Appetite to learn: An allostatic role for AgRP neurons in the maintenance of energy balance

Reed, Felicia; Lockie, Sarah H.; Reichenbach, Alex; Foldi, Claire J.; Andrews, Zane B.

doi:10.1016/j.coemr.2022.100337

Cited by 9 publications

(14 citation statements)

References 100 publications

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“…Recent data shows that AgRP neurons are rapidly inhibited by food-predictive cues, with the greatest response to calorie-rich food in hungry mice. These data are in line with the idea that temporally-defined inhibition of AgRP neuronal activity upon food-cue presentation influences learning (Berrios et al, 2021; Reed et al, 2022; Su et al, 2017). Under physiological conditions, post-ingestive feedback from calories maintains the suppression of AgRP neural activity; however, the role of the acute silencing to food-predictive cues independent of post-ingestive feedback remains unclear.…”

Section: Resultssupporting

confidence: 89%

“…It is interesting to note that AgRP neurons drive learning in passive conditioning studies, such as those presented here, and in other studies using operant conditioning (Betley et al, 2015;Krashes et al, 2011;Reichenbach et al, 2022), suggesting they facilitate appetitive conditioning more generally. This is consistent with the idea that hunger has been used as a key motivational tool for learning in behavioural neuroscience for decades and uncovers an important and largely unexplored role for AgRP neurons in learning and memory, as we recently discussed (Reed et al, 2022). Moreover, the fact that activation of AgRP neurons with Gq DREADDs drives food seeking and consumption but not CIF, whereas the temporal suppression of AgRP neurons induces CIF in the absence of food intake, highlights for the first time that AgRP neurons may promote motivation and learning through distinct downstream pathways.…”

Section: Discussionsupporting

confidence: 89%

“…Thus, the acute inhibitory control of AgRP neurons seems important to guide learning. Based on these findings, we have recently argued that sensory and temporal integration of food or food cues regulate AgRP neurons in a predictive and experience-dependent manner (Reed et al, 2022). Therefore, memories of past feeding episodes, prompted by food-associated cues, may regulate AgRP activity in manner proportionate to expected outcomes and influence future feeding episodes.…”

Section: Introductionmentioning

confidence: 99%

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Temporal regulation of AgRP neurons mediates context-induced feeding

Reed¹,

Dempsey²,

Clarke³

et al. 2023

Preprint

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An environment can have a powerful influence over appetite and feeding behaviour. For example, an environmental context, which reliably predicts food, will increase the appetitive food drive to the same environment context. Interestingly, mice are required to be hungry to develop such a context-induced feeding (CIF) response, suggesting the neural circuits sensitive to hunger play an important role to associate an internal energy state with a particular environment context. Hunger-sensing Agouti related peptide (AgRP) neurons are activated by circulating signals of energy deficit and reset to a silenced state by gut feedback mechanisms following food consumption. We hypothesised that AgRP neurons are both necessary and sufficient to drive CIF in the absence of hunger. While fasting increased CIF, chemogenetic inhibition of AgRP neurons during context acquisition prevented this effect. Intriguingly, chemogenetic activation of AgRP neurons during context acquisition did not increase CIF, suggesting precise temporal firing properties may be required. Indeed, photostimulation of AgRP neurons, only during context exposure (ON-OFF in context), increased CIF. Moreover, AgRP photostimulation prior to context exposure, coupled with the termination of photostimulation in the context in the absence of food consumption, was sufficient to drive a subsequent CIF. Our results suggest that AgRP neurons regulate the acquisition of CIF when the temporal firing properties are matched to context exposure. These results further highlight that acute AgRP inhibition is a salient neural event underscoring the effect of hunger on associative learning.

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Temporal regulation of AgRP neurons mediates context-induced feeding

Reed¹,

Dempsey²,

Clarke³

et al. 2023

Preprint

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“…In this way, Npas4 could be important both as a neuroprotective factor but also through regulating synaptic inhibitory tone, as has been studied in other cell types [29,30,32,36]. In addition, since AgRP neurons have also been suggested to fit the model of allostasis rather than homeostasis [62], it seems reasonable to expect that POMC neurons would also fit this model, and Npas4 and other IEGs could be essential in coupling the environmental changes to long-term predictive responses to perceived future demand.…”

Section: Discussionmentioning

confidence: 99%

NPAS4 is an allostatic regulator of POMC neuronal activity during diet-induced obesity

Yoon,

Gamu,

Gibson

et al. 2024

Preprint

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Rationale: Obesity is characterized by impaired energy balance and altered function of cell types that regulate food intake. These cell types include POMC neurons in the arcuate nucleus (ARC) of the hypothalamus that detect peripheral signals and promote a reduction in food intake upon activation. Downstream of neuronal activation, activity-regulated genes such as Neuronal PAS domain protein 4 (Npas4) are induced as part of the response to environmental stimuli. Npas4 is known to have cytoprotective roles in both neurons and pancreatic beta cells. A previous Npas4 knockout study in both mouse pancreatic beta cells and ARC neurons implied a potential role of Npas4 in ARC neurons in regulating food intake. However, the specific sites of Npas4 action in the ARC are unknown. We hypothesized that Npas4 in POMC neurons of the ARC has a role in regulating food intake during obesity. Methods: We quantified Npas4 expression in POMC neurons of the arcuate nucleus in mice exposed to various positive energy states known to activate POMC neurons using RNAscope fluorescent in situ hybridization. Next, we generated adult male mice with a conditional Npas4 knockout specifically in their ARC POMC neurons (POMC-NPAS4 KO) and metabolically characterized them for 30 weeks on regular chow or 60% high-fat diet (HFD). In addition, we performed single cell RNA sequencing (scRNA-seq) on microdissected ARC tissue and neighbouring regions from fasted or 1hr refed POMC-NPAS4 KO mice and controls at 6 weeks of HFD, in order to identify Npas4-regulated and feeding-regulated transcriptional changes in POMC neurons. Results: Npas4 was expressed in POMC neurons, and its expression was induced in response to positive energy states such as refeeding, oral glucose, and acute HFD feeding. HFD-fed POMC-NPAS4 KO males showed significantly reduced body weight starting at 10 weeks of HFD, and weighed 8-10 grams less than controls by 30 weeks of HFD. With metabolic cages and manual food intake measurements, we determined this difference was not the result of increased energy expenditure or activity, but was due to decreased food intake prior to the significant reduction in body weight. Using the ARC single-cell dataset, we found that POMC neurons of KO mice showed an enhanced refeeding-induced transcriptional response, dysregulated immediate early gene expression in response to refeeding, and reduced expression of genes encoding GABA-A receptor subunits. Furthermore, cell-to-cell communication analysis revealed that POMC neurons of KO mice specifically lost inhibitory GABAergic signaling inputs, some of which came from AgRP neurons, and gained excitatory glutamatergic signaling inputs compared to POMC neurons of control littermates. Conclusions: Taken together, the results suggest that activity-dependent expression of Npas4 in POMC neurons tempers the activity of these cells upon overnutrition. Loss of Npas4 causes cell-autonomous loss of the capacity to sense nutrient intake. Molecularly, this is driven by reduced expression of inhibitory GABA-A receptors and an overall increase in POMC neuronal activity, leading to decreased food intake and decreased weight gain. In conclusion, for the first time we report a role for the transcription factor Npas4 in POMC neurons of the ARC, and demonstrate it plays an indispensable role in controlling feeding behavior in states of overnutrition.

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“…Hunger-sensing AgRP neurons are also thought to optimise foraging and recent studies highlight the importance of sensory detection of calorie availability to AgRP neurons 70 . For example, the sensory detection of food resets activity of hypothalamic AgRP and POMC neuronal activity within seconds, with a response magnitude that predicts the calorie content of the food to be consumed and the energy need of the animal 2 .…”

Section: Discussionmentioning

confidence: 99%

Hunger signalling in the olfactory bulb primes exploration, food-seeking and peripheral metabolism

Stark

Dempsey

Sassi

et al. 2023

Preprint

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Growing evidence highlights a complex interaction between olfaction and metabolism with impaired olfactory function observed in obesity and increased olfactory sensitivity during hunger. The mechanisms linking metabolic state and olfaction remain unknown, but increased accessibility of hormones, such as ghrelin, and the diverse expression of hormone receptors such as those for ghrelin (GHSRs) in the olfactory system suggests an underappreciated neuroendocrine role. Here, we examined the hypothesis that GHSRs in the olfactory bulb (OB) link hunger with olfactory sensitivity to influence foraging behaviours and metabolism. Selective deletion of OBGHSRs in adult male mice was achieved with adeno-associated viral expression of cre-recombinase in the OB of floxed-Ghsr mice. OBGHSR deletion significantly affected olfactory discrimination and habituation to both food and pheromone odours, with greatest effect under fasted conditions. Anxiety-like and depression-like behaviour was significantly greater after OBGHSR deletion using 3 independent anxiety behavioural tasks and testing for anhedonia, whereas exploratory behaviour was reduced. No effect on spatial navigation and memory was observed. Although OBGHSR deletion did not affect cumulative food intake, it significantly impacted feeding behaviour as evidenced by altered bout number and duration. Moreover, food-finding after fasting or ip ghrelin was attenuated. Intriguingly, OBGHSR deletion caused an increase in body weight and fat mass, spared fat utilisation on a chow diet and impaired glucose metabolism indicating metabolic dysfunction. We conclude that OBGHSRs maintain olfactory sensitivity, particularly during hunger, and facilitate behavioural adaptations that optimise food-seeking in anxiogenic environments, priming metabolic pathways in preparation for food consumption.

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Appetite to learn: An allostatic role for AgRP neurons in the maintenance of energy balance

Cited by 9 publications

References 100 publications

Temporal regulation of AgRP neurons mediates context-induced feeding

Temporal regulation of AgRP neurons mediates context-induced feeding

NPAS4 is an allostatic regulator of POMC neuronal activity during diet-induced obesity

Hunger signalling in the olfactory bulb primes exploration, food-seeking and peripheral metabolism

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