The role of lepTin in regulating HepAtic Lipid metAbolisM

Background: Non-alcoholic fatty liver disease is a common liver pathology that is strongly associated with the occurrence of disorders of glucose metabolism such as type 2 diabetes and obesity. An imbalance between increased lipid production/uptake and low lipid export from the liver is a pivotal factor in the development of fatty liver disease. The hormone leptin, a messenger protein that is exclusively assembled in white adipose tissue and released into the circulation, is an important factor in regulating liver fat content. Patients suffering from lipodystrophy almost completely lack adipose tissue due to a rare genetic defect. These individuals do not produce leptin in sufficient amounts and develop pronounced fatty liver disease and diabetes. Hormone replacement therapy with leptin injections markedly improve fatty liver disease and insulin sensitivity in these patients, yet the mechanism by which leptin lowers liver fat content is as of yet unexplored. We were able to show in rodent experiments that leptin action on hepatic lipid metabolism is mainly mediated via the brain and the central nervous system. In addition to its well-known appetite suppressing effects, leptin can also positively affect hepatic lipid metabolism by lowering liver lipids via activation of the autonomic nervous system. Hypothesis: The purpose of this study is to determine whether leptin increases hepatic lipid export and thereby lowers liver fat content also in humans. Methods: Here, we test the effects of a single dose of leptin on liver fat content and fat export using a combination of non- invasive magnetic resonance (MR) imaging followed by an intralipid infusion study to determine the hepatic lipid export rate. Healthy volunteers, patients with lipodystrophy and patients after a liver transplantation will be examined. The latter is an experimental model, in which the brain is unable to communicate with the liver via the autonomic nervous system allowing us to check whether the effects of leptin on liver metabolism are actually mediated via a signal originating from the brain going all the way to the liver. Novelty and Clinical Importance: The study is designed to offer a comprehensive overview of leptin action on liver lipid metabolism in humans and has major implications for patients with the orphan disease lipodystrophy. However, an improved understanding of the physiologic regulatory pathways between the brain and the liver will also support the development of new pharmacological strategies to fight fatty liver disease, for which as of yet no clinically approved therapy exists.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity and type 2 diabetes and represents the hepatic manifestation of metabolic syndrome. A key factor in the development of fatty liver is an imbalance between increased lipid production or intake and simultaneously reduced lipid export from the liver. The hormone leptin, a signaling molecule produced exclusively in adipose tissue by adipocytes and released into the bloodstream in proportion to fat mass, plays an important role in regulating liver fat content. Patients with lipodystrophy, who are unable to develop sufficient fat tissue and therefore produce little to no leptin, often develop pronounced fatty liver disease and suffer from type 2 diabetes. These metabolic sequelae can be treated with hormone replacement therapy via regular subcutaneous injections of recombinant leptin. However, the exact mechanism by which leptin reduces liver fat content remains unknown. In previous experiments with rodents, we demonstrated that leptin primarily acts through the brain and central nervous system, and that in addition to its well-known appetite-suppressing effects, it can positively influence liver fat metabolism by increasing lipid export via activation of the autonomic nervous system, particularly the vagus nerve (FWF Project P26766). The aim of this project was to investigate the food intake-independent effects of leptin on human liver fat metabolism and to test whether a comparable mechanism also regulates liver fat content in humans. In line with our hypothesis, we showed that a single leptin injection mobilized fat from the liver in healthy, normal-weight men and reduced liver fat content. A similar effect was observed after stimulation of the autonomic nervous system through sham eating-a process in which a test meal is chewed and spat out without swallowing-which serves as a natural stimulus for the vagus nerve. In contrast, leptin lost its effect on hepatic fat mobilization in liver-transplanted patients, where the liver is no longer connected to the brain. These anti-steatotic effects of leptin were also confirmed in patients with lipodystrophy and low circulating leptin, where the positive effect of leptin injections on fat export from the liver was even more pronounced. In summary, our studies suggest that leptin regulates liver fat content in humans via the brain and autonomic nervous system. Consistent with previous findings in animal models, leptin in humans also stimulates lipid release from the liver, thereby reducing hepatic fat content through the central nervous system and the vagus nerve. It is therefore likely that leptin can prevent the development of fatty liver independently of its anorexigenic effects, influencing liver fat metabolism via the brain and autonomic nervous system. These findings may open up new therapeutic avenues targeting the central nervous system to combat steatotic liver disease in the future.