A fundamental principle of life is the capacity to integrate information about the external milieu with basic homeostatic metabolic pathways, thus optimizing adaptation to changing environments. In addition to our ability to detect external cues such as smell, vision or touch, we have developed complex internal sensory perception to monitor our physiological state. Most efforts have revealed that the central nervous system (CNS) integrates signals from the periphery of the body to adapt not only food intake, energy expenditure and fuel fluxes across different organs but also higher cognitive and behavioral functions. Particularly, autonomic responses arising from the sympathetic and parasympathetic nervous systems are orchestrated by extensive and often reciprocal connections between the hypothalamus and brainstem nuclei, allowing the adjustment of whole body homeostasis in response to variations in hormonal and metabolic cues. Nevertheless, how this system integrates chemosensory information remains unknown. A molecular and genetic classification of the sensory communication that controls homeostasis is not available and would facilitate mechanistic studies of periphery-to-brain signaling in health and disease. Our lab aims at defining the chemosensory circuits relaying intrinsic and extrinsic cues to modulate metabolic health.
1. Role of dorsal root ganglion neurons (DRG) sensory fibers in regulating metabolic decline.
Previously, we reported the role of the transient receptor potential vanilloid 1 (TRPV1), a chemosensory receptor present on afferent Aδ and C sensory fibers projecting to DRGs, in the onset on metabolic decline with age. Lack of TRPV1 neurons decreases circulating levels of calcitonin gene-related peptide (CGRP), a neuropeptide implicated in pain responses, neuro-immune communication and vasodilation. Because CGRP levels increase in old animals, we showed that high CGRP levels cause metabolic decline in wild-type animals through blockade of insulin secretion with age. Importantly, pharmacological inhibition of CGRP receptors restores metabolic health in old mice and improves age-dependent loss in insulin secretion. These data highlight a role for the neuropeptide CGRP as a critical regulator of metabolic flexibility upon aging and suggest that DRG fibers may contribute to metabolic homeostasis through neuropeptidic communication with visceral organs.
2. Evaluation of central olfactory circuits of metabolic control.
Obesity is often associated with abnormal feeding behavior implicating CNS motivation and feeding centers. The sense of smell is intrinsically connected to food palatability, however whether olfactory inputs affect energy homeostasis remained unclear. We are interested in the role of olfactory sensory neurons (OSNs) on whole body metabolism and energy homeostasis. Recently, we demonstrated that acute loss of smell perception after obesity onset not only abrogates further weight gain, but improves fat mass and insulin resistance. Reduced olfactory input activates sympathetic nerve activity, resulting in stimulation of β-adrenergic receptors (β-AR) on white and brown adipocytes to promote lipolysis. Conversely, we found that conditional ablation of the IGF1 receptor in OSNs enhances olfactory performance in mice by improving OSN neurogenesis and leads to increased adiposity and insulin resistance. These findings unravel a new bidirectional function for the olfactory system in controlling energy homeostasis in response to sensory and hormonal signals.