Molecular Medicine Israel

Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism

Highlights

Intersectional mapping of sensory neurons identifies distinct gut innervation patterns•

Gut-innervating GLP1R+ vagal afferents relay anorexigenic signals to brainstem neurons•

Gut-innervating GPR65+ vagal afferent stimulation increases hepatic glucose production•

GLP1R+ vagal afferent activity is required to control glycemia during feeding

Summary

Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.

Sign up for our Newsletter