An Alternative Pharmacological Therapy for Obesity Through Modulation of Vagus Nerve Synaptic Receptors

Obesity is a rapidly spreading disease globally. It causes serious complications, including type 2 diabetes, hypertension, dyslipidemia, fatty liver disease, and other serious cardiovascular consequences. Weight loss, the primary driver of the healing process, is extremely difficult to achieve due to the body’s strong resistance, a legacy of an evolutionary process that protected the human species from extinction due to nutritional deficiency. The few drugs currently available and recognized as effective, however, are not free from side effects and, more importantly, do not guarantee a permanent cure, but only a temporary suspension of symptoms during administration. Bariatric surgery, however, has proven highly effective. The ideal goal would be to find an equally effective pharmacological solution that reproduces the same mechanism. Currently, only hypotheses exist. Many clues point to a modified function of the ascending vagal afferent fibers that connect the gastro-intestinal tract to the brain. In this narrative, hypothesis-driven review, it is hypothesized that pharmacological modulation of glutamatergic (NMDA) receptors at the synapses between vagal afferent fibers and their central targets may represent a novel therapeutic strategy for obesity. This approach would target the putative altered mechanism present in obesity, with the hypothetical potential to promote sustained weight loss or durable disease modification, pending experimental and clinical confirmation. There are already some encouraging signs in this direction.