title: miR-378 Activates the Pyruvate-PEP Futile Cycle and Enhances Lipolysis to Ameliorate Obesity in Mice.
abstract: 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.
authors.affiliation: The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Changyin
authors.initials: C
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Centre for Biospectroscopy and Metabonomics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, PR China.
authors.forename: Yipeng
authors.initials: Y
authors.lastname: Song
authors.affiliation: The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Yixia
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Centre for Biospectroscopy and Metabonomics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, PR China.
authors.forename: Huiru
authors.initials: H
authors.lastname: Tang
authors.affiliation: The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China.
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000235:genetics*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008066:Lipolysis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000008:administration & dosage / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009843:Oligoribonucleotides / Q000008:administration & dosage / Q000235:genetics; D019289:Pyruvic Acid / Q000378:metabolism; D015219:Substrate Cycling / Q000235:genetics*; D022722:Thermogenesis
chemical_list: C546119:MIRN378 microRNA, mouse; D035683:MicroRNAs; D009843:Oligoribonucleotides; D019289:Pyruvic Acid; D005947:Glucose
keywords: Energy homeostasis; Futile cycle; Lipolysis; Obesity; SCD1; miR-378