Study opens new approaches to treating fatty liver disease

Study opens new approaches to treating fatty liver disease

A study group at MedUni Vienna has identified a leptin-controlled regulatory circuit through which this adipocyte-derived hormone regulates hepatic lipid metabolism via the autonomic nervous system. The study shows that this fatty tissue-brain-liver axis, which has already been identified in animal models, also exists in humans and opens up new approaches to the treatment of metabolic diseases such as fatty liver disease.

The aim of the study by Thomas Scherer and Matthäus Metz from the Clinical Department of Endocrinology and Metabolism (University Clinic for Internal Medicine III of MedUni Vienna and Vienna General Hospital) was to identify the leptin-independent effects on liver fat metabolism in humans and its anorexic effects. The fatty tissue hormone leptin circulates in the blood in proportion to the fat mass and acts primarily as a satiety signal in the brain. In addition to controlling appetite, it is also involved in regulating glucose and lipid metabolism. These effects are mediated by the autonomic nervous system, which connects the brain to peripheral organs such as the liver and fatty tissue. Human recombinant leptin (metreleptin) is approved for the treatment of lipodystrophy. In these patients with leptin deficiency, metreleptin reduces hepatic lipid content independent of food intake. However, the underlying mechanism was previously unclear.

In previous animal experiments, the study group was able to show that leptin stimulates the release of lipids from the liver and at the same time suppresses the formation of new lipids, thereby reducing liver fat content. This effect was dependent on intact autonomic innervation of the liver and was abolished after transection of the vagus nerve.

In the present study, the authors tested whether a comparable mechanism regulates hepatic lipid metabolism in humans. They show that a single metreleptin injection stimulated hepatic lipid export in healthy, normal-weight men and reduced liver fat content. A similar effect occurred after modified sham feeding, a procedure that induces head phase reflexes and thereby physiologically stimulates the vagus nerve. In contrast, metreleptin failed to promote hepatic lipid secretion in liver transplant recipients whose livers were not innervated by the autonomic nervous system as a result of transplantation.

The study therefore suggests that leptin also regulates liver fat content in humans via the brain and the autonomic nervous system, explained study leader Thomas Scherer: "Our results suggest that, similar to previous observations in animal models, leptin also stimulates the release of lipids from the liver in humans and thus reduces liver fat via the central nervous system and the vagus nerve."

The researchers therefore assume that leptin can prevent the development of fatty liver disease independently of its appetite-suppressing effect. The study also suggests that the human brain has an influence on liver fat metabolism via the autonomic nervous system. This could open up new treatment options involving the central nervous system to prevent the widespread fatty liver disease.

Source:

Medical University of Vienna

Reference:

Metz, M., et al. (2022) Leptin increases hepatic triglyceride export via a vagal mechanism in humans. Cell metabolism. doi.org/10.1016/j.cmet.2022.09.020.

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