The development of metabolism-targeting drugs, particularly GLP-1 agonists, has transformed obesity treatment, expanding access to effective weight-loss medications but also raising concerns about adverse effects, long-term dependence, and weight regain after discontinuation. In this Special Issue of Science, three Reviews a Policy Forum, and two Perspectives highlight the need to better understand fat-tissue biology and to develop treatments that work through different mechanisms – with fewer unwanted effects. Research investigating whether these medications may have broader effects on neurological conditions, cancer prevention, and addiction therapies is also highlighted.
Therapies that seek to target metabolism to treat diseases are challenging to develop, as Karima Drareni and Patrick Seale lay out in a Review. Healthy remodeling of adipose tissue helps maintain metabolic balance and protect surrounding organs. But when this process is disrupted, it can lead to harmful cellular changes that contribute to metabolic disease and that damage nearby tissues. Although weight loss can reverse many aspects of fat-tissue dysfunction, some changes may persist. According to Drareni and Seale, understanding which changes are reversible and which leave lasting effects is key to helping researchers develop treatments that don't just reduce fat mass, but also restore healthy fat-tissue function and improve metabolic resilience.
In another Review, Matthias Blüher highlights progress in the development of obesity management medications, including GLP-1 receptor agonists, as well as key limitations associated with these medications, such as gastrointestinal side effects, variable treatment responses, loss of muscle mass, and weight regain after stopping treatment. Newer approaches are increasingly focused on combining multiple biological mechanisms to achieve greater weight loss while minimizing these side effects, he says. Promising developments include triple incretin-receptor agonists, amylin-based medications, oral formulations, and therapies designed to prevent muscle loss. Ultimately, Blüher notes that the goal is to move beyond simply reducing body weight to develop treatments that improve overall health and address obesity-related complications.
In the final Review, Stina Börchers and colleagues discuss the emerging effects obesity medications, such as GLP-1-based therapies, have on cognition and brain health. Although preclinical studies in animal models and humans have suggested possible cognitive benefits of these drugs, Börchers et al. note that the findings remain mixed, and their effectiveness in improving cognition has not yet been fully established. Current studies are investigating whether these effects result from medications acting directly on brain circuits, improvements in metabolic and cardiovascular health, or a combination of both. Emerging research is examining GLP-1-based drugs and combination therapies that target additional metabolic pathways, with the goal of understanding how these treatments might influence cognition, aging, and Alzheimer's disease and potentially help preserve brain health.
While the myriad promises of GLP-1-based drugs are rapidly emerging, their access globally remains a foundational challenge. In a Policy Forum, Kenneth Shadlen and Olivier Wouters argue that access to these treatments remains concentrated in wealthier countries, despite the disproportionate burden of obesity and diabetes in low- and middle-income nations. Expanding global access to newer GLP-1 medications will depend heavily on pharmaceutical companies' willingness to offer affordable pricing and licensing agreements that allow generic manufacturers to produce and distribute these drugs. Yet affordable generic production alone will not guarantee widespread availability, note the authors, as many countries will still need substantial funding for purchasing, distributing, and administering these medications. Ultimately, improving access must coincide with broader public health efforts to address the dietary, environmental, and socioeconomic factors contributing to obesity and diabetes.
In a Perspecitve, Nora Volkow and Eric Wargo highlight the emerging research supporting the use of GLP-1s in addiction therapy. A growing body of evidence shows potential for GLP-1s to not only reduce cravings for food, but also for alcohol and other illicit drugs. Although this research has primarily explored these effects through the medications' influence on the brain's dopamine-based reward system, emerging evidence suggests their impact may involve broader interactions between the brain and the body's metabolic, hormonal, inflammatory, and cardiovascular systems. This points toward a more comprehensive understanding of addiction that considers the interconnected biological, behavioral, and social factors that contribute to substance use.
In the final Perspective, Blánaid Hicks and Anton Pottegård discuss GLP-1 therapies and cancer risk, arguing that more rigorous research combining clinical trials, observational studies, and laboratory evidence is needed to establish whether these increasingly widely used medications meaningfully influence cancer risk.
For reporters interested in research integrity-related topics, Perspective author Anton Pottegård notes that his team is focused on transparency and reproducibility in real-world evidence generation. "Some of our effort is described at the site www.RWERR.com and with recent key publications being the HARPER protocol template, the transparency statement proposal, and orchestrating a pledge for transparency and reproducibility across … the two major scientific societies within the epidemiological domain."
Furthermore, Chris Clemmensen, a co-author on the Börchers et al. Review said: "In obesity and metabolic research, increasing attention is being paid to reproducibility, transparency and the translation of preclinical findings into clinically meaningful outcomes. In particular, we need greater emphasis on rigorous trial design, appropriate controls and careful interpretation of observational data. This is especially important when evaluating potential benefits of metabolic therapies beyond their established indications."
