Obesity history exacerbates liver macrophage-mediated fibrosis via IGFBP7

Weight regain is a frequent outcome after lifestyle-induced weight loss and is closely linked to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the mechanisms by which prior obesity predisposes to metabolic dysfunction-associated steatohepatitis (MASH) development remain unclear. This study investigates how obesity history influences hepatic steatosis and fibrosis during weight regain. A diet-switch model was used to establish obesity, weight loss (WL), weight regain (RCHFD), and short-term obesity (STHFD) conditions, enabling comparisons between groups with and without prior obesity. Hepatic fibrosis during weight regain was induced using carbon tetrachloride (CCl₄) alongside a second high-fat diet challenge. Obesity history exacerbated hepatic fibrosis during weight regain in the CCl₄ model, accompanied by pronounced liver macrophage (Mφ) activation. Even without CCl₄ treatment, RCHFD mice displayed worsened hepatic steatosis and fibrosis compared to mice without prior obesity, associated with sustained liver Mφ accumulation. Despite the resolution of steatosis and inflammation after weight loss, Mφ persistence coincided with continuous hepatic stellate cell (HSC) activation, as evidenced by elevated alpha-smooth muscle actin (α-SMA) expression. Co-culture studies revealed that liver Mφs from WL mice could activate HSCs, recapitulating the effects of obesity. Mechanistically, IGFBP7 was upregulated in liver Mφs during both obesity and WL, and its secretion mediated HSC activation. These findings demonstrate that obesity history accelerates MASH progression during weight regain through a macrophage/IGFBP7/HSC axis. Targeting IGFBP7 may represent a potential therapeutic approach to prevent fibrosis progression in individuals with a history of obesity.