Periodic Reporting for period 4 - BARINAFLD (Using Bariatric Surgery to Discover Weight-Loss Independent Mechanisms Leading to the Reversal of Fatty Liver Disease)
Okres sprawozdawczy: 2023-05-01 do 2024-10-31
Metabolic dysfunction associated fatty liver disease (NAFLD) affects over a quarter of the adult world population. This disease, which is characterised by accumulation of lipid droplets in the liver, can progress to hepatic inflammation, liver failure and liver cancer, and is associated with type 2 diabetes and cardiovascular diseases. Finding new means to treat MAFLD and understand its development are therefore of great importance to society and public health.
Obesity can cause NAFLD, and indeed the best treatment for NAFLD is weight-loss. However only a small fraction of patients manage to to lose weight and maintain weight-loss. Bariatric, or weight-loss surgeries, achieve substantial weight-loss and are associated with a dramatic improvement in MAFLD. We have shown in animal models that these surgeries can improve MAFLD even without weight-loss and can improve MAFLD to a greater extent compared with calorie restriction. Analysis of data from patients have shown that the post-bariatric metabolism is different than the hepatic metabolism of both healthy and NAFLD patients.
The hypothesis of this project is that bariatric surgeries induce a biological process that affects positively MAFLD, independent of weight-loss. Our objectives are to identify this project using animal models and patient data, and to test candidate biological pathways on animal models, as a first step towards finding new treatments for this common and grave disease.
Obesity can cause NAFLD, and indeed the best treatment for NAFLD is weight-loss. However only a small fraction of patients manage to to lose weight and maintain weight-loss. Bariatric, or weight-loss surgeries, achieve substantial weight-loss and are associated with a dramatic improvement in MAFLD. We have shown in animal models that these surgeries can improve MAFLD even without weight-loss and can improve MAFLD to a greater extent compared with calorie restriction. Analysis of data from patients have shown that the post-bariatric metabolism is different than the hepatic metabolism of both healthy and NAFLD patients.
The hypothesis of this project is that bariatric surgeries induce a biological process that affects positively MAFLD, independent of weight-loss. Our objectives are to identify this project using animal models and patient data, and to test candidate biological pathways on animal models, as a first step towards finding new treatments for this common and grave disease.
We have shown using rats and mice models for obesity and by modeling several bariatric surgery types that bariatric surgery improves MAFLD more than expected by weight loss alone. Moreover, we have shown that the molecular changes associated with bariatric surgery are different than those induced by caloric restriction. Therefore, bariatric surgery induces a whole new metabolic "state". We have shown this state is characterized by a change in metabolic pathway that were not associated with obesity. Functioanally, the liver uptakes more insulin than normally, which may explain the improvement in MAFLD and in diabetes. We have shown using data from national registries and from patients suffering from severe genetic obesity, that indeed improvement in MAFLD is independent of surgically induced weight loss.
We identified that inhibition of somatostatin can enhance the metabolic outcomes of surgery - in mice - by increasing secretion of gastrointestinal and pancreatic hormones, providing compelling pre-clinical data for future development. The results of the project are summarized in over 10 publications, that explain the weight loss independent effects of bariatric surgery on hepatic and systemic metabolism, and provide mechanistic explanations for the metabolic outcomes of surgery that extend beyond weight loss.
We identified that inhibition of somatostatin can enhance the metabolic outcomes of surgery - in mice - by increasing secretion of gastrointestinal and pancreatic hormones, providing compelling pre-clinical data for future development. The results of the project are summarized in over 10 publications, that explain the weight loss independent effects of bariatric surgery on hepatic and systemic metabolism, and provide mechanistic explanations for the metabolic outcomes of surgery that extend beyond weight loss.
We have now completed the project and provided molecular and epidemiological evidence for the weight loss-independent effects of bariatric surgery to MAFLD. We discovered new metabolic and hormonal pathways that may affect the outcome of surgery, or can contribute to improvement in MAFLD and obesity. These resutls raise new questions that we are currently pursuing.