title: Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation.
abstract: The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids.
authors.affiliation: Harrington Heart and Vascular Institute and Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, OH 44106, USA. saptarsi.haldar@case.edu
authors.forename: Saptarsi M
authors.initials: SM
authors.lastname: Haldar
authors.forename: Darwin
authors.initials: D
authors.lastname: Jeyaraj
authors.forename: Priti
authors.initials: P
authors.lastname: Anand
authors.forename: Han
authors.initials: H
authors.lastname: Zhu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Domenick A
authors.initials: DA
authors.lastname: Prosdocimo
authors.forename: Betty
authors.initials: B
authors.lastname: Eapen
authors.forename: Daiji
authors.initials: D
authors.lastname: Kawanami
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Okutsu
authors.forename: Leticia
authors.initials: L
authors.lastname: Brotto
authors.forename: Hisashi
authors.initials: H
authors.lastname: Fujioka
authors.forename: Janos
authors.initials: J
authors.lastname: Kerner
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Rosca
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
authors.forename: Rod J
authors.initials: RJ
authors.lastname: Snow
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Gerber
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Bai
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Nosek
authors.forename: Marco
authors.initials: M
authors.lastname: Brotto
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D015444:Exercise; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D050356:Lipid Metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*
chemical_list: D000596:Amino Acids; C414172:KLF15 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D005947:Glucose