Blog

Why Weight Regain Happens After GLP-1s and Weight Loss and What Practitioners Can Do About It

Why Weight Regain Happens After GLP-1s and Weight Loss and What Practitioners Can Do About It

Rebound Weight Gain After Weight Loss: Why it Occurs and How to Prevent It.

It’s long been known that deliberate weight loss is typically followed by rebound weight gain unless a concerted effort is made to continue whatever method induced the loss. This rebound weight gain occurs after a variety of weight loss methods, including exercise modification, dietary restrictions and obesity medications. In fact, even those undergoing surgical management of weight loss are not immune to rebound weight gain: within 2-5 years of their surgery, 20-30% of such patients regain ≥15% of their initial weight lost.1

The recent successes seen with the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) such as semaglutide and tirzepatide to facilitate weight loss in the overweight and obese has led to a surge in their popularity (even amongst those who are not necessarily overweight by typical BMI metrics). But as with other weight loss methods, they too are associated with rebound weight gain once users stop taking them, with participants gaining back around half the weight they’d lost a year after stopping semaglutide or tirzepatide, even while receiving lifestyle interventions (reduced calorie diets and exercise advice).2,3 In a study without lifestyle interventions, patients gained back over two-thirds of their previous semaglutide-assisted loss.4

Weight regain in semaglutide and tirzepatide extension trials:


Rubino et al. JAMA. 2021;325(14):1414-1425. doi: https://doi.org/10.1001/jama.2021.3224

Aronne et al. JAMA. 2023;331(1). doi: https://doi.org/10.1001/jama.2023.24945

Why Rebound Weight Gain Occurs

There has been much research into why rebound weight gain occurs, looking at a variety of mechanisms, many of which require further investigation. What is certain, is that it’s much more complex than ‘poor willpower’. Some of these theories are as follows:

Energy Gap When calories are restricted, reduced nutrient availability (due to reduced intake and increased clearance by tissues) and depleted energy stores signal the hypothalamus and hindbrain via low leptin and insulin levels to increase appetite and reduce energy expenditure (the so-called ‘energy gap’).5 If the energy gap is not countered by active efforts to maintain the reduced weight, overfeeding occurs (in the setting of rapid clearance of nutrients) and weight gain recurs. Overeating generally continues until the lost weight returns or is exceeded.

Obesogenic Memory This describes the phenomenon of weight regain and reversion to less healthy metabolic markers, including blood cholesterol, insulin sensitivity and adipokines.6 Immune cells in various tissues and organs are thought to be closely involved with the obesogenic memory and play a role in weight regain, as certain T-cells can ‘remember’ the obese state and promote the release of adipokines such as IL-6 and TNFα, which impair glucose metabolism and insulin sensitivity.6 Indeed, Hinte et al demonstrated that cellular transcriptional alterations in human and mouse adipose tissues remain after appreciable weight loss, with these stable epigenetic changes contributing to the obesogenic memory.7 Furthermore, DNA methylation of CD4 T helper cells has been estimated to last 5-10 years after weight loss, driven by epigenetic changes in autophagy and senescence.8 RNA sequencing of adipocytes from bariatric surgery patients before and years after they’d lost 25% of their weight showed persistent changes in the epigenomes.8 While chronic inflammation in obese white adipose tissue is of most importance in the obesogenic memory, other tissues where inflammation may contribute to weight gain include the CNS, skeletal muscle and liver.

Hypothalamic Inflammation and Gliosis These contribute to obesity in animal models and there is increasing evidence of their role in human obesity.9 (Gliosis is an inflammatory response characterized by more astrocytes and microglia in their reactive forms.) Radiologic evidence of hypothalamic inflammation and gliosis is associated with obesity, increased visceral adiposity and insulin resistance, glucose intolerance and type 2 diabetes mellitus, and weight gain. If such structural changes are permanent (which is still a subject of debate) then hypothalamic inflammation and gliosis may be a contributing factor in rebound weight gain.

Microbiome Obesity is associated with changes in the gut microbiome, such as reduced bacterial biodiversity and increased intestinal permeability, both of which may be triggers for inflammation (and its subsequent effect on the obesogenic memory).6,9 A reduction in Parasutterella species in obese adults has been associated with hypothalamic gliosis and increased dietary fat intake.9 Moreover, in mice with a history of obesity, the previous obese gut microbiome persisted and was thought to contribute to faster weight regain.6

Adipocytes The number of adipocytes in a normal healthy individual is relatively constant throughout adulthood as new cells are created and mature ones cleared, but within ‘adipose depots’ there are variations in the sizes of individual cells.5 With weight loss, adipocytes decrease in volume and conversely increase with weight gain. It’s been suggested that the fluctuations in adipocyte volume with weight loss causes both molecular and mechanical stresses, the relief of which may contribute to the biological drive to regain weight. In addition, in rodent models of weight loss and regain, adipocytes actually increased in number early in the relapse process and then continued to grow. This so-called ‘relapse-induced hyperplasia’ in humans with a genetic predisposition for obesity would explain why some people gain back even more weight than they originally lost.5 Unfortunately, this increase in adipocyte numbers seems to be a permanent effect. Functional changes in adipocytes and neuroendocrine signals affecting adipose tissue may also play a role in weight regain.5

Adipocyte cellularity changes with weight loss and weight regain.
Adapted from MacLean et al.5 Obesity Reviews. 2015;16 (Suppl 1):45-54. doi: https://doi.org/10.1111/obr.12255

Discontinuing GLP-1 RAs

From continuation studies of GLP-1 RAs, it’s clear that the benefits of these agents are maintained only while they continue to be taken. When considering obesity as a chronic disease, this is not surprising: other chronic diseases such as diabetes mellitus and hypertension are not cured by treating them but rather require continued management (typically medication) long-term.

However, it’s evident that many GLP-1 RA users do not continue their treatment long-term. Indeed, in one study 50% of patients with diabetes stopped using them and were more likely to stop GLP-1 RAs than other second-line anti-diabetic agents.10 There are many reasons that the medications are stopped, including adverse events (especially gastrointestinal), cost, lack of supply, needle phobia and achieving goal weight.

Given the body’s apparent inherent mechanisms to regain lost weight, is there anything that can be done to counter this? Furthermore, GLP-1 RA treatment has been shown to reduce the normal post-prandial rise in endogenous GLP to almost zero (much as testosterone replacement therapy is associated with suppression of natural testosterone production).11 This effect provides another route by which weight regain occurs in the particular setting of using GLP-1 RAs for weight loss. Fortunately, research out of New Zealand provides help.

Activating Endogenous GLP-1 Production

Over the last 14 years, the New Zealand government has funded US$15M worth of research at its Plant and Food Research institute, looking for plant-based substances that would activate endogenous production of GLP-1 via the bitter taste receptors (TAS2Rs) on enteroendocrine L-cells lining the gut lumen. After analyzing the distribution of TAS2Rs throughout the gut and testing over 1000 different plants in a human enteroendocrine cell model, researchers identified a bitter substance extracted from a variety of hops grown in New Zealand.12 Patented as Amarasate® and encapsulated as Calocurb ®, clinical studies have shown that when taken an hour before a meal, this all-natural nutraceutical activates GLP-1 6.4 times above baseline and 2 times above the expected peak following food ingestion. Moreover, other satiety hormones, cholecystokinin and peptide YY were also increased (by 6 and 1.7 times, respectively) after Amarasate. Together, these hormones combined to produce an almost 20% decrease in calories at the subsequent ad libitum meal.13 Other studies have demonstrated that Calocurb also reduced overall hunger during a 24-hour fast by 25% and 30% in men and women, respectively, as well as reducing overall cravings in women by 40%.14,15

Side effects with Calocurb are rare, but because up to 10% of individuals may experience diarrhea when starting it, the dose should be gradually titrated up over a week, from 125 mg once a day to up to 250 mg, twice a day. Most patients need 250 mg taken at least an hour before the meals they want to reduce in size, in order to induce weight loss. Calocurb can also be taken to prevent eating, for example, in the evenings for those trying to avoid late night snacking.

It's thus been suggested that Calocurb should be used either concurrently with or when stopping GLP-1 RAs. Concurrent use may help counter the negative feedback loop induced by the high levels of circulating synthetic GLP-1 and help maintain endogenous production. Obesity practitioners have anecdotally reported that their patients can be prescribed lower doses of the synthetic analogs with fewer side effects, when concurrently treated with Calocurb. They advise starting the Calocurb at the same time as the RA, gradually increasing the dose from one an hour before breakfast up to two an hour before breakfast and two more an hour before the biggest meal of the day over a period of a week.16

When stopping GLP-1 RAs (in patients who are not already taking the nutraceutical), it’s suggested that Calocurb will help ‘kick start’ the body back into production of the endogenous hormone. In those cases, practitioners advise starting Calocurb a week or two before the last dose of the synthetic analog at one x 125 mg capsule an hour before breakfast and an hour before the biggest meal of the day. After a week, the dose can be increased to one x 250 mg capsules at these times. Patients who have been taking the prescription medications seem to tolerate Calocurb better and do so can start it more quickly.16

Conclusion

When weight is lost, there is a physiological drive via various mechanisms to regain weight. With much focus on the GLP-1 RAs over recent years, considerable weight regain after stopping them has been demonstrated for both semaglutide and tirzepatide. However, the use of Calocurb, a nutraceutical that activates endogenous production of GLP-1, either concurrently or when GLP-1 RAs are stopped, provides a tool to help prevent rebound weight gain. Furthermore, the reasonable cost of Calocurb means that its long-term use is not financially untenable — of particular concern, given the evidence that the obesogenic memory is long-lasting ,and obesity and overweight are chronic conditions that require ongoing management.

References

  1. Anekwe CV, Knight MG, Seetharaman S, Dutton WP, Chhabria SM, Stanford FC. Pharmacotherapeutic options for weight regain after bariatric surgery. Curr Treat Options Gastroenterol. 2021;19(3):524-541. doi:10.1007/s11938-021-00358-7.
  2. Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 randomized clinical trial. JAMA. 2021;325(14):1414-1425. doi:10.1001/jama.2021.3224
  3. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: The SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38-48. doi:10.1001/jama.2023.24945
  4. 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
  5. MacLean PS, Higgins JA, Giles ED, Sherk VD, Jackman MR. The role for adipose tissue in weight regain after weight loss. Obes Rev. 2015;16 Suppl 1(Suppl 1):45-54. doi:10.1111/obr.12255
  6. Sun M, Zheng S, Gao X, Lin Z. The role of immune cells in obesogenic memory. Cell Mol Immunol. 2020;17(8):884-886. doi:10.1038/s41423-020-0448-1
  7. Hinte LC, Castellano-Castillo D, Ghosh A, et al. Adipose tissue retains an epigenetic memory of obesity after weight loss. Nature. 2024;636(8042):457-465. doi:10.1038/s41586-024-08165-7 .
  8. Niven J, Kucuk S, Gope A, et al. DNA methylation-mediated memory of obesity in CD4 T lymphocytes perpetuates immune dysregulation. EMBO Rep. Published online April 27, 2026. doi:10.1038/s44319-026-00765-w
  9. Sewaybricker LE, Huang A, Chandrasekaran S, Melhorn SJ, Schur EA. The significance of hypothalamic inflammation and gliosis for the pathogenesis of obesity in humans. Endocr Rev. 2023;44(2):281-296. doi:10.1210/endrev/bnac023
  10. Liss DT, Cherupally M, O'Brien MJ, et al. Treatment modification after initiating second-line medication for type 2 diabetes. Am J Manag Care. 2023;29(12):661-668. doi:10.37765/ajmc.2023.89466
  11. Kim SH, Abbasi F, Nachmanoff C, et al. Effect of the glucagon-like peptide-1 analogue liraglutide versus placebo treatment on circulating proglucagon-derived peptides that mediate improvements in body weight, insulin secretion and action: A randomized controlled trial. Diabetes Obes Metab. 2021;23(2):489-498. doi:10.1111/dom.14242
  12. Walker E, Walmsley R, Richards K, McGill A-T 4, Poppitt SD, Ingram JR. Gastrointestinal bitter taste receptors exhibit inter-regional and inter-individual variation. Preprints. Preprint posted online 2024 Nov 25. doi:10.20944/preprints202410.1917.v1
  13. Walker EG, Lo KR, Pahl MC, et al. An extract of hops (Humulus lupulus L.) modulates gut peptide hormone secretion and reduces energy intake in healthy-weight men: a randomized, crossover clinical trial. Am J Clin Nutr. 2022;115(3):925-940. doi:10.1093/ajcn/nqab418
  14. Walker E, Lo K, Tham S, et al. New Zealand bitter hops extract reduces hunger during a 24 h water only fast. Nutrients. 2019;11(11):2754. Published 2019 Nov 13. doi:10.3390/nu11112754
  15. Walker E, Lo K, Gopal P. Gastrointestinal delivery of bitter hop extract reduces appetite and food cravings in healthy adult women undergoing acute fasting. Obes Pillars. 2024;11:100117. Published 2024 Jun 20. doi:10.1016/j.obpill.2024.100117
  16. Gonzàlez B. Personal communication.