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.

Sucrose overconsumption impairs AgRP neuron dynamics and promotes palatable food intake.

Rapid gut-brain communication is critical to maintain energy balance and is disrupted in diet-induced obesity. In particular, the role of carbohydrate overconsumption in the regulation of interoceptive circuits in vivo requires further investigation. Here, we report that an obesogenic high-sucrose diet (HSD) selectively blunts silencing of hunger-promoting agouti-related protein (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 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.

IL-22 Binding Protein Controls IL-22-Driven Bleomycin-Induced Lung Injury.

The high mortality rates of acute lung injury and acute respiratory distress syndrome challenge the field to identify biomarkers and factors that can be exploited for therapeutic approaches. IL-22 is a cytokine that has antibacterial and reparative properties in the lung. However, it also can exacerbate inflammation and requires tight control by the extracellular inhibitory protein known as IL-22 binding protein (IL-22BP) (Il22ra2). This study showed the necessity of IL-22BP in controlling and preventing acute lung injury using IL-22BP knockout mice (Il22ra2-/-) in the bleomycin model of acute lung injury/acute respiratory distress syndrome. Il22ra2-/- mice had greater sensitivity (weight loss and death) and pulmonary inflammation in the acute phase (first 7 days) of the injury compared with wild-type C57Bl/6 controls. The inflammation was driven by excess IL-22 production, inducing the influx of pathogenic IL-17A+ γδ T cells to the lung. Interestingly, this inflammation was initiated in part by the noncanonical IL-22 signaling to macrophages, which express the IL-22 receptor (Il22ra1) in vivo after bleomycin challenge. This study further showed that IL-22 receptor alpha-1+ macrophages can be stimulated by IL-22 to produce a number of IL-17-inducing cytokines such as IL-1ß, IL-6, and transforming growth factor-ß1. Together, the results suggest that IL-22BP prevents IL-22 signaling to macrophages and reduces bleomycin-mediated lung injury.