ORIGINALLY PUBLISHED
12 May 2025
There remains a pressing need for advanced strategies and solutions to address the growing obesity epidemic. As scientific understanding of obesity grows, so too has our understanding of the biological systems that drive it. Once viewed primarily through the lens of body weight, obesity is now recognised as a complex, chronic disease involving interconnected pathways that influence metabolism, adipose tissue, body composition and impact multiple organs throughout the body.1,2
Nearly three billion people globally are living with obesity or overweight, and more than half of the world’s population is expected to be affected by 2035.3,4 Obesity is associated with more than 200 complications,5 and, in the US, nearly nine out of ten people living with obesity or overweight have at least one cardiovascular, renal or metabolic (CVRM) comorbidity.6
This growing understanding of obesity’s biological complexity is helping to reshape scientific thinking. Increasing attention is being paid to the multiple mechanisms that contribute to obesity and its related conditions, and how these interconnected systems influence long-term health.7
Understanding the biology of adipose tissue
Obesity results from a chronic imbalance between energy intake and expenditure.8 Beneath this simple equation, however, lies a complex network of biological signals that regulate appetite, metabolism, energy balance and organ function.7
Adipose tissue, commonly referred to as body fat, plays a central role in these processes. Far from being a passive store of excess energy, adipose tissue is an active organ that communicates with other tissues throughout the body through hormones, inflammatory signals and metabolic pathways.9
Not all adipose tissue functions in the same way. Subcutaneous fat, located beneath the skin, serves as an energy reserve and provides insulation. Visceral fat, which surrounds organs, is associated with greater health risks and can contribute to metabolic dysfunction.10
Figure: Adipocytes store excess calories as fat. Subcutaneous adipocytes do this safely, but those that surround the organs as visceral fat are much more metabolically active.11
When adipose tissue becomes dysregulated, it can contribute to inflammation, insulin resistance and impaired metabolic function, affecting multiple organ systems throughout the body.2,9 This understanding has changed our approach to obesity from a condition defined by excess weight alone to one characterised by complex biological interactions.
The gut-brain axis and the role of GLP-1
One of the most important biological systems involved in regulating metabolism is the gut-brain axis – a communication network connecting the gastrointestinal tract, pancreas and brain.12,28 A key component of this system is glucagon-like peptide 1 (GLP-1), a hormone that is part of the incretin family of hormones that are secreted in response to food intake.12 GLP-1 is produced in the intestinal enteroendocrine called L-cells as well as part of the brain, providing a link between food intake, appetite and metabolic function.13,14
GLP-1 helps coordinate several important physiological processes. It slows gastric emptying, suppresses glucagon secretion, promotes glucose-dependent insulin secretion and contributes to feelings of fullness following meals.15 Through these actions, GLP-1 helps regulate energy balance, glucose metabolism and overall metabolic health.16
GLP-1 receptor agonists regulate glycaemic control and body weight, and research has shown that they may play a role in liver, respiratory and neurological health.15 Ongoing research is being conducted to better understand the potential effects in these areas. 15
Beyond these areas, there is a lot of interest in understanding the full extent of GLP-1’s impact throughout the body; receptors are primarily located in the pancreas but are present in other organs and tissues, including the brain, heart, kidneys, and lungs, as well as in immune cells, highlighting the interconnected nature of the biological systems involved in obesity and related diseases.17,18 These findings have led to further research to explore the therapeutic potential beyond metabolic and cardiovascular disease.
GLP-1 receptor agonists have been described by researchers as one of the most impactful scientific discoveries in modern medicine, given their impact throughout a multitude of interrelated biological mechanisms. From their effects on the heart and blood vessels, to glucose regulation, to evidence suggesting they may reduce neuroinflammation and potentially promote nerve growth, among many other actions, the GLP-1 mechanisms underscore the intricate interconnectedness of our biological systems.
The role of amylin in metabolic regulation
Another important hormone involved in energy balance and metabolism is amylin, which is co-secreted with insulin by the pancreas following food intake.19 Amylin works alongside insulin to support glucose regulation and metabolic balance. They slow gastric emptying, helps regulate the rate at which glucose enters the bloodstream and contributes to feelings of fullness after eating.20
In addition, amylin helps regulate glucagon secretion, a hormone that raises blood glucose levels, providing another layer of control over blood sugar and overeating. This multifaceted action makes amylin an essential component of the body's natural glucose regulation process.19,20,21
Amylin is emerging as an important puzzle piece in unraveling the complexity of adiposity. This hormone connects how the pancreas regulates blood sugar, how the brain signals fullness, and even how organs like the liver process nutrients. By revealing these overlapping systems, we are increasingly showing that obesity is a web of metabolic and neurological interactions.
Beyond weight: the role of activin in maintaining a healthy body composition
As understanding of obesity continues to evolve, increasing attention is being paid not only to body weight, but also to body composition and physical function.
Skeletal muscle plays a critical role in metabolic health, physical strength and overall wellbeing.22 Maintaining healthy muscle mass can support mobility, independence and systemic metabolic function throughout life.22,23
Among the pathways involved in regulating muscle and body composition are activin signalling pathways. These pathways play important roles in muscle growth, fat metabolism and broader metabolic processes.24,25 Evidence suggests that activin signalling may become dysregulated in chronic obesity, and blocking these pathways may help to preserve muscle mass. This is key for healthy, sustainable weight loss, supporting people maintain strength, function and metabolic health as weight comes down.25,26
This growing understanding reflects an important evolution in obesity science. Increasingly, attention is shifting beyond weight reduction alone towards broader measures of health, including body composition, metabolic function and physical wellbeing.
The role of glucagon in metabolic regulation
Glucagon is a naturally occurring hormone that plays an important role in energy metabolism.27 While its receptors are found in several tissues, glucagon has particularly important effects in the liver, where activation increases energy expenditure as well as regulates glucose and fat metabolism by increasing hepatic glucose production, inhibiting lipogenesis (fat storage) and stimulating lipolysis (fat breakdown).27 Research suggests these mechanisms may help mobilise fat stores and support reductions in inflammation and fibrosis while maintaining metabolic balance and promoting weight loss.24,27
Glucagon acts through biological pathways that may complement those of GLP-1, making dual GLP-1/glucagon receptor agonists an important area of ongoing research.28 These approaches aim to combine effects on appetite regulation with increased energy expenditure, reflecting the growing understanding that multiple interconnected mechanisms contribute to obesity and metabolic disease.28
As obesity science continues to evolve, combining complementary biological pathways represents an important area of research. By targeting different mechanisms involved in metabolism and organ function, these approaches have the potential to deliver broader protection for the heart, blood vessels, liver, and kidneys while providing sustainable weight management.
Why multiple mechanisms matter
Obesity is a multifactorial, chronic disease resulting from genetic, hormonal, environmental, and behavioural interactions, 1,2,29 meaning it cannot be fully understood through a single biological mechanism or addressed through a one-size-fits-all approach.
The biological systems that contribute to obesity are highly interconnected. Different biological pathways influence different aspects of health, from appetite regulation and glucose metabolism to adipose tissue function, body composition and physical wellbeing.7 This complexity highlights the importance of continuing to explore multiple scientific approaches that reflect the diverse needs of people living with obesity and its associated conditions.
Advancing obesity science through a deeper understanding of biology
At AstraZeneca, our approach is informed by a growing understanding of the biological root causes of obesity and its relationship with CVRM diseases. Building on decades of expertise across CVRM diseases, we are working to advance research that reflects the complexity of obesity and supports developing solutions that can be tailored to individual needs to deliver efficacious weight loss and organ protection across related co-morbidities.
At AstraZeneca, our approach is guided by a growing understanding of the biological complexity of obesity and its relationship with cardiovascular, renal and metabolic diseases. By advancing research across multiple biological pathways, we aim to deepen scientific understanding of these interconnected conditions and support future approaches that address the diverse needs of people living with obesity.
