Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized weight loss management, and researchers are now exploring how these medications can further transform obesity care and offer new possibilities for long-term weight management, according to a recent review article published in Endocrinology.
Authors Lauren A. Jones and Daniel I. Brierley, PhD, both of the Centre for Cardiovascular and Metabolic Neuroscience, University College London, write that obesity has reached epidemic dimensions — more than one billion people now live with obesity, with rates doubling in men, tripling in women, and quadrupling in children over the last 30 years.
Previous anti-obesity medications, such as amphetamines and orlistat (Xenical, Alli), only offered modest (≤5%) weight loss along with side-effects that made compliance difficult and were in some cases even life-threatening.
Originally a drug used to treat type 2 diabetes, semaglutide (Wegovy) received approval for weight loss and management by the U.S. Food and Drug Administration in 2021 and the European Medicines Agency the following year. Other GLP-1-based drugs, such as tirzepatide (Mounjaro/Zepbound), followed suit in 2023 (Europe and U.S.). Yet while it is known that these drugs reduce weight primarily by decreasing food consumption, via activation of the GLP-1 receptor on neuronal cells, the exact sites of action and the neural circuits involved, as well as other issues remain in question.
“Here we provide a targeted synthesis of what we consider some of the most important recent developments in the fast-moving field of GLP-1 neurobiology, specifically relevant to obesity,” Jones and Brierley write. “In particular, we highlight studies which have advanced our understanding of how GLP-1 signaling modulates eating, and we identify what we consider important open questions and future challenges to be addressed surrounding GLP-1-based AOMs to aid the prevention and/or treatment of obesity.”
The authors describe gut-brain pathways and sites of action of endogenous and exogenous GLP-1 signaling that are involved in the control of eating and bodyweight. In this context they highlight the particular importance of brain areas including the brainstem (area postrema, nucleus tractus solitarus, locus coeruleus), hypothalamus (arcuate nucleus, dorsomedial nuclei), and lateral septum.
Identifying which neural populations specifically mediate the beneficial effects of GLP-1RAs is of vital importance. “[C]rucial questions for rationally designed pharmacological strategies for tuning GLP-1RA action in the brainstem include: what specific GLP-1R subpopulations, and non-GLP-1R-expressing neurons within the same local circuitry, are actually recruited by these drugs; and are these apparently functionally dissociable subpopulations which mediate nausea vs satiation/satiety differentially druggable?” Jones and Brierley write.
Furthermore, the authors address the issue of drug cessation and weight regain; once patients stop these drugs, more than half regain much of the weight they loss. The authors point to studies that using lower doses instead of the cold-turkey approach might be more beneficial.
Lastly, Jones and Brierley point out that for a third of people living with overweight or obesity, current GLP-1RAs may not provide meaningful weight loss, emphasizing the fact that obesity is a heterogenic disease. “The increasingly sophisticated genetic and molecular tools now available should provide the specificity required to dissociate and selectively target the neural circuits recruited by GLP-1RA AOMs for their therapeutic and adverse effects,” the authors write in their conclusion. “This should enable the rational design of next-generation pharmacotherapies to meet the diverse clinical needs of people living with obesity, and to aid preventative efforts to reverse the prevalence of the global obesity epidemic.”
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