Obesity has been linked to many health problems,such as diabetes.However,there is no drug that effectively treats obesity.Here,we reveal that miR-378 transgenic mice display reduced fat mass,enhanced lipolysis,and increased energy expenditure.Notably,administering AgomiR-378 prevents and ameliorates obesity in mice.We also found that the energy deficiency seen in miR-378 transgenic mice was due to impaired glucose metabolism.This impairment was caused by an activated pyruvate-PEP futile cycle via the miR-378-Akt1-FoxO1-PEPCK pathway in skeletal muscle and enhanced lipolysis in adipose tissues mediated by miR-378-SCD1.Our findings demonstrate that activating the pyruvate-PEP futile cycle in skeletal muscle is the primary cause of elevated lipolysis in adipose tissues of miR-378 transgenic mice,and it helps orchestrate the crosstalk between muscle and fat to control energy homeostasis in mice.Thus,miR-378 may serve as a promising agent for preventing and treating obesity in humans.