The chronic consumption of a Western diet or obesity are both risk factors for poor liver regeneration after surgical resection or after drug-induced liver injuries (DILI), which can be observed in obese individuals and patients with non-alcoholic fatty liver disease (NAFLD) but also in animal models. Liver-resident macrophages, also called Kupffer cells (KC), were identified as cells that significantly affect tissue regeneration and the maintenance of organ homeostasis and integrity, in general. While it is now understood that obesity-induced inflammation (i.e., metaflammation) leads to a significant transcriptomic and epigenomic reprogramming of macrophages and their myeloid progenitors, the exact mechanisms by which metaflammation affects liver regeneration remain largely unknown. Here we propose that reprograming of hepatic macrophages and their precursors results in developmental and functional disorders, as well as an altered reconstitution that affect liver regeneration under metaflammation conditions. This proposal aims at identifying the functional and transcriptional reprogramming of hepatic macrophage subsets under conditions of obesity. We further aim to define the cellular and molecular mechanisms by which metaflammation alters hepatic macrophage replenishment, differentiation and function that lead to impaired liver regeneration in obese mice. In human translational studies, we will validate our findings from mouse models by analysing hepatic macrophage subsets in liver samples from obese individuals and patients with nonalcoholic steatohepatitis (NASH). In the long term, we would like to target the identified molecular and cellular pathways as a therapeutic intervention to promote liver regeneration under obesity conditions.