UC Davis

The vagus nerve is a neurochemical expressway that carries sensory and motor signals between the viscera and central nervous system and represents an important metabolic actuator. Vagal sensory neurons (VANs) densely innervate the wall of the GI tract and relay visceral and chemical sensory information from the gut to the brain, coordinate digestion, and regulate food intake and metabolism. Short-lived peptide enteroendocrine hormones are released from the gut wall and act upon receptors located on VANs to regulate satiety. Chronic consumption of calorie-dense foods reduces the sensitivity of VANs to satiety hormones, leading to excessive eating and weight gain. In addition to sensing peripheral peptide hormones, VANs also express receptors for dietary and microbial metabolites, such as tryptophan derivatives. Recent evidence suggests that these microbiota-derived byproducts may act directly on VANs to alter satiety signaling. However, the role of these microbial metabolites on VAN activity is unknown. Previous work shows that one of the microbial metabolite receptors, GPR35, is co-expressed with CCKAR, the cognate receptor for CCK, a key peripheral satiety signal. However, the role of GPR35 on VANs in peripheral satiety signaling has not been studied.The first two data chapters of the dissertation show that natural and synthetic GPR35 agonists activate VANs in vitro and reduce food intake in vivo. We also demonstrate that GPR35 and CCKAR interact on VANs in vitro, which is also reflected in our feeding behavior studies using short hairpin-RNA-mediated knockdown of GPR35 in VANs. The last section of this dissertation introduces a new in vitro model for a gut-brain axis on-a-chip, which demonstrates primary VAN cultures can be used as a “living” biosensor for screening neuroactive metabolites that are produced in the gut. Taken together, the data show that GPR35 activation on VANs increases satiety signaling and reduces food intake in mice. Furthermore, this dissertation details the first studies demonstrating that the deorphaned receptor GPR35 may modulate the activity of CCKAR on VANs. This work is impactful for the field by revealing a potential new peripheral target for treating and perhaps preventing diet-induced hyperphagia and subsequent weight gain.