Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding

Abstract

The overconsumption of highly caloric and palatable foods has caused a surge in obesity rates in the past half century, thereby posing a healthcare challenge due to the array of comorbidities linked to heightened body fat accrual. Developing treatments to manage body weight requires a grasp of the neurobiological basis of appetite. In this Review, we discuss advances in neuroscience that have identified brain regions and neural circuits that coordinate distinct phases of eating: food procurement, food consumption, and meal termination. While pioneering work identified several hypothalamic nuclei to be involved in feeding, more recent studies have explored how neuronal populations beyond the hypothalamus, such as the mesolimbic pathway and nodes in the hindbrain, interconnect to modulate appetite. We also examine how long-term exposure to a calorically dense diet rewires feeding circuits and alters the response of motivational systems to food. Understanding how the nervous system regulates eating behaviour will bolster the development of medical strategies that will help individuals to maintain a healthy body weight.

Fig. 1 ∣. Neural circuitry underlying the three acts of appetite.

Left, act I: food procurement. Inhibitory ARC^AgRP neuronal projections to the BNST, PVH, LH, and PVT promote food seeking and subsequent food intake. Middle, act II: food consumption. Activation of LH^VGAT and inhibition of LH^VGLUT2 neurons increases food intake through direct projections to the VTA. Inhibitory circuits from the BNST and NAc^D1R neurons feed into this circuit to modulate consumption. GABAergic TB^SST neurons, via projections to the BNST and PVH, and ZI neurons, via projections to the PVT, potently drive ingestive behaviours. Excitatory PVH neurons regulate food intake through projections to the ARC, DR/PAG, PBN, and periLC. Right, act III: meal termination. Stimulation of excitatory PBN^CGRP suppresses food intake, generates learnt and defensive responses, and induces malaise via projections to the CeA, BNST, SI, PSTN, VPMpc, and IC. Activation of excitatory aDCN neurons reduces meal size by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Solid arrows indicate direct connections. Dashed arrows indicate indirect connections. ARC, arcuate nucleus of the hypothalamus; AgRP, Agouti-related peptide; BNST, bed nucleus of the stria terminalis; PVH, paraventricular nucleus of the hypothalamus; LH, lateral hypothalamus; PVT, paraventricular nucleus of the thalamus; VGAT, vesicular gamma-aminobutyric acid transporter; VGLUT2, vesicular glutamate transporter 2; VTA, ventral tegmental area; D1R, dopamine 1 receptor; TB, tuberal nucleus; SST, somatostatin; ZI, zona incerta; DR, dorsal raphe nucleus; PAG, periaqueductal grey; PBN, parabrachial nucleus; periLC, peri-locus coeruleus; CeA, central amygdala; SI, substantia innominata, PSTN, parasubthalamic nucleus; VPMpc, parvicellular portion of the ventroposteromedial nucleus; IC, visceral insular cortex; aDCN, anterior deep cerebellar nuclei.

Fig. 2 ∣. Feeding neurons conform to energy status and food palatability.

Real-time recordings of neurons regulating appetite reveal stronger responses under periods of caloric deprivation and towards energy-dense food substrates. These changes can be determined directly by in vivo electrical-wire recordings and/or indirectly via the monitoring of calcium dynamics using genetically encoded calcium sensors (GECIs) that serve as a proxy of neural activity. These excitatory or inhibitory response properties can occur prior to, at the onset of, or after consumption. a, Example of optical-fibre photometry traces in fasted (left) or fed (right) mice expressing the GECI GCaMP (a synthetic fusion of green fluorescent protein, calmodulin and M13, a peptide sequence from myosin light-chain kinase) aligned to exposure of food (dotted vertical line). Although population dynamics are insensitive to false food (black traces), activity is rapidly and robustly suppressed to standard food, but in only energy-deficient mice (silver traces). Palatable-food presentation increases the magnitude of this inhibitory response and is even observed in calorically replete mice (red traces). dF/F in this case refers to the difference between initial fluorescence intensity at the resting state and after food exposure. Adapted from ref. b, Example of single-photon microendoscopic or two-photon individual cellular activity (regions of interest, ROIs) in fasted or fed mice expressing GCaMP, aligned to exposure to food. In vivo miniepifluorescence image of GCaMP expression (top left). Schematized cell map of an example animal’s GCaMP-expressing neurons during a free-access feeding task (top right). The same neurons can be tracked between sessions (coloured cells). Calcium traces of individual neurons tracked in response to chow (left) or HFD (right) in fed versus fasted animals. Individual cells exhibit a variety of responses to food with activation (shifts upwards) or inhibition (shifts downwards) observed before, during, or after consumption. These responses are often exacerbated in hungry animals and towards energy-rich food, such as a HFD. Some neurons are non-responsive to food.

Fig. 3 ∣. Fine tuning of satiation circuits is required to avoid aversive outcomes.

The most common side effect of effective anti-obesity drugs is visceral malaise, including nausea, vomiting, and gastrointestinal issues. This likely stems from the overlapping features of cell types, such as PBN^CGRP neurons. Modest activation may signal meal termination or satiety, ultimately leading to the feeling of a full stomach. However, further stimulation could result in unpleasantness, including anxiety-like behaviour, pain, and malaise brought on by physiological changes, including tachycardia, vasoconstriction, and hyperventilation. Even stronger rousing of these circuits could ultimately culminate in severe sickness, impaired movement, and starvation. Therefore, understanding how this information is encoded at distinct brain nodes will aid in the careful crafting of therapeutics that curb overeating without negative consequences.