title: The protective effect of FGF21 on diabetes-induced male germ cell apoptosis is associated with up-regulated testicular AKT and AMPK/Sirt1/PGC-1α signaling.
abstract: Fibroblast growth factor 21 (FGF21) is a metabolic regulator that is required for normal spermatogenesis and protects against diabetes-induced germ cell apoptosis. Here, we tried to define whether diabetes-induced germ cell apoptosis that is predominantly due to increased oxidative stress was associated with impaired glucose and fatty acid metabolism, by examining the effects of Fgf21 gene knockout (FGF21-KO) or FGF21 treatment on the glucose and fatty acid metabolic pathways in streptozotocin-induced diabetic mice. Western blottings revealed that protein kinase B (AKT)-mediated glucose signaling was down-regulated in diabetic testes and further decreased in FGF21-KO diabetic group both 10 days and 2 months after diabetes onset, reflected by reduced glycogen synthase (GS) kinase (GSK)-3β phosphorylation and increased GS phosphorylation. Deletion of the Fgf21 gene also inactivated fatty acid metabolism-related factors, AMP-activated protein kinase (AMPK), sirtuin 1 (Sirt1), and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), along with exacerbating diabetes-induced testicular oxidative stress and damage. Treatment with recombinant FGF21 partially prevented these diabetic effects. In FGF21-KO nondiabetic mice, testicular AMPK/Sirt1/PGC-1α signaling was down-regulated and AKT1 and murine double minute 2 were inactivated along with the increased p53 expression but not AKT2, GSK-3β, and GS. These results suggest that the role of FGF21 in maintaining spermatogenesis is associated with its activation of AKT1 and inhibition of p53. Deletion of the Fgf21gene significantly exacerbates diabetes-induced down-regulation of testicular AKT/GSK-3β/GS and AMPK/Sirt1/PGC-1α pathways and testicular oxidative stress and cell apoptosis.
authors.affiliation: The First Hospital of Jilin University (X.J., Z.Z.) and Key Laboratory of Pathobiology (Y.X.), Ministry of Education, Jilin University, Changchun 130021, China; Kosair Children's Hospital Research Institute at the Department of Pediatrics (X.J., J.C., Z.Z., Y.T., Y.X., L.C.), and Departments of Medicine (W.F.) and Pharmacology and Toxicology (Y.T., W.F., M.S., L.C.), University of Louisville, Louisville 40202; and Nursing School of Wenzhou Medical University (J.C.) and The Chinese-American Research Institute for Diabetic Complications (C.Z., Y.T., M.S., L.C.), Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.forename: Wenke
authors.initials: W
authors.lastname: Feng
authors.forename: Melissa
authors.initials: M
authors.lastname: Skibba
authors.forename: Ying
authors.initials: Y
authors.lastname: Xin
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D005854:Germ Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1