Peripheral and Central Nutrient Sensing Underlying Appetite Regulation

Abstract

The precise regulation of fluid and energy homeostasis is essential for survival. It is well appreciated that ingestive behaviors are tightly regulated by both peripheral sensory inputs and central appetite signals. With recent neurogenetic technologies, considerable progress has been made in our understanding of basic taste qualities, the molecular and/or cellular basis of taste sensing, and the central circuits for thirst and hunger. In this review, we first highlight the functional similarities and differences between mammalian and invertebrate taste processing. We then discuss how central thirst and hunger signals interact with peripheral sensory signals to regulate ingestive behaviors. We finally indicate some of the directions for future research.

Keywords: hunger; sensory valence; taste; thirst; top-down regulation.

Figure 1. Taste detection in insects and mammals

Taste organs in Drosophila melanogaster and mouse (top). In flies, taste stimuli are detected by gustatory receptor neurons (GRNs) in labella of the proboscis, legs, and wings (left, highlighted in orange). These taste organs express distinct but partially overlapping subsets of taste receptors. In mammals, taste buds are distributed in different regions of the tongue including fungiform (front), foliate (side), circumvallate (back) papilla, as well as soft palate (right, highlighted in orange). Most taste receptors are expressed in all papilla on the tongue, but functional ENaC is expressed only in fungiform or palate buds. Each basic taste quality is mediated by a unique subset of gustatory receptors (Grs), ionotoropic receptors (Irs) or ppk channels in flies. In mammals, taste receptors (T1Rs and T2Rs) and ion channels are responsible for basic taste detection. Vertebrates and invertebrates share similar cellular organization for taste detection in that different taste qualities are generally encoded by anatomically distinct neural populations.

Figure 2. Anticipatory nature of hunger and thirst regulation

a) A schematic of feedforward-feedback regulation of thirst and hunger. Sensory cues and food ingestion (hunger), or liquid drinking (for thirst) directly modulate the interoceptive circuits. Feedback and feedforward signals help optimize the amount and timing of ingestion on a real-time basis. b) Hunger interoceptive neurons in the arcuate nucleus (AgRP neurons) detect energy deficits and drive feeding. A number of peripheral signals modulate the activity of AgRP neurons. Leptin receptor-expressing neurons in the DMH are the only known neurons underlying this feedforward regulation[89]. c) The excitatory neurons of the lamina terminalis (composed of the SFO, MnPO and OVLT), marked by nNOS, form a hierarchical circuit to process thirst. Thirst interoceptive neurons (SFO^nNOS and OVLT^nNOS) respond to deviations in body fluid balance and convey this information to MnPO^nNOS neurons. SFO^nNOS neurons are also rapidly modulated upon water intake. The inhibitory MnPO^GLP1R neurons are activated by drinking (gulping) action, which monosynaptically inhibit SFO^nNOS neurons of the SFO[65]. AgRP, Agouti Related Peptide; LepR, Leptin Receptor; nNOS, neuronal Nitric Oxide Synthase; GLP1r, Glucagon-like peptide 1 receptor; Arc, Arcuate Nucleus; DMH, Dorsomedial Hypothalamic Nucleus; SFO, Subfornical Organ; OVLT, Vascular Organ of Lamina Terminalis; MnPO, Median Preoptic Nucleus

Figure 3. Neural pathways for sensory and interoceptive processing of thirst and hunger signals

Schematics showing the sensory and interoceptive pathways in the mammalian brain. The NTS and PBN are potential sites that integrate peripheral and visceral signals. a) Thirst: Black arrows indicate sensory ascending pathways, while blue arrows show thirst-related circuits. b) Hunger: Red arrows show hunger-related circuits. ACC, Anterior Cingulate Cortex; BLA, Basolateral Amygdala; BNST, Bed Nucleus of the Stria Terminalis; InsCtx, Insular Cortex; OVLT, Vascular Organ of Lamina Terminalis; SON, Supraoptic Nucleus; PVH, Paraventricular Hypothalamic Nucleus; Arc, Arcuate Nucleus; LH, Lateral Hypothalamus; PAG, Periaqueductal Gray; SFO, Subfornical Organ; MnPO, Median Preoptic Nucleus; PBN, Parabrachial Nucleus; NTS, Nucleus Tractus Solitarius