived from the upper gut called GIP, and studies are showing this combination therapy to be even more effective at promoting weight loss than GLP-1-only therapies like Wegovy and Ozempic.¹⁴⁾Jastrebroff A et.al. Tirzepatide Once Weekly for the Treatment of Obesity. DOI: 10.1056/NEJMoa2206038

These drugs complement other measures like gastric bypass surgery that are used in the most extreme cases of metabolic disease. These surgeries may in part work much like Wegovy and Ozempic by bypassing digestion in segments of the gastrointestinal tract and bathing your gut microbes in less digested food.¹⁵⁾Chelsea R Hutch, Darleen Sandoval, The Role of GLP-1 in the Metabolic Success of Bariatric Surgery, Endocrinology, Volume 158, Issue 12, 1 December 2017, Pages 4139–4151, https://doi.org/10.1210/en.2017-00564
Magouliotis, D.E., Tasiopoulou, V.S., Sioka, E. et al. Impact of Bariatric Surgery on Metabolic and Gut Microbiota Profile: a Systematic Review and Meta-analysis. OBES SURG 27, 1345–1357 (2017). https://doi.org/10.1007/s11695-017-2595-8 This awakens the microbes to stimulate your gut cells to produce GLP-1 and PYY, effectively regulating appetite and metabolism.¹⁶⁾Webb, D. L., Abrahamsson, N., Sundbom, M., & Hellström, P. M. (2017). Bariatric surgery – time to replace with GLP-1? Scandinavian Journal of Gastroenterology, 52(6–7), 635–640. https://doi.org/10.1080/00365521.2017.1293154
Guida, Claudia et al. PYY plays a key role in the resolution of diabetes following bariatric surgery in humans. eBioMedicine, Volume 40, 67 – 76 https://doi.org/10.1016/j.ebiom.2018.12.040

Many patients have seen significant improvements to not only their weight and blood glucose but also reductions in important cardiovascular outcomes like strokes and heart attacks.¹⁷⁾Lincoff AM et.al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. DOI: 10.1056/NEJMoa2307563 Medical guidelines support the use of new incretin-based medications like Wegovy, Ozempic and Mounjaro to manage the interrelated metabolic conditions of diabetes, obesity and cardiovascular disease.¹⁸⁾Marx N. et.al. GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes. https://doi.org/10.1161/CIRCULATIONAHA.122.059595

Considering the effects incretin-based medications have on the brain and cravings, medical researchers are also evaluating their potential to treat nonmetabolic conditions like alcohol abuse, drug addiction and depression.¹⁹⁾Chuong V et.al. The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission. https://doi.org/10.1172/jci.insight.170671
Leslie M. Hot weight loss drugs tested as addiction treatments. Science, August 28, 2023
Daniel H. Cooper, et.al. Glucagon-like peptide 1 (GLP-1) receptor agonists as a protective factor for incident depression in patients with diabetes mellitus: A systematic review, Journal of Psychiatric Research,
Volume 164, 2023, Pages 80-89, https://doi.org/10.1016/j.jpsychires.2023.05.041.

A near-magic bullet?

Despite the success and prospect of these drugs to help populations that may benefit most from them, current prescribing practices have raised some questions.²⁰⁾Wojtara, Magda, Mazumder, Ashmita, Syeda, Yusra, Mozgała, Nikodem, Glucagon-Like Peptide-1 Receptor Agonists for Chronic Weight Management, Advances in Medicine, 2023, 9946924, 7 pages, 2023. https://doi.org/10.1155/2023/9946924 Should people who are only a little overweight use these drugs? What are the risks of prescribing these drugs to children and adolescents for lifelong weight management?²¹⁾Ducharme J. Teens Are Taking Wegovy for Weight Loss. But Doctors Have a Lot to Learn. Time, June 6, 2023

While incretin-based therapies seem close to magic bullets, they are not without gastrointestinal side effects like nausea, vomiting, diarrhea and constipation.²²⁾Consoli, A., & Formoso, G. (2014). Potential side effects to GLP-1 agonists: understanding their safety and tolerability. Expert Opinion on Drug Safety, 14(2), 207–218. https://doi.org/10.1517/14740338.2015.987122 These symptoms are related to how the drugs work to slow the gastrointestinal tract. Other more severe, but rare, side effects include pancreatitis and irreversible gastroparesis, or inflammation of the pancreas and stomach paralysis.²³⁾Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023;330(18):1795–1797. doi:10.1001/jama.2023.19574

These drugs can also lead to a loss of healthy lean muscle mass in addition to fat, particularly in the absence of exercise.²⁴⁾Sargeant JA, Henson J, King JA, Yates T, Khunti K, Davies MJ. A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans. Endocrinol Metab. 2019;34(3):247-262. https://doi.org/10.3803/EnM.2019.34.3.247 Significant weight gain after stopping the drugs raises further questions about long-term effects and whether it’s possible to transition back to using only lifestyle measures to manage weight.²⁵⁾Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022; 24(8): 1553-1564. doi:10.1111/dom.14725
Peter C. Butler, Sarah Dry, Robert Elashoff; GLP-1–Based Therapy for Diabetes: What You Do Not Know Can Hurt You. Diabetes Care 1 February 2010; 33 (2): 453–455. https://doi.org/10.2337/dc09-1902

All roads lead to lifestyle

Despite our greatest aspirations for quick fixes, it’s very possible that a healthy lifestyle remains the most important way to manage metabolic disease and overall health. This includes regular exercise, stress management, sleep, getting outdoors and a balanced diet.²⁶⁾Unlocking Health: The Power of the 4 M’s. Gut Bites MD

For the majority of the population who don’t yet have obesity or diabetes, restarting the gut’s built-in appetite and metabolism control by reintroducing whole foods and awaking the gut microbiome may be the best approach to promote healthy metabolism.

Adding minimally processed foods back to your diet, and specifically those replete in fiber and polyphenols like flavonoids and carotenoids, can play an important and complementary role to help address the epidemic of obesity and metabolic disease at one of its deepest roots.²⁷⁾Polyphenols Ignite Metabolic Health via Mitochondria & GLP-1. Gut Bites MD

This article is republished from The Conversation under a Creative Commons license. Read the original article.