Identifies the liver-brain connection as a key factor in the management of circadian eating habits and obesity

The study highlights the role of the hepatic vagus nerve in regulating food intake rhythms, offering new perspectives for potential treatments for obesity.

A study published in the journal Science found that communication between the hepatic afferent nerve (HVAN) and the brain influences circadian eating habits. In mice, surgical removal of the HVAN corrected altered eating rhythms and reduced weight gain during a high-fat diet, suggesting that HVAN may be a target for fighting obesity.

Circadian rhythms are 24-hour cycles that regulate physical, mental, and behavioral changes in animals, usually synchronized with cycles of light and darkness. Although these rhythms are usually stable, they can be disrupted by changes in behavior or exposure to light, as in the case of jet lag or night shift work, which leads to desynchronization of organ systems.

The suprachiasmatic nucleus (SCN) serves as the master circadian clock, using light signals to establish feedback loops (TTFLs) of molecular clock genes. Recent research suggests that nearly all somatic cells also maintain their own TTFLs, which help balance circadian rhythms with other processes such as food intake.

Synchronization between the SCN and nutrient-driven liver rhythms is important for maintaining metabolic balance in the face of environmental change. Studies in rodents and humans suggest that desynchronization of these systems is detrimental to health, increasing the risk and severity of metabolic diseases such as obesity and diabetes. However, the precise mechanisms and signals governing these interactions remain unclear.

The study investigates the mechanisms of circadian communication between the liver and brain by deleting the nuclear receptors REV-ERBα/β in mice.

These receptors have previously been identified as key elements of chronometabolic homeostasis. Their removal causes desynchronization.

Unlike previous studies in this area, the scientists used injections of adenoviruses capable of removing REV-ERB via the tail vein, giving the study the unique advantage of disrupting the biological clock locally (instead of systemically).

The methodology allowed us to observe and manipulate asynchrony between the liver and brain while leaving other organ systems unchanged, significantly reducing background noise and confounding factors.

Surgical and experimental interventions were performed on three different groups of adult laboratory mice.

The study also focused on the role of the hepatic vagus nerve (HV) in signaling to the brain and weight regulation. Although it was previously known that the HV transmits metabolic data from the liver to the brain, its precise role in circadian communication and eating rhythms remained speculative.

The study highlights that food intake rhythms act as a zeitgeber (an external signal that synchronizes biological rhythms) for circadian modulation in the liver, similar to how light and dark cycles drive SCN rhythms in the body.

In gene-silencing mouse models, deletion of REV-ERBα and REV-ERBβ receptors disrupted feeding rhythms without affecting SCN-driven cycles.

The ablation activated the Arntl and Per2 genes responsible for chronometabolic balance, leading to altered feeding rhythms and increased daylight feeding, ultimately causing significant weight gain. Interestingly, transection of the hepatic vagus afferent nerve (HVAN) abolished these effects, reducing food intake and leading to weight loss.

This highlights the important role of HV in signaling for feeding rhythms, with parallel studies showing opposite results: activation of intestinal afferents in humans resulted in weight loss, highlighting the complexity of gut-brain interactions in metabolic regulation.

The study used mouse models to identify mechanisms underlying chronometabolic homeostasis and disturbances in feeding rhythms.

The results showed that HV serves as a communication hub, transmitting signals to the brain about changes in feeding rhythms detected through the nuclear receptors REV-ERBα/β. These signals lead to increased food intake during daylight hours and significant weight gain.

Removal of HV eliminated these effects, indicating it as a potential target for future weight loss studies.