Humanity has long struggled to maintain an ideal weight, although notions of the optimal body shape vary between cultures and over time. Ancient Greeks and Romans used emetics and laxatives to shed the pounds.1 In the late 19th century, doctors started using thyroid extracts. Patients lost weight, but risked developing muscle and bone damage, arrythmias, tachycardia and heart failure.1,2 During the 1930s, doctors turned to 2-4 dinitrophenol, which increased fat metabolism, but caused cataracts, rashes and toxic hyperthermia.1,2 Around the same time, doctors started treating obesity with amphetamine and methamphetamine, which are, of course, highly addictive.1,2
More recently, several weight-loss drugs were withdrawn following reports of serious adverse events including fenfluramine and dexfenfluramine (valvular heart disease), sibutramine (cardiovascular disease) and rimonabant (psychiatric side effects).1,2 Historically, weight-loss drugs were not pharmacology’s finest hour. But during studies of glucagon-like peptide (GLP-1) receptor agonists (GLP-1RA) for diabetes, researchers noted that participants lost weight, which prompted investigations into their potential as anti-obesity treatments.3
Currently, several drugs are approved for weight loss in selected patients (see the BNF for details). Orlistat, for instance, inhibits an enzyme called pancreatic lipase. So, orlistat reduces the digestion and absorption of fats from the small intestine by about 30%.1 Setmelanotide is an agonist of melanocortin-4 receptors, one of several chemical mediators that influence weight. Setmelanotide is used, under expert supervision, to reduce weight in people with certain genetic diseases, such as Barden-Biedel syndrome.
Today, GLP-RAs are one of the few drugs that form part of our common cultural parlance alongside, for instance, Viagra, aspirin and penicillin. Politicians use GLP-RAs to capture the headlines, suggesting the jabs could help the unemployed into work. GLP-RAs prompted countless ‘celebrity endorsements’ and even inspired a South Park episode. This article focuses on the mechanisms through which GLP-RAs liraglutide, semaglutide and tirzepatide help people lose weight. Tirzepatide is also an agonist (binds to and stimulates) glucose-dependent insulinotropic polypeptide (GIP) receptors. But it’s about more than pharmacology: anti-obesity drugs stand at the intersection between politics, culture and social justice.
All in the mind
You may think that GLP-RAs rentimately linked. The vagal nerve carries signals about the stretching of the gastrointestinal tract after a meal to the brain stem.4 Nerves project from the brainstem to food-intake centres in the hypothalamus.3
The hypothalamus interprets signals from peripheral tissues and sends signals back telling the body to, for instance, spend or store energy.5 Fundamentally, the hypothalamus is homeostatic: balancing food intake against energy expenditure.6 So, damage to the hypothalamus from, for example, tumours; inflammation (such as from tuberculosis or encephalitis); head injury; neurosurgery; radiation and cerebral aneurysms or some genetic diseases, can cause obesity.5
Another brain region, the mesolimbic system, influences motivational aspects of feeding, including the ‘reward’ from food, learning to obtain and memories about sources of nutrition.7 Hormones such as leptin, insulin and ghrelin link the hypothalamic and mesolimbic systems.6 The mechanisms that hinder weight loss are stronger than those that prevent weight gain.6 This makes evolutionary sense: you gain weight in case food becomes scarce. As we will see, social pressure, cognition and environment can override the homeostatic mechanisms.6
GLP-1, GIP and other peptides (small proteins) released from adipose and gastrointestinal cells inhibit appetite and modulate hunger and satiety from meal-to-meal and from day-to-day.6
Members of the prohormone convertase group of enzymes cut GLP-1 from a longer protein called proglucagon3,4 ‘L-cells’ in the small intestine and colon, pancreatic islet -cells and neurons in the nucleus of the solitary tract in the brainstem synthesise most of the body’s GLP-1.3,4 Nerves that project from the brainstem to food-intake centres in the hypothalamus also produce GLP-1.3
GLP-1 production in the central nervous system (CNS) and peripheral tissues are essentially separate. CNS production contributes little to circulating levels of GLP-1.3 Several factors, most notably carbohydrates, fat, protein and bile acids, stimulate GLP-1 secretion in the gut.3 However, GLP-1 produced by the gut does not reach sufficiently high levels to affect normal food intake.3 Furthermore, blocking GLP1 receptors in the gut increases levels of GLP-1 and some other messengers, such as peptide YY (a satiety signal), as the body tries to overcome the inhibition.3
GLP-1 binds to specific receptors that are expressed by (present on) numerous tissues including the gastrointestinal tract, pancreas, certain brain regions, heart, vascular smooth muscle, kidney, lungs and some immune cells.3,8 But GLP-1 is not suitable as a drug for obesity or diabetes. Typically, dipeptidyl peptidase-4 (DPP-4) breaks GLP-1 down in 1-2 minutes.4 (DPP-4 inhibitors are important anti-diabetic drugs: by blocking breakdown they maintain levels of GLP-1 and GIP.) A drug needs to remain in the blood for much longer. The solution came from an unexpected source.
Famous monsters
The Gila monster (Heloderma suspectum), a venomous lizard that lives in the deserts of the southwest USA and northwest Mexico, can eat up to half its body weight in one sitting. Despite such huge meals, the lizard’s blood sugar levels remain stable.4 The Gila monster produces a small protein called exendin-4, which stimulates insulin secretion and regulates blood glucose levels.4
Exendin-4 shares about half its amino acids with GLP-1. This is sufficiently similar for exenatide, the therapeutic version of the lizard’s protein, to treat type 2 diabetes in humans. But the structure is sufficiently different so that DPP-4 does not degrade exenatide as readily as endogenous GLP-1. So, exenatide persists in the blood long enough to allow twice-daily dosing with immediate-release formulations. (A prolonged-release exenatide suspension now allows once-weekly dosing.) Other GLP-1RAs are even more resistant, allowing up to once weekly dosing.4
By binding to and stimulating GLP-1 receptors, GLP-1RAs mimic endogenous GLP-1. So, GLP-1RAs inhibit glucagon release and enhance insulin secretion.4 Indeed, GLP-RAs can stimulate GLP-1 receptors to levels above those attained physiologically, which increases insulin secretion in people with T2D.3 GLP1-RAs reduce appetite by targeting GLP-1 receptors in the brainstem, hypothalamus or both, slowing gastric emptying, increasing satiety and changing food preferences.3,8,9 Moreover, the vagal nerve expresses GLP-1 receptors. So, the increase in GLP-1 tiggered by nutrients enhances the neuronal responses to gastric and intestinal stretching. The brain stem receives an integrated signal regarding a meal’s volume and nutritional content.3,4
Tirzepatide is also an agonist of GIP receptors. ‘K-cells’ in the small intestine secrete GIP, which, in healthy people, induces glucose-dependent insulin and glucagon release.10 Again many tissues express GIP receptors including the pancreas, adipocytes, bones and the CNS. So, GIP regulates of food intake, lipoprotein lipase activity and fat decomposition in adipose tissue. GIP is also lipolytic during hyperglycaemia, when insulin levels are low.10 Interestingly, used alone GIP seems to increase weight and fat storage, but used with GLP markedly reduces weight.10,11 Researchers are still unravelling the exact mechanisms underlying this seemingly paradoxical effect.12,13
In addition to the hypothalamus and brain stem, GLP-1 RAs and GIP agonists seem to reduce appetite by, in part, acting on the mesolimbic system: the same brain region that contributes to addiction. Indeed, a recent retrospective study reported that GLP-1 RAs and GIP agonists could be effective in opioid use (OUD) and alcohol use (AUD) disorders.14
The study included 503,747 adults with a history of OUD. Of these, 8103 had been prescribed a GLP-1 RA or GIP agonist for T2D or obesity. People with OUD who received a GLP-1 RA or GIP agonist had a 40% lower rate of opioid overdose compared with controls who did not have a prescription for one of these medicines.14
The study also enrolled 817,309 adults with a history of AUD. Of these, 5621 had received a prescription for a GLP-1 RA or GIP agonist. AUD patients who used a GLP-1 RA or GIP agonist had a 50% lower rate of alcohol intoxication than controls. The protective effects were consistent across subgroups. ‘Although the results are promising, they highlight the need for further research, particularly prospective clinical trials, to validate these associations and understand the underlying mechanisms,’ the authors conclude.14
A matter of taste
Humans are, unless you choose otherwise, omnivores. Our ability to consume a vast range of food, from escargot to eels, from eclairs to einkorn, from eggs to elderflowers, helped our ancestors to colonise almost every part of the planet.6
Certainly, we’re born with innate taste preferences. Shortly after birth, babies seem to prefer sweet and umami tastes and dislike bitter and sour tastes. This makes sense: sweetness signals calories, umami indicates protein and bitterness warns of potential poisons.15 But food choice depends more on, for instance, geography, climate, religion and culture, than biology.6 Ancient Roman patricians, for example, ate a meal called the Shield of Minerva consisting of pike livers, pheasants and peacock’s tongues, flamingo brains and lamprey intestines.16
So, researchers distinguish hunger from appetite. You feel hungry when you need calories.7 Appetite is the desire to eat a specific food regardless of whether or not you need the calories.7 I’ll eat a cheese sandwich to sate my hunger. But I can’t resist a slice of cheesecake even if I’ve just had lunch. Appetite links and reflects the complex interplay of the internal (physiological) and the external (social, cultural, physical and psychological) and environmental factors.6
Against this background, GLP-1RAs seem to change food preferences, which probably contributes to the weight loss. For example, patients taking semaglutide reported less desire for dairy, starchy, salty spicy and energy-dense foods. They also experienced fewer problems controlling eating and resisting cravings, and ate smaller meals.8 The effect seems most marked during the weight-loss phase, rather than when patients maintain their new weight.8
The eye of the beholder
Anti-obesity drugs stand at a four-way intersection between pharmacology, politics, social justice and culture. ‘Acceptable’ body size, for example, is in the eye of the beholder. In the 17th and 18th centuries, excess body weight signified wealth, health, well-being, fertility and beauty: think of the classic Rubenesque female. At the time, society faced widespread poverty, epidemics and food insecurity1 and a few extra pounds could mean the difference between life and death.
Today, obesity is a societal bête noire. Women, in particular, face ‘social pressures’ to be thin, which ‘helps to explain the high levels of body dissatisfaction and disordered eating among women’.17 Meanwhile, the morbidly obese of yesteryear’s freakshow migrated to tabloid streaming channels, in ‘documentaries’ that combine a supposed ‘voyeuristic appeal’ with ‘sympathetic images’. But at their core, the distinguished historian Professor Gary Cross notes, ‘The audience is to cheer [the morbidly obese] on … like the freak show crowd of old, aghast at their bodies’.18
We also look aghast at obesity’s costs to the NHS and patients’ inability to participate fully in society’s economic life. Health Secretary Wes Streeting’s suggestion that anti-obesity drugs could help unemployed people into work and reduce costs to the NHS certainly captured the headlines.
Yet obesity, Alcantara and colleagues note, ‘is an absurdly monolithic label encompassing the many physiological and psychological consequences of a positive energy balance’.7 In other words, numerous factors influence food intake and energy expenditure including genetics, socioeconomics, food availability and marketing, stress, anxiety, depression and misleading health and nutritional information.7 That’s not to mention the plethora of other factors that hinder employment prospects. It seems unlikely that a jab, even embedded in well-designed services, could prove a magic bullet for obesity’s causes, complications and consequences. Moreover, the long-term effects in obese people without diabetes taking GLP-RAs for weight loss are ‘largely unknown’.9
In any case, we are nowhere near treating all those who could benefit from anti-obesity medications. The Obesity Health Alliance notes that, currently, 4.1 million people in England are eligible for semaglutide for weight-loss. Yet NHS projections estimate that by 2028, fewer than 50,000 people per year will receive semaglutide for weight-loss, despite new funding. NICE’s approval of tirzepatide will increase the pressure. Indeed, NHS England estimate that implementing the draft NICE guidance for tirzepatide could take up to 12 years.19
Meanwhile, GLP-1RAs are finding numerous additional roles, including slowing the progression of Alzheimer’s and Parkinson’s diseases, and exhibiting potentially valuable anti-inflammatory actions for conditions such as osteoarthritis, rheumatoid arthritis and cardiovascular diseases.4 The impact of these emerging roles on services, political rhetoric and patients remains moot. Nevertheless, one thing seems certain: for all the time they’ve already spent on the front pages, GLP-RAs are set to a fixture in the headlines.
Mark Greener is a freelance medical writer
References
1.Haslam D. 2016. Weight management in obesity - past and present. Int J Clin Pract. 70 (3):206-17. https://doi.org.10.1111/ijcp.12771.
2. Sumiska M, Podgórski R, Bogusz-Górna K et al. 2022. Historical and cultural aspects of obesity: From a symbol of wealth and prosperity to the epidemic of the 21st century. Obesity Rev. 23 (6):e13440. https://doi.org.https://doi.org/10.1111/obr.13440.
3. Gribble FM and Reimann F. 2021. Metabolic messengers: glucagon-like peptide 1. Nat Metab. 3 (2):142-8. https://doi.org.10.1038/s42255-020-00327-x.
4. Zheng Z, Zong Y, Ma Y et al. 2024. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Sig Transduct Target Ther. 9 (1):234. https://doi.org.10.1038/s41392-024-01931-z.
5. Kim JH and Choi JH. 2013. Pathophysiology and clinical characteristics of hypothalamic obesity in children and adolescents. Ann Pediatr Endocrinol Metab. 18 (4):161-7. https://doi.org.10.6065/apem.2013.18.4.161.
6. Casanova N, Finlayson G, Blundell JE et al. 2019. Biopsychology of human appetite — understanding the excitatory and inhibitory mechanisms of homeostatic control. Curr Opin Physiology. 12:33-8. https://doi.org.https://doi.org/10.1016/j.cophys.2019.06.007.
7. Alcantara IC, Tapia APM, Aponte Y et al. 2022. Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding. Nat Metab. 4 (7):836-47. https://doi.org.10.1038/s42255-022-00611-y.
8. Bettadapura S, Dowling K, Jablon K et al. 2024. Changes in food preferences and ingestive behaviors after glucagon-like peptide-1 analog treatment: techniques and opportunities. Int J Obes. https://doi.org.10.1038/s41366-024-01500-y.
9. Moll H, Frey E, Gerber P et al. 2024. GLP-1 receptor agonists for weight reduction in people living with obesity but without diabetes: a living benefit-harm modelling study. EClinicalMedicine. 73:102661. https://doi.org.10.1016/j.eclinm.2024.102661.
10. Kaneko S. 2022. Tirzepatide: a novel, once-weekly dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes. touchREV Endocrinol. 18 (1):10-9. https://doi.org.10.17925/ee.2022.18.1.10.
11. Jastreboff AM, Aronne LJ, Ahmad NN et al. 2022. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 387 (3):205-16. https://doi.org.10.1056/NEJMoa2206038.
12. Rees TA, Buttle BJ, Tasma Z et al. 2024. Tirzepatide, GIP(1-42. and GIP(1-30. display unique signaling profiles at two common GIP receptor variants, E354 and Q354. Front Pharmacol. 15. https://doi.org.10.3389/fphar.2024.1463313.
13. Holst JJ and Rosenkilde MM. 2020. GIP as a therapeutic target in diabetes and obesity: insight from incretin co-agonists. J Clin Endocrinol Metab. 105 (8):e2710-6. https://doi.org.10.1210/clinem/dgaa327.
14. Qeadan F, McCunn A and Tingey B. 2024. The association between glucose-dependent insulinotropic polypeptide and/or glucagon-like peptide-1 receptor agonist prescriptions and substance-related outcomes in patients with opioid and alcohol use disorders: A real-world data analysis. Addiction. https://doi.org.10.1111/add.16679.
15. Ventura AK and Worobey J. 2013. Early influences on the development of food preferences. Curr Biol. 23 (9):R401-8. https://doi.org.10.1016/j.cub.2013.02.037.
16. Beard M. 2023. Emperor of Rome: Profile Books. p. 99.
17. Katzmarzyk PT and Davis C. 2001. Thinness and body shape of Playboy centerfolds from 1978 to 1998. Int J Obes Relat Metab Disord. 25 (4):590-2. https://doi.org.10.1038/sj.ijo.0801571.
18. Cross G. 2021. Freak Show Legacies: Bloomsbury Academic. p. 210.
19. Obesity Health Alliance. 2024. Position Statement: A Way Forward for the Treatment of Obesity. Available at https://obesityhealthalliance.org.uk/2024/10/16/treatment/ Accessed November 2024.