Obesity Reveals Its Secrets Between Genes and Hormones

Obesity now affects nearly 30% of the global population, a figure that has tripled since 1975. Long perceived as a simple imbalance between energy intake and expenditure, this complex disease actually results from a close interaction between genetics, environment, and hormonal signals. The mechanisms underlying it are beginning to be better understood, paving the way for more targeted and effective treatments.

At the heart of this progress is the discovery, in 1994, of leptin, a hormone produced by fat cells. Its role is simple but crucial: to inform the brain of energy reserve levels in order to regulate appetite and energy expenditure. In obese individuals, leptin levels are often high, but the brain becomes less sensitive to its signals, a phenomenon known as leptin resistance. The latter significantly limits the effectiveness of leptin-based treatments, despite initial hopes.

Meanwhile, another hormone, glucagon-like peptide-1 or GLP-1, has emerged as a promising avenue. Secreted by the intestine in response to food intake, it acts on several fronts: it reduces appetite, slows gastric emptying, and stimulates insulin secretion, while also improving sensitivity to insulin. Unlike leptin, GLP-1 receptors retain their functionality in obese individuals, making them a prime therapeutic target.

Treatments based on GLP-1 receptor agonists, such as semaglutide or liraglutide, have revolutionized obesity management. They enable significant weight loss, often exceeding 10%, while improving glycemic control and reducing cardiovascular risks. Their mechanism of action relies on a prolonged imitation of the natural effect of GLP-1, thanks to chemical modifications that make them resistant to rapid degradation in the body.

Genetics also plays a key role in the predisposition to obesity. Rare mutations, such as those affecting the leptin gene or its receptor, cause severe obesity from childhood. More commonly, minor genetic variations, present in hundreds of genes, combine to increase the risk. Among these, the FTO gene is one of the most influential on body mass index. These genetic predispositions interact with the environment: a rich diet and a sedentary lifestyle amplify their impact.

Polymorphisms, these natural variations in DNA, also influence the response to treatments. For example, certain variants of the GLP-1 receptor gene modify the effectiveness of agonists, explaining why some patients respond better than others. These discoveries highlight the importance of personalized medicine, where the genetic profile could guide the choice of the most suitable treatment.

The interaction between leptin and GLP-1 is another fascinating area of research. Studies show that GLP-1 could partially restore leptin sensitivity, particularly by acting on the gut microbiota. This synergy opens the prospect of combined therapies, associating both hormones to enhance their effects. Molecules like tirzepatide, which activate both GLP-1 and GIP receptors (another intestinal hormone), have already demonstrated superior efficacy compared to treatments targeting only GLP-1.

However, these therapeutic advances are not without challenges. Side effects, mainly digestive such as nausea or diarrhea, can limit adherence. The high cost of these drugs also poses an access problem, widening health inequalities. Additionally, stopping treatment often leads to weight regain, underscoring the need for a long-term approach.

Obesity is therefore no longer considered a simple matter of willpower, but as a multifactorial disease where biology, genetics, and lifestyle intertwine. Recent progress in understanding hormones like leptin and GLP-1, as well as in identifying genetic factors, is transforming how this condition is addressed. Current treatments, while promising, will need to evolve further to become accessible to all and sustainable in the long term.

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Official Study Source

DOI: https://doi.org/10.1007/s13353-026-01084-5

Title: Unravelling obesity: from leptin to glucagon-like peptide-1 receptor agonists

Journal: Journal of Applied Genetics

Publisher: Springer Science and Business Media LLC

Authors: Taiwo Oluwafemi Idowu; Agata Chmurzynska