Blog

Rebound Weight Gain After Weight Loss: Why It Occurs And How To Prevent 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. 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.7 (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).6,7 A reduction in Parasutterella species in obese adults has been associated with hypothalamic gliosis and increased dietary fat intake.7 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. 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.8 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, especially in the setting of GLP-1 RA treatment, where it’s also been suggested that these agents may incur a negative feedback loop against the body’s production of its own natural GLP-1—much as testosterone replacement therapy is associated with suppression of natural testosterone production? 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 cells. 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. Patented as Amarasate®, clinical studies have shown that when taken an hour before a meal, this all-natural nutraceutical activates GLP-1 6 times above baseline and 2 times above the expected peak following food ingestion, with an almost 20% decrease in calories at the subsequent meal.9 Other studies have demonstrated that Amarasate also reduced overall hunger during a 24-hour fast by 25% and 30% in men and women, respectively.10,11

Side effects with Amarasate 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 one a day to up to two, twice a day.

It's thus been suggested that Amarasate should be used either concurrently with or when stopping GLP-1 RAs. Concurrent use may help counter a negative feedback loop induced by the high levels of circulating synthetic GLP-1 (should that loop exist) 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 Amarasate. They advise starting the Amarasate 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.12

When stopping GLP-1 RAs (in patients who are not already taking the nutraceutical), it’s suggested that Amarasate will help ‘kick start’ the body back into production of the endogenous hormone. In those cases, practitioners advise starting Amarasate in the week of the last dose of the synthetic analog at one capsule an hour before breakfast and an hour before the biggest meal of the day. After a week, the dose can be increased to two capsules at these times. Patients who have been taking the prescription medications seem to tolerate Amarasate better and do so can start it more quickly.12

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 Amarasate, a nutraceutical that activates endogenous production of GLP-1, either concurrently or when GLP-1 RAs are stopped, provides a tool to help counter weight regain. Furthermore, the reasonable cost of Amarasate means that its long-term use is not financially untenable.

- Written for Calocurb by Dr. Tracey Lambert

References

  1. Anekwe C, Knight M, Seetharaman S, Dutton W, Chhabria S, Stanford f. Pharmacotherapeutic Options for Weight Regain After Bariatric Surgery. Current Treatment Options in Gastroenterology. 2021;19(3):524-541. doi: https://doi.org/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: https://doi.org/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. 2023;331(1). doi: https://doi.org/10.1001/jama.2023.24945
  4. Wilding J, Batterham R, Davies M, et al. Weight Regain and Cardiometabolic Effects after Withdrawal of Semaglutide: The STEP 1 Trial Extension. Diabetes, Obesity and Metabolism. 2022;24(8):1553-1564. doi: https://doi.org/10.1111/dom.14725
  5. MacLean P, Higgins J, Giles E, Sherk V, Jackman M. The Role for Adipose Tissue in Weight Regain After Weight Loss. Obesity Reviews. 2015;16 (Suppl 1):45-54. doi: https://doi.org/10.1111/obr.12255
  6. Sun M, Zheng S, Gao X, Lin Z. The Role of Immune Cells in Obesogenic Memory. Cellular and Molecular Immunology. 2020;17(8):884-886. doi: https://doi.org/10.1038/s41423-020-0448-1
  7. Sewaybricker L, Huang A, Chandrasekaran S, Melhorn S, Schur E. The Significance of Hypothalamic Inflammation and Gliosis for the Pathogenesis of Obesity in Humans. Endocrine Reviews. 2023;44(2):281-296. doi: https://doi.org/10.1210/endrev/bnac023
  8. Liss D, Cherupally M, O’Brien M, et al. Treatment Modification After Initiating Second-Line Medication for Type 2 Diabetes. Am J Manag Care. 2023;29(12). Accessed April 6, 2024. https://www.ajmc.com/view/treatment-modification-after-initiating-second-line-medication-for-type-2-diabetes
  9. 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. The American Journal of Clinical Nutrition. 2022;115(3):925-940. doi: https://doi.org/10.1093/ajcn/nqab418
  10. 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. doi: https://doi.org/10.3390/nu11112754
  11. Walker, E.; Lo, K.; Gopal, P. Gastrointestinal Delivery of Bitter Hops Extract Reduces Appetite and Food Cravings in Healthy Adult Women Undergoing Acute Fasting. Preprints 2023, 2023090416. https://doi.org/10.20944/preprints202309.0416.v1
  12. Gonzàlez B. Personal communication.