Tackling Obesity: Innovations That Tip the Scale

14 mars 2025

World Obesity Day, celebrated every year on the 4^th of March, aims to highlight the health emergency that this disease represents to the public and governments . As part of this global day, ABGi offers you its expert view on the disease.

Obesity is a chronic, progressive and relapsing disease that affects more than one billion people worldwide. In Canada, two out of every three adults are overweight or obese (Figure 1).

Figure 1. Prevalence of obesity in adults in Canada in 2017/2018.

Figure taken from Lytvyak et al., 2022.

The prevailing paradigm of obesity as an excessive accumulation of fat due to an energy imbalance (intake > expenditure) is being challenged by emerging research. The field has moved beyond a simplistic understanding of obesity as a mere energy imbalance, acknowledging its multifaceted aetiology involving complex interactions between genetic, environmental, and physiological factors. Contemporary perspectives emphasise that obesity is also influenced by energy absorption modulated by digestive enzymes, bile acids, microbiota, hormones, and neural signals. According to the World Health Organization (WHO), a body mass index (BMI = weight/height²) of >30 kg/m² defines obesity. This condition is associated with an increased risk of adverse health outcomes, including cardiovascular disease, diabetes, cancer, musculoskeletal and mental disorders, thereby impacting quality of life. In this alarming epidemic context, pharmacological innovation is becoming increasingly important.

Understanding obesity: a multifaceted disease

Obesity is a complex, multifactorial disease that goes far beyond calories.

Obesity has long been considered the result of excess calories combined with a sedentary lifestyle. However, it is now recognised as a multifactorial disease in which genetic, epigenetic, hormonal and environmental factors interact closely. The idea that you can lose weight simply by “eating less and moving more” is therefore outdated.

Genetics play a key role in determining susceptibility to obesity, with several studies highlighting the involvement of specific genetic mutations in monogenic forms of the disease. For example, mutations in the melanocortin 4 receptor (MC4R) disrupt satiety regulation and lead to excessive weight gain from childhood. Similarly, genetic variations that affect the production of and sensitivity to leptin, a key hormone in appetite control, can lead to severe and early-onset obesity. However, it should be noted that these mutations are rare. Most cases of obesity are the result of a complex interaction between genetic predisposition and environmental factors.

The role of the environment is also crucial. The spread of diets rich in fast sugars and saturated fats, often combined with high energy density and increased palatability, has been favoured by industrialisation and urbanisation. These diets stimulate the brain’s pleasure circuits and encourage excessive consumption. At the same time, the rise of service sector jobs and the ubiquity of screens has led to a significant decrease in daily energy expenditure due to the increase in sedentary lifestyles.

Epigenetics provides new insights into the origins of obesity. Specific chemical alterations to DNA, induced by diet or exposure to endocrine disruptors, can exert a long-lasting influence on the expression of genes involved in regulating energy metabolism. For instance, prenatal exposure to a high-fat diet can alter the methylation of the pivotal POMC gene, thereby affecting the brain’s ability to regulate food intake from birth. These findings lay the foundation for the development of targeted prevention strategies, especially during the crucial developmental periods of obesity.

The physiological and neurophysiological mechanisms involved

Obesity can be primarily attributed to an imbalance in the brain’s regulatory mechanisms governing body weight, orchestrated by the hypothalamus and various neural circuits involved in the management of appetite and energy metabolism.

The hypothalamus, located at the base of the brain, acts as a veritable control centre for energy balance.

It integrates signals from the periphery, such as hormones and nutrients, to adjust eating behaviours that regulate body weight, such as food intake, meal frequency and size, energy expenditure, lipid and carbohydrate metabolism and insulin resistance.

Two main neuronal populations are involved in these mechanisms: proopiomelanocortin (POMC) neurons, which promote satiety, and neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons, which stimulate hunger. The balance between the activity of POMC and AgRP neurons and the resulting melanocortin signalling is essential for maintaining energy homeostasis.

In particular, the role of hormones in regulating these brain circuits is crucial for maintaining energy balance. Leptin, a hormone secreted by adipose (fat) cells, signals to the brain to reduce appetite. In cases of obesity, the body can become resistant to leptin, preventing it from reducing calorie intake despite high levels of body fat.

Conversely, ghrelin, a hormone produced by the stomach during fasting, stimulates orexigenic neurons and increases hunger. Recent research has also highlighted the role of GLP-1 (glucagon-like peptide-1), an intestinal hormone that modulates satiety and glucose metabolism. The pharmacological exploitation of the physiological mechanisms of GLP-1 now represents a major advance in the treatment of obesity.

Conventional treatments for obesity: between effectiveness and limitations

Conventional treatment of obesity involves lifestyle modifications, such as dietary changes and increased physical activity, along with bariatric surgery for more severe cases.

Diets aim to create a calorie deficit and change the nutritional composition of meals. The Mediterranean diet, rich in fibre and unsaturated fatty acids, improves metabolism and reduces cardiovascular risk. Low-carbohydrate diets, such as ketogenic diets, stimulate lipolysis and optimise insulin sensitivity. Intermittent fasting, which involves alternating periods of fasting and normal eating, has been demonstrated to promote hormonal regulation of appetite. However, it should be noted that the majority of patients regain weight due to metabolic adaptations.

Exercise has been shown to improve insulin sensitivity and energy expenditure. It is recommended that 150 to 300 minutes of moderate exercise be completed per week, including aerobic exercise and muscle strengthening. However, the weight loss associated with exercise is limited to 2 to 3 kg over six months and must be combined with dietary restrictions for optimal effectiveness.

Bariatric surgery is the most effective method for patients with severe obesity. Gastric bypass and sleeve gastrectomy allow permanent weight loss of 30 to 35% of initial body weight, with significant metabolic benefits. However, these procedures require lifelong medical follow-up due to the risk of nutritional deficiencies and digestive complications.

Whilst these procedures remain the primary treatment option, the increased appetite and cravings frequently observed after weight loss present a considerable challenge to long-term weight maintenance. It is therefore essential today to innovate in the treatment alternatives for this pathology.

The revolution in new anti-obesity drugs

Scientific advances have transformed the treatment of obesity in recent years. While traditional approaches based on lifestyle changes remain essential, they often prove insufficient to induce significant and sustained weight loss in patients with severe obesity. Faced with this challenge, researchers have developed innovative therapeutic strategies. These strategies aim to modulate the neural circuits that control appetite, the hormonal signals that regulate metabolism, and the digestive mechanisms involved in nutrient absorption.

Pharmacological advances have enabled the development of molecules that specifically target the neurohormonal mechanisms involved in the regulation of satiety and energy metabolism. The failure of the first generation of drugs, such as sibutramine and rimonabant, due to their cardiovascular and psychiatric side effects, has prompted researchers to explore safer and more effective approaches. Today, glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide (Wegovy) and tirzepatide (Mounjaro) represent a major breakthrough in this field.

How GLP-1 receptor agonists work

GLP-1 agonists have revolutionised the treatment of obesity by exploiting a natural biological mechanism involved in the regulation of appetite and metabolism. GLP-1 is an incretin, an intestinal hormone secreted after a meal that plays a key role in modulating satiety and carbohydrate metabolism.

It plays a key role in the regulation of blood glucose and appetite by acting on multiple biological targets:

• Central appetite regulation: GLP-1 receptors are highly expressed in the hypothalamus where they activate POMC neurons. This activation leads to an increase in the production of melanocortins, anorectic neurotransmitters that reduce hunger. At the same time, these agonists inhibit AgRP/NPY neurons, which normally stimulate appetite.
• Slowing gastric emptying: Activation of GLP-1 receptors in the gut slows gastric emptying, prolonging the feeling of fullness after a meal, and reducing postprandial glycaemic peaks and limits excessive calorie consumption.
• Improves pancreatic function: By acting directly on the pancreas, GLP-1 agonists stimulate insulin secretion, thereby improving glycaemic control, and reducing the secretion of glucagon, a hyperglycaemic hormone that promotes better metabolic balance. Collectively, these actions contribute to a significant reduction in the risk of type 2 diabetes.

These mechanisms explain why GLP-1 agonists not only induce significant weight loss, but also improve comorbidities associated with obesity, including type 2 diabetes, fatty liver disease and cardiovascular disease.

Semaglutide: a major breakthrough in the treatment of obesity

Semaglutide (marketed as Wegovy) is a GLP-1 agonist that represents a major advance in the pharmacology of obesity. Originally developed for the treatment of type 2 diabetes (Ozempic), its efficacy in weight loss led to its repositioning as a specific treatment for obesity.

Semaglutide has a long half-life (~7 days), allowing for weekly administration via subcutaneous injection. This feature enhances patient compliance by reducing the frequency of injections in comparison to older agonists.

Semaglutide has been shown to effectively reduce body weight by more than 10% and reduce hyperphagia with minimal side effects when administered weekly. This weight loss is comparable to some of the effects of bariatric surgery, positioning semaglutide as a less invasive yet effective alternative.

In addition to the well-known positive effects on glucose regulation and weight control, GLP-1R agonists also have other beneficial effects on cardiometabolic parameters and lipid metabolism.

However, the observed weight loss often plateaus around week 6. In addition, the effects of this treatment vary considerably from person to person.

What does the future hold for the treatment of obesity?

The future of pharmacological treatment of obesity is moving towards optimisation of GLP-1 agonists and new biological targets. Several avenues are being explored, including the use of GLP-1 agonists in combination with one or more other molecules. These combination treatments could improve the regulation of carbohydrate metabolism, increase energy expenditure and/or have synergistic metabolic effects. For instance, recent research investigating these synergies with dexamethasone or tesaglitazar has yielded encouraging initial results in this regard.

Furthermore, given that obesity is a chronic condition, it is essential to take the duration of treatment into account when developing new pharmaceutical forms. This involves the development of oral treatments and the extension of the half-life of subcutaneously injected drugs.

These innovations, when combined with advances in personalised medicine, should improve the efficacy of treatments while reducing their side effects, thus providing sustainable solutions to fight obesity and improve the well-being of patients.

Finally, a change in the care pathways for obesity is now being implemented in order to address the multifactorial nature of this pathology. The development of centres specialising in the multidisciplinary management of obesity (CSO) will improve support for patients and health professionals, in the management of severe/morbid obesity.

Conclusion

In conclusion, obesity is a complex disease with multiple biological and environmental mechanisms, which extend far beyond the simple equation of calories consumed versus calories expended. While conventional approaches have shown significant results, they have sometimes struggled to ensure long-term maintenance of weight loss. Recent pharmacological advances, particularly with GLP-1 agonists and GLP-1/GIP combination molecules, are opening up promising new therapeutic perspectives.

By directly and indirectly targeting the neurohormonal circuits of satiety and metabolism, these treatments offer results comparable to surgery, while being less invasive. However, challenges remain, particularly in terms of accessibility, side effects and inter-individual variability in response to treatment. The future of obesity management will undoubtedly lie in an innovative, integrative approach combining precision pharmacology and optimisation of behavioural therapies to provide an appropriate and sustainable solution for each patient.

By Stéphane Léon

ABGi Innovation Finance Advisor

PhD in neurosciences (specialty: neurobiology of obesity)