title: Association between insulin resistance and impairment of FGF21 signal transduction in skeletal muscles.
abstract: Fibroblast growth factor (FGF) 21, was identified as a potent metabolic regulator of glucose and lipid metabolism. We investigated whether the levels and signalings of FGF21 changed in the skeletal muscle of type 2 diabetes mellitus (T2DM) patients, participants with impaired glucose tolerance (IGT), human skeletal muscle myotubes (HSMMs) under insulin-resistant conditions, and mice with diet-induced obesity (DIO). A percutaneous biopsy sample of the vastus lateralis muscle of T2DM patients, IGT subjects, and participants with normal glucose tolerance was obtained and the levels and signalings of FGF21 were assessed. We determined whether the expression and signalings of FGF21 in HSMMs altered according to palmitate concentrations and exposure time. Also, we confirmed whether changes of FGF21 signal transduction resulted in the alteration of FGF21 functions. DIO mice were treated intravenously with recombinant FGF21, and the levels and signalings of FGF21 were assessed in their soleus muscles. We checked whether or not FGF21 played a role in the gene transcription related to lipid oxidation. Levels of FGF21 increased, whereas levels of phosphorylated FGF receptor (p-FGFR), phosphorylated FGFR substrates 2α (p-FRS2α), and phosphorylated extracellular signal-regulated kinases (p-ERK) decreased in the skeletal muscle of both T2DM patients and IGT subjects. In vitro, palmitate increased the levels of FGF21 and significantly reduced the levels of β-klotho, p-FGFR, p-FRS2α, and p-ERK1/2 in HSMMs exposed to palmitate. Palmitate also decreased glucose uptake and glycogen contents of FGF21. Consistently, the levels of FGF21 were significantly higher and the levels of β-klotho and p-FGFR were lower in the DIO mice than in normal lean mice. The levels of FGF21 increased but its signal transduction and actions were impaired in skeletal muscles of T2DM patients, IGT subjects, in insulin-resistant HSMMs, and DIO mice.
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Jeon
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea.
authors.forename: Eun Suk
authors.initials: ES
authors.lastname: Ha
authors.affiliation: Division of Endocrine and Metabolism, Department of Internal Medicine, Seoul Medical Center, Seoul, Republic of Korea.
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea.
authors.forename: Jong Gab
authors.initials: JG
authors.lastname: Jung
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Han
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea.
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea.
authors.forename: Dae Jung
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, 443-721, Republic of Korea. lkw65@ajou.ac.kr.
authors.forename: Kwan-Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000328:Adult; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004032:Diet; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C538995:KLB protein, human; D008565:Membrane Proteins; D017468:Receptors, Fibroblast Growth Factor; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins
keywords: Diabetes mellitus, type 2; Fibroblast growth factors; Insulin resistance; Muscle, skeletal