Smichi_2025_Cell.Rep.Med__102147

Heart failure can be worse when associated with obesity, elevated serum pancreatic enzymes, elevated non-esterified fatty acids (NEFAs), or acute pancreatitis (AP). To understand this, here we study doxorubicin-induced heart failure, experimental AP, or pancreatic lipase-induced visceral fat necrosis in lean, genetically obese (ob/ob), or dual ob/ob pancreatic triglyceride lipase (PNLIP)-knockout mice. NEFA generation and resulting cardiac injury are measured. We note that ob/ob mice develop fat necrosis containing PNLIP and phospholipase A(2). This generates excess NEFAs that worsen cardiac injury, cause hypotension, and reduce survival. All these are prevented by PNLIP deletion or pharmacologic inhibition. Live imaging shows that phospholipase A(2) damages adipocyte membranes, resulting in PNLIP entry and leakage of adipocyte lipases. PNLIP hydrolyzes adipose triglyceride, generates NEFAs, and causes lipid droplet loss and adipocyte necrosis. Therefore, pancreatic injury can worsen antecedent heart failure by leaked PNLIP, causing excessive visceral adipose lipolysis. Inhibition of such lipolysis may improve heart failure outcomes.