title: High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor γ signaling.
abstract: Circulating fibroblast growth factor 21 (FGF21) levels are elevated in diabetic subjects and correlate directly with abnormal glucose metabolism, while pharmacologically administered FGF21 can ameliorate hyperglycemia. The pancreatic islet is an FGF21 target, yet the actions of FGF21 in the islet under normal and diabetic conditions are not fully understood. This study investigated the effects of high glucose on islet FGF21 actions in a diabetic mouse model by investigating db/db mouse islet responses to exogenous FGF21, the direct effects of glucose on FGF21 signaling, and the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in FGF21 pathway activation. Results showed that both adult db/db mouse islets and normal islets treated with high glucose ex vivo displayed reduced β-klotho expression, resistance to FGF21, and decreased PPARγ expression. Rosiglitazone, an antidiabetic PPARγ ligand, ameliorated these effects. Our data indicate that hyperglycemia in type 2 diabetes mellitus may lead to FGF21 resistance in pancreatic islets, probably through reduction of PPARγ expression, which provides a novel mechanism for glucose-mediated islet dysfunction.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Wing Yan
authors.initials: WY
authors.lastname: So
authors.forename: Qianni
authors.initials: Q
authors.lastname: Cheng
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Po Sing
authors.initials: PS
authors.lastname: Leung
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000502:physiology*; D010766:Phosphorylation; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones
chemical_list: C488187:FRS2alpha protein, mouse; C418622:Klb protein, mouse; D008565:Membrane Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; C414620:fibroblast growth factor 21; D000077154:Rosiglitazone; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins; D005947:Glucose
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