Biology subjects

Hayes, N. W.

Publications and source records attributed to Hayes, N. W..

5 recordsLinked to original sources

bioRxiv2026

IL-1β engages distinct peripheral sensory circuits to suppress feeding across time

Loss of appetite is a hallmark of acute and chronic inflammation, and sustained anorexia causes malnutrition and worsens disease outcomes. Interleukin-1{beta} (IL-1{beta}) is one of the most potently anorexigenic inflammatory cytokines, yet how it engages neural circuits that suppress feeding remains incompletely understood. Specifically, the role of peripheral sensory neurons in mediating IL-1{beta}-induced anorexia is unresolved. Here, using DREADD-mediated inhibition of discrete peripheral sensory neuron populations and fiber photometry, we show that IL-1{beta}-induced anorexia occurs in at least two temporally and mechanistically distinct phases. Shortly after IL-1{beta} administration, prostaglandin signaling through non-vagal sensory afferents rapidly inhibits hypothalamic AgRP neurons to suppress food intake. At later time points, anorexia becomes partially prostaglandin-independent and vagal afferent neuron-dependent. Our findings demonstrate that multiple molecular signals mediate IL-1{beta}-induced anorexia, and that diverse peripheral sensory pathways, including a previously unappreciated contribution from non-vagal afferents, are critical links between systemic inflammation and neural control of appetite.

neuroscience↗

bioRxiv2025

GIP receptor agonism suppresses inflammation-induced aversion and food intake via distinct circuits

Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived incretin hormone, and pharmacologic modulation of central GIP receptors (GIPR) improves energy homeostasis. Recent reports have demonstrated that GIPR agonism is also anti-aversive. However, the mechanisms by which GIPR signaling impact food intake and aversion are incompletely understood. Here, we show that GIPR agonism abrogates the aversive and enhances the anorexigenic effects of the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}). Aversion-encoding parabrachial calcitonin-gene related peptide (CGRP) neurons were required for IL-1{beta}-induced conditioned taste avoidance (CTA) but not anorexia. Moreover, systemic IL-1{beta} increased in vivo CGRP neural activity, and this was significantly attenuated by co-administration of a GIPR agonist. By contrast, GIPR in the dorsal vagal complex were required for the acute anorectic effect of GIPR agonism but not its anti-aversive effect. Taken together, our data suggest that GIPR agonism reduces food intake and prevents aversion via distinct circuits, and that GIPR agonism may represent an effective approach to alleviate inflammation-induced aversion.

neuroscience↗

bioRxiv2024

Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite

Analogs of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have become mainstays of obesity and diabetes management. However, both the physiologic role of incretin hormones in the control of appetite and the pharmacologic mechanisms by which incretin-mimetic drugs suppress caloric intake remain incompletely understood. Hunger-promoting AgRP-expressing neurons are an important hypothalamic population that regulates food intake. Therefore, we set out to determine how incretins analogs affect their activity in vivo. Using fiber photometry, we observed that both GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) agonism acutely inhibit AgRP neuron activity in fasted mice and reduce the response of AgRP neurons to food. Moreover, optogenetic stimulation of AgRP neurons partially attenuated incretin-induced feeding suppression, suggesting that AgRP neuron inhibition is necessary for the full appetite-suppressing effects of incretin-based therapeutics. Finally, we found that GIP but not GLP-1 is necessary for nutrient-mediated AgRP neuron inhibition, representing a novel physiologic role for GIP in maintaining energy balance. Taken together, these findings reveal neural mechanisms underlying the efficacy of incretin-mimetic obesity therapies. Understanding these drugs mechanisms of action is crucial for the development of next-generation obesity pharmacotherapies with an improved therapeutic profile.

neuroscience↗

bioRxiv2023

Sucrose overconsumption impairs feeding circuit dynamics and promotes palatable food intake

Rapid gut-brain communication is critical to maintain energy balance and is disrupted in diet-induced obesity through mechanisms that remain obscure. Specifically, the role of carbohydrate overconsumption in the regulation of interoceptive circuits has been minimally examined in vivo. Here we report that an obesogenic high-sucrose diet (HSD) selectively blunts silencing of hunger-promoting AgRP neurons following intragastric delivery of glucose, whereas we previously showed that overconsumption of a high-fat diet (HFD) selectively attenuates lipid-induced neural silencing. By contrast, both HSD and HFD reversibly dampen rapid AgRP neuron sensory inhibition following chow presentation and promote intake of more palatable foods. Our findings reveal that excess sugar and fat pathologically modulate feeding circuit activity in both macronutrient-dependent and -independent ways, and thus may additively exacerbate obesity.

neuroscience↗

bioRxiv2018

The damage signal IL-33 promotes a focal protective myeloid cell response to Toxoplasma gondii in the brain

Understanding how invading pathogens are sensed within the brain is necessary to uncover how effective immune response are mounted in immunoprivileged sites. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts and initiates robust immune cell recruitment, but little is known about innate recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment of peripheral anti-parasitic immune cells, including IFN-{gamma}-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33R-deficient astrocytes fail to promote an adaptive immune response in the CNS and control parasite burden, demonstrating that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released and sensed locally, to engage the peripheral immune system in controlling a neurotropic pathogen.

immunology↗