Abstract
SummarySensory 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.
Highlights
Gut-innervating sensory neurons are a major afferent pathway of the gut-brain axis (Clemmensen et al, 2017; Kim et al, 2018; Soty et al, 2017)
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
Intersectional genetic targeting molecularly defined sensory neurons To investigate the functional neurocircuits of gut-innervating sensory neurons, we sought to develop a genetic approach that allows non-invasive targeting individual vagal and spinal afferent populations (Figures 1A and 1B)
Summary
Gut-innervating sensory neurons are a major afferent pathway of the gut-brain axis (Clemmensen et al, 2017; Kim et al, 2018; Soty et al, 2017). Consistent with this, nutrient administration directly into the stomach or duodenum reduces food intake and adapts insulin sensitivity, and these regulatory actions are prevented by ablating sensory neurons (Liebling et al, 1975; Reidelberger et al, 1983; Wang et al, 2008; Welch et al, 1988; Yox and Ritter, 1988). Impairment of this feedback communication has been associated with systemic metabolic dysfunction.
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