Modelling metabolic diseases and drug response using stem cells and organoids

Metabolic diseases, including obesity, diabetes mellitus and cardiovascular disease, are a major threat to health in the modern world, but efforts to understand the underlying mechanisms and develop rational treatments are limited by the lack of appropriate human model systems. Notably, advances in stem cell and organoid technology allow the generation of cellular models that replicate the histological, molecular and physiological properties of human organs. Combined with marked improvements in gene editing tools, human stem cells and organoids provide unprecedented systems for studying mechanisms of metabolic diseases. Here, we review progress made over the past decade in the generation and use of stem cell-derived metabolic cell types and organoids in metabolic disease research, especially obesity and liver diseases. In particular, we discuss the limitations of animal models and the advantages of stem cells and organoids, including their application to metabolic diseases. We also discuss mechanisms of drug action, understanding the efficacy and toxicity of existing therapies, screening for new treatments and pursuing personalized therapies. We highlight the potential of combining stem cell-derived organoids with gene editing and functional genomics to revolutionize the approach to finding treatments for metabolic diseases. Organoids are a promising tool for modelling diseases in vitro. This Review discusses the progress in developing liver and adipose tissue organoids to study metabolic diseases such as obesity and non-alcoholic fatty liver disease and assesses the strengths and limitations of these systems. Key points Animal models of metabolic diseases are limited by unique human biology. Human adipose and liver organoid models can be generated from pluripotent stem cells and healthy or diseased tissues. Adipose stem cells and organoids can model white and brown adipogenesis and the progression of obesity. Hepatic organoids can be used to model acquired metabolic diseases of the liver. Human stem cells and organoid models have utility in drug discovery and precision medicine for metabolic diseases.