Farr OM, et al. - Since GLP-1 analogs have recently emerged as efficacious weight reduction therapies via actions in the central nervous system (CNS), researchers studied their actions in the human brain at the highest dose approved for obesity (liraglutide 3.0mg) after long-term administration. They investigated neurocognitive and neuroimaging (fMRI) responses to food cues at the clinical research center of Beth Israel Deaconess Medical Center. In a randomized, placebo-controlled, double-blind, cross-over trial after 5 weeks of dose escalation, 20 subjects with obesity were treated with placebo and liraglutide (3.0mg). Unlike previous studies, the authors show for the first time that liraglutide treatment given at the highest doses approved for obesity over a longer period of time does not change brain activation to food cues. When neuroimaging data are controlled for changes in BMI, a counter-regulatory increase in reward-related OFC activation to food cues can be noted, showing changes in CNS that might lead to later weight loss plateaus. These data point to an encouraging focus on interventions that could provide tangible benefits for reversing the plateauing phenomenon and promoting further weight loss by contributing to the CNS reward system.