title: Ablation of Lgr4 enhances energy adaptation in skeletal muscle via activation of Ampk/Sirt1/Pgc1α pathway.
abstract: Leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is a newfound obese-associated gene. Previous study reveals that heterozygous mutation of Lgr4 correlates with decreased body weight in human. In our recent study, we demonstrate that Lgr4 ablation promotes browning of white adipose tissue and improves whole-body metabolic status. However little is known about its role in other metabolic tissues. Herein, we show that Lgr4 homozygous mutant (Lgr4(m/m)) mice show increased respiratory exchange ratio (RER, closer to 1.0) than wild-type mice at 12:00 AM (food-intake time for mice) while decreased RER (closer to 0.75) at 12:00 PM (fasting for mice), indicating a glucose-prone versus fatty acid-prone metabolic pattern, respectively. Furthermore, Lgr4 ablation increases lipid oxidation-related gene expression while suppresses glucose transporter type 4 (Glut4) levels in skeletal muscle under fasting condition. These data suggest that Lgr4 ablation enhances the flexibility of skeletal muscle to switch energy provider from glucose to fatty acid in response to glucose depletion. We further reveal the activation of Ampk/Sirt1/Pgc1α pathway during this adaptive fuel shift due to Lgr4 ablation. This study suggests that Lgr4 might serve as an adaptive regulator between glucose and lipid metabolism in skeletal muscle and reveals a potentially new regulator for a well-established adaptive network.
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Yingkai
authors.initials: Y
authors.lastname: Sun
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hong
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Maopei
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Geriatrics, The 6th People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Ke
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Shaoqian
authors.initials: S
authors.lastname: Zhao
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Qinyun
authors.initials: Q
authors.lastname: Ma
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China.
authors.forename: Yaoyu
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China.
authors.forename: Tinglu
authors.initials: T
authors.lastname: Ning
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xiner198287@163.com.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Liu
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: jiqiuwang@163.com.
authors.forename: Jiqiu
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Key Laboratory for Medical Genomes, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200025, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism; D005215:Fasting; D007328:Insulin / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D007328:Insulin; C496200:LGR4 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D000263:Adenylate Kinase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Energy adaptation; LGR4; Skeletal muscle