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Background: Bacterial endotoxin lipopolysaccharide (LPS) is a main initiator of sepsis, which, is responsible for inflammatory events and multiorgan dysfunction, could lead to myocardial depression that is a common feature of endotoxemia.Adiponectin is an important adipocytokine.Accumulating experimental evidence has indicated that adiponectin possesses anti-inflammatory, anti-atherogenic, anti-diabetic properties and plays an important role in its cardiovascular implications.This study was designed to test the potent new mechanism(s) that adiponectin may protect against LPS-induced cardiac dysfunction.Methods: LPS (4mg/kg) was injected into the abdomen in age-matched (5-6 month old) C57 and APO mice 6 hours prior to sacrifice.And mechanical properties of isolated cardiac myocytes as well as analysis of western blot, caspase-3 activation, ROS production, GSSG/GSH detection, TUNEL from cardiac tissues, inflammatory factors,pAMPK-mTOR-autophgic signals were examined.AICAR((5-aminoimidazole-4-carboxamide-3-ribonucleoside, AMPK stimulator) were used to delineate whether the protective mechanism(s) of adiponectin in LPS challenge.Results: LPS injection led to depressed PS, ±dL/dt, and prolonged TR90 in C57 mice, all of which were exaggerated by adiponectin knockout.LPS-induced caspase-3 activation, ROS generation, apoptosis, were significantly increased in APO mice compared with C57 mice.On the contrary, autophagy was significantly increased in C57 mice than that in APO ice as evidenced by increased expression of LC3I and decreased expression of P62.LPS-induced contractile dysfunction was reversed by AICAR.Conclusion: Our data suggests that adiponectin may protect against LPS-induced cardiac dysfunction by AMPK mediated autophagic signaling pathways.