Study reveals liver-brain communication as key to managing circadian eating patterns and obesity

Research highlights the hepatic vagal nerve’s role in regulating food intake rhythms, offering new insights for potential anti-obesity treatments.

Study: Hepatic Vagal Afferents Convey Clock-Dependent Signals to Regulate Circadian Food Intake. Image Credit: alexkich/Shutterstock.com

A recent Science study found that communication between the hepatic vagal afferent nerve (HVAN) and the brain influences circadian eating patterns. In mice, surgical HVAN removal corrected altered food intake and reduced weight gain from high-fat diets, suggesting HVAN could be a target for anti-obesity treatments.

Background

Circadian rhythms are 24-hour cycles regulating physical, mental, and behavioral changes in animals, typically aligned with light and dark cycles. While usually stable, these rhythms can be disrupted by changes in behavior or light exposure, as seen with jetlag or shift work, leading to desynchrony between organ systems.

The suprachiasmatic nucleus (SCN) serves as the master circadian clock, using light cues to establish feedback loops (TTFLs) of molecular-clock genes. Recent findings show that almost all somatic cells also maintain their own TTFLs, which help balance circadian rhythms with other processes, like food intake.

Synchrony between the SCN and food-entrained liver rhythms is crucial for maintaining metabolic balance amidst environmental changes. Studies in both rodents and humans suggest that desynchrony between these systems harms’ health, increasing the risk and severity of metabolic disorders like obesity and diabetes. However, the precise mechanisms and signals driving these interactions remain unclear.

About the study

The present study investigates the mechanisms of circadian rhythm-establishing communication between the liver and the brain by deleting REV-ERBα/β nuclear receptors in murine model systems.

These nuclear receptors have previously been identified as central regulatory components of chrono-metabolic homeostasis. Consequently, their deletion induces desynchrony.

Contrasting previous investigations in the field, researchers used tail vein injections of REV-ERB deletion-capable adenoviruses, providing the present study with the unique advantage of location-specific (rather than system-wide) clock disruptions.

Specifically, this study methodology allowed for the observation and manipulation of asynchrony between the liver and the brain while leaving other organ systems unaltered, thereby substantially reducing background noise and confounding results.

Surgical and experimental interventions were carried out on three different cohorts of adult laboratory mice – C57Bl/6J, Nr1d1^fl/fl/Nr1d2^fl/fl, and Arntl^fl/fl.

Outcomes under investigation include changes in gene expression between control (sham surgery) and case (HepDKO) mice and comparisons between their respective body weight gains during the study period.

The study additionally focused on the role of the hepatic vagus nerve (HV) in brain signaling and weight modulation. While previously known to serve as a transmission center for supplying the brain with liver metabolic data, HV’s explicit role in circadian communication and food intake rhythms remains hypothetical.

The present study explores HV’s role via the surgical removal of surgical ablation of HV in case mice and the subsequent comparisons of their weight gain with controls under diet-induced obesity (DIO) conditions.

Study findings

The present study emphasizes the role of food intake as a zeitgeber (an external cue that synchronizes biological rhythms) for circadian modulation in the liver, similar to how light-dark cycles serve as the zeitgeber for SCN-driven circadian rhythms across the body.

This means that daily cycles of hunger and satiation don’t necessarily need to match light-dark cycles; each rhythm operates independently based on its cue (food or light), with liver-brain communication maintaining balance between them.

In gene knockdown mouse models, deleting REV-ERBα and REV-ERBβ nuclear receptors disrupted food intake rhythms without affecting SCN-regulated cycles.

This deletion activated clock genes Arntl and Per2, known for their role in chrono-metabolic balance, leading to altered food intake patterns and increased eating during light periods, ultimately causing significant weight gain. Interestingly, severing the hepatic vagal afferent nerve (HVAN) reversed these effects, reducing food intake and resulting in weight loss.

This highlights HV’s crucial role in brain signaling for food-driven rhythms, with parallel studies showing contrasting outcomes: activating gut signaling afferents in humans led to weight loss, underscoring the complexity of gut-brain interactions in metabolic regulation.

Conclusions

The present study used murine model systems to identify the mechanisms underpinning chrono-metabolic homeostasis and corresponding food intake dysregulation.

Study findings revealed that the HV serves as a communication and signaling center, informing the brain of alterations in food intake rhythms detected via REV-ERBα/β nuclear receptors. This signaling results in increased light-cycle food intake and substantial weight gain.

Ablation of the HV was observed to reverse these effects, pinpointing it as a target in future weight loss research.