Obesity is a key risk factor for metabolic-dysfunction associated liver disease (MASLD) and type 2 diabetes. This presentation explores the intricate relationship between these conditions, focusing on the role of hepatokines, which are proteins secreted by the liver. Recent evidence suggests that dysregulated hepatokine secretion from fatty, inflamed livers may contribute to metabolic dysfunction in other tissues. Mass spectrometry proteomics studies have revealed the extensive number of hepatokines and their alterations in obesity and MASLD, and subsequent and subsequent studies using metabolic tracers have advanced our understanding of endocrine regulation in health and disease. This research has also identified potential targets for diagnostics and therapies. The talk will examine the biology of hepatokine secretion in health and disease, proposing that whilst hepatokine concentrations are often insufficient to counteract the lipid and inflammatory burden in obesity and MASLD, understanding these alterations could lead to novel therapeutic approaches. We will explore the potential of reintroducing specific hepatokines at pharmacological doses as a strategy to exploit this natural biology for treating metabolic disorders.