Sex-specific signatures of GLP-1 and amylin on resting state brain activity and functional connectivity in awake rats

Gut-produced glucagon-like peptide-1 (GLP-1) and pancreas-made amylin robustly reduce food intake by directly or indirectly affecting brain activity. While for both peptides a direct action in the hindbrain and the hypothalamus is likely, few studies examined their impact on whole brain activity in rodents and did so evaluating male rodents under anesthesia. However, both sex and anesthesia may significantly alter the influence of feeding controlling molecules on brain activity. Therefore, we investigated the effect of GLP-1 and amylin on brain activity and functional connectivity (FC) in awake adult male and female rats using resting-state functional magnetic resonance imaging (rsfMRI). We further examined the relationship between the altered brain activity or connectivity and subsequent food intake in response to amylin or GLP-1. We observed sex divergent effects of amylin and GLP-1 on the brain activity and FC patterns. Most importantly correlation analysis between FC and feeding behavior revealed that different brain areas potentially drive reduced food intake in male and female rats. Our findings underscore the distributed and distinctly sex divergent neural network engaged by each of these anorexic peptides and suggest that different brain areas may be the primary drivers of the feeding outcome in male and female rats. Moreover, prominent activity and connectivity alterations observed in brain areas not typically associated with feeding behavior in both sexes may either indicate novel feeding centers or alternatively suggest the involvement of these substances in behaviors beyond feeding and metabolism. The latter question is of potential translational significance as analogues of both amylin and GLP-1 are clinically utilized.