Nutritive, Post-ingestive Signals Are the Primary Regulators of AgRP Neuron Activity
TL;DR: It is discovered that nutrients are necessary and sufficient for sustained reductions in AgRP neuron activity and that activity reductions are proportional to the calories obtained, and it is shown that the nutritive value of food trains sensory systems-in a single trial-to drive rapid, anticipatory Ag RP neuron activity inhibition.
About: This article is published in Cell Reports.The article was published on 2017-12-05 and is currently open access. It has received 128 citations till now.
Citations
More filters
Journal Article•
TL;DR: The authors showed that post-prandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
Abstract: Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.
1,960 citations
TL;DR: It is found that, in addition to the well-described classical paracrine transduction, enteroendocrine cells also form fast, excitatory synapses with vagal afferents (see the Perspective by Hoffman and Lumpkin), this more direct circuit for gut-brain signaling uses glutamate as a neurotransmitter.
Abstract: INTRODUCTION In 1853, Sydney Whiting wrote in his classic Memoirs of a Stomach , “…and between myself and that individual Mr Brain, there was established a double set of electrical wires, by which means I could, with the greatest ease and rapidity, tell him all the occurrences of the day as they arrived, and he also could impart to me his own feelings and impressions” Historically, it is known that the gut must communicate with the brain, but the underlying neural circuits and transmitters mediating gut-brain sensory transduction still remain unknown In the gut, there is a single layer of epithelial cells separating the lumen from the underlying tissue Dispersed within this layer reside electrically excitable cells termed enteroendocrine cells, which sense ingested nutrients and microbial metabolites Like taste or olfactory receptor cells, enteroendocrine cells fire action potentials in the presence of stimuli However, unlike other sensory epithelial cells, no synaptic link between enteroendocrine cells and a cranial nerve has been described The cells are thought to act on nerves only indirectly through the slow endocrine action of hormones, like cholecystokinin Despite its role in satiety, circulating concentrations of cholecystokinin peak only several minutes after food is ingested and often after the meal has ended Such a discrepancy suggests that the brain perceives gut sensory cues through faster neuronal signaling Using a mouse model, we sought to identify the underpinnings of this neural circuit that transduces a sense from gut to brain RATIONALE Our understanding of brain neural circuits is being propelled forward by the emergence of molecular tools that have high topographical and temporal precision We adapted them for use in the gut Single-cell quantitative real-time polymerase chain reaction and single-cell Western blot enabled the assessment of synaptic proteins A monosynaptic rabies virus revealed the neural circuit’s synapse The neural circuit was recapitulated in vitro by using nodose neurons cocultured with either minigut organoids or purified enteroendocrine cells This system, coupled to optogenetics and whole-cell patch-clamp recording, served to determine the speed of transduction Whole-nerve electrophysiology, along with optical excitation and silencing, helped to uncover the neurotransmission properties of the circuit in vivo The underlying neurotransmitter was revealed by using receptor pharmacology and a fluorescent reporter called iGluSnFR RESULTS Single-cell analyses showed that a subset of enteroendocrine cells contains presynaptic adhesion proteins, including some necessary for synaptic adhesion Monosynaptic rabies tracing revealed that enteroendocrine cells synapse with vagal nodose neurons This neuroepithelial circuit connects the intestinal lumen with the brainstem in one synapse In coculture, this connection was sufficient to transduce a sugar stimulus from enteroendocrine cells to vagal neurons Optogenetic activation of enteroendocrine cells elicited excitatory postsynaptic potentials in connected nodose neurons within milliseconds In vivo recordings showed that enteroendocrine cells are indeed necessary and sufficient to transduce a sugar stimulus to the vagus By using iGluSnFR, we found that enteroendocrine cells synthesize the neurotransmitter glutamate, and pharmacological inactivation of cholecystokinin and glutamate receptors revealed that these cells use glutamate as a neurotransmitter to transduce fast, sensory signals to vagal neurons CONCLUSION We identified a type of gut sensory epithelial cell that synapses with vagal neurons This cell has been referred to as the gut endocrine cell, but its ability to form a neuroepithelial circuit calls for a new name We term this gut epithelial cell that forms synapses the neuropod cell By synapsing with the vagus nerve, neuropod cells connect the gut lumen to the brainstem Neuropod cells transduce sensory stimuli from sugars in milliseconds by using glutamate as a neurotransmitter The neural circuit they form gives the gut the rapidity to tell the brain of all the occurrences of the day, so that he, too, can make sense of what we eat
468 citations
TL;DR: The findings establish the vagal gut-to-brain axis as an integral component of the neuronal reward pathway and suggest novel vagal stimulation approaches to affective disorders.
443 citations
TL;DR: Current evidence of the impact gut microbes and their metabolites have on blood-brain barrier integrity and brain function is summarized, and the communication networks between the gastrointestinal tract and brain, which they may modulate are summarized.
Abstract: The human gastrointestinal (gut) microbiota comprises diverse and dynamic populations of bacteria, archaea, viruses, fungi, and protozoa, coexisting in a mutualistic relationship with the host. When intestinal homeostasis is perturbed, the function of the gastrointestinal tract and other organ systems, including the brain, can be compromised. The gut microbiota is proposed to contribute to blood-brain barrier disruption and the pathogenesis of neurodegenerative diseases. While progress is being made, a better understanding of interactions between gut microbes and host cells, and the impact these have on signaling from gut to brain is now required. In this review, we summarise current evidence of the impact gut microbes and their metabolites have on blood-brain barrier integrity and brain function, and the communication networks between the gastrointestinal tract and brain, which they may modulate. We also discuss the potential of microbiota modulation strategies as therapeutic tools for promoting and restoring brain health.
255 citations
TL;DR: It is found that food intake is most sensitive to stimulation of mechanoreceptors in the intestine, whereas nutrient-activated mucosal afferents have no effect, and a key role is identified in the regulation of feeding.
217 citations
Cites background from "Nutritive, Post-ingestive Signals A..."
...Hunger-promoting Agouti-related Peptide (AgRP)neurons in thearcuate nucleus (ARC) are activated by food deprivation and inhibited by GI nutrients (Beutler et al., 2017; Hahn et al., 1998; Su et al., 2017)....
[...]
...Gastrointestinal Distension Is Sufficient to Inhibit Food Intake and AgRP Neuron Activity Prior work has emphasized the importance of nutrients rather than stretch in regulating AgRP neurons (Beutler et al., 2017; Su et al., 2017)....
[...]
...Although AgRP neurons are potently inhibited by intragastric nutrients (Beutler et al., 2017; Su et al., 2017), we observed no change in their activity following stimulation of nutrient-activated Gpr65 neurons (Figure 6K)....
[...]
...As expected, gavage of lipid and glucose inhibited AgRP neurons, as well as subsequent food intake, relative to controls (Beutler et al., 2017; Su et al., 2017)....
[...]
References
More filters
TL;DR: Findings in this work indicate that dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events can be understood through quantitative theories of adaptive optimizing control.
Abstract: The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.
8,163 citations
TL;DR: In this paper, the authors showed that post-prandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
Abstract: Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus(1). The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons(2) in the arcuate nucleus, which is accessible to peripheral hormones(3). Peptide YY3-36 (PYY3-36), a Y2R agonist(4), is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal(5-7). Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons(8). In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
2,110 citations
Journal Article•
TL;DR: The authors showed that post-prandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut-hypothalamic pathway.
Abstract: Food intake is regulated by the hypothalamus, including the melanocortin and neuropeptide Y (NPY) systems in the arcuate nucleus. The NPY Y2 receptor (Y2R), a putative inhibitory presynaptic receptor, is highly expressed on NPY neurons in the arcuate nucleus, which is accessible to peripheral hormones. Peptide YY3-36 (PYY3-36), a Y2R agonist, is released from the gastrointestinal tract postprandially in proportion to the calorie content of a meal. Here we show that peripheral injection of PYY3-36 in rats inhibits food intake and reduces weight gain. PYY3-36 also inhibits food intake in mice but not in Y2r-null mice, which suggests that the anorectic effect requires the Y2R. Peripheral administration of PYY3-36 increases c-Fos immunoreactivity in the arcuate nucleus and decreases hypothalamic Npy messenger RNA. Intra-arcuate injection of PYY3-36 inhibits food intake. PYY3-36 also inhibits electrical activity of NPY nerve terminals, thus activating adjacent pro-opiomelanocortin (POMC) neurons. In humans, infusion of normal postprandial concentrations of PYY3-36 significantly decreases appetite and reduces food intake by 33% over 24 h. Thus, postprandial elevation of PYY3-36 may act through the arcuate nucleus Y2R to inhibit feeding in a gut–hypothalamic pathway.
1,960 citations
TL;DR: Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, it is demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores.
Abstract: Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.
1,170 citations
TL;DR: Contrary to the appetite-stimulating effects of ghrelin, treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain.
Abstract: Ghrelin, a circulating appetite-inducing hormone, is derived from a prohormone by posttranslational processing. On the basis of the bioinformatic prediction that another peptide also derived from proghrelin exists, we isolated a hormone from rat stomach and named it obestatin—a contraction of obese, from the Latin “obedere,” meaning to devour, and “statin,” denoting suppression. Contrary to the appetite-stimulating effects of ghrelin, treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain. Obestatin bound to the orphan G protein–coupled receptor GPR39. Thus, two peptide hormones with opposing action in weight regulation are derived from the same ghrelin gene. After differential modification, these hormones activate distinct receptors.
1,132 citations