Has the arrival of GLP-1 analogs signaled the end of obesity research? That provocative question framed a session on January 15 at the French Association for the Study of Obesity (AFERO) congress. In her introduction, Karine Clément, MD, PhD, endocrinologist at Assistance Publique-Hôpitaux de Paris, Paris, France, and president of AFERO, reminded attendees that “In 1994, the discovery of leptin generated a lot of hope. We thought obesity research was over, which was not the case. That invites us to reflect on the advances and limits of scientific discoveries.”

Limits of GLP-1 analogs

Those limits are already becoming apparent for GLP-1 analogs. “I want to mention a recent article, which you may have read in The BMJ,” Clément said. “The authors conducted a meta-analysis of more than 9300 adult participants, pooling studies of available drugs, notably incretin therapies, in patients who had never been treated with them, as well as behavior-modification programs. According to this publication, treatment discontinuation typically occurs after about 1 year for various reasons. The authors also note that weight regain after stopping the medication is rapid in kinetic terms, sometimes even faster than after dietary interventions. This observation prompts clinical reflection, especially since in France nearly 10,000 people had early access to GLP-1 analogs, mainly patients with severe obesity — a body mass index greater than 40 with complications.” This early access program has now ended, and patients must consider paying for their treatment to continue receiving support.

Nervous System

Christophe Magnan, a biologist at Université Paris‑Santé, Paris, reviewed the research on the role of the central and peripheral nervous systems in food intake. Here again, not all the answers have been found, and many questions remain unanswered, demonstrating that further research is still very much needed. “The hypothalamus is traditionally seen as the homeostatic center, but other regions — such as the olfactory bulb, the prefrontal cortex, and the limbic system — play important roles in motivation, memory, and emotions related to food. The olfactory bulb, for example, expresses GLP‑1 receptors, and its activation can reduce food intake in mice. The peripheral nervous system, notably the nodose ganglia and vagal afferents, is also at the center of current research, which is opening new therapeutic avenues,” he said.

Adipose Dysfunction in Obesity

Research on adipose tissue is also booming, as Dominique Langin, PhD, who led the research and directs the Institute of Metabolic and Cardiovascular Diseases at the University of Toulouse, Toulouse, France, demonstrated, “Recent work shows that certain forms of obesity, notably those associated with severe insulin resistance, may be linked to adipose tissue dysfunction. Observations in familial partial lipodystrophies illustrate the complexity of clinical phenotypes. Finally, epigenetics is discussed as a possible factor in the reversibility of weight loss or in weight regain after treatment.”

Fermented Fibers Boost GLP-1

Nathalie Delzenne, of the Faculty of Pharmacy and Biomedical Sciences at UCLouvain University, Brussels, Belgium, addressed the central role of the gut — notably the intestinal microbiota — in metabolic regulation and the endogenous production of GLP‑1. Diet, particularly the intake of fibers fermented by certain bacteria, stimulates GLP‑1 production by intestinal L cells, especially in the distal gut (the colon). Short‑chain fatty acids produced by fermentation are ligands for receptors (FFAR2, FFAR3) that promote GLP‑1 secretion. She also noted that studies on the direct impact of GLP‑1 agonists on the microbiota and on endogenous GLP‑1 production remain scarce, and the results are inconsistent. In addition, side effects and tolerance to treatments vary among individuals, which calls for personalized nutritional and behavioral management, notably integrating the microbiota as a modulatory factor. Prevention and nutritional recommendations remain essential pillars, alongside pharmacologic treatments.

The message from the session was clear: obesity research is far from over.

This story has been translated from Univadis France, part of the Medscape Professional network.