title: Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas.
abstract: Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator expressed in multiple tissues including liver and adipose tissue. Although highest levels of expression are in pancreas, little is known about the function of FGF21 in this tissue. In order to understand the physiology of FGF21 in the pancreas, we analyzed its expression and regulation in both acinar and islet tissues. We found that acinar tissue express 20-fold higher levels than that observed in islets. We also observed that pancreatic FGF21 is nutritionally regulated; a marked reduction in FGF21 expression was noted with fasting while obesity is associated with 3-4 fold higher expression. Acinar and islet cells are targets of FGF21, which when systemically administered, leads to phosphorylation of the downstream target ERK 1/2 in about half of acinar cells and a small subset of islet cells. Chronic, systemic FGF21 infusion down-regulates its own expression in the pancreas. Mice lacking FGF21 develop significant islet hyperplasia and periductal lymphocytic inflammation when fed with a high fat obesogenic diet. Inflammatory infiltrates consist of TCRb+ Thy1+ T lymphocytes with increased levels of Foxp3+ regulatory T cells. Increased levels of inflammatory cells were coupled with elevated expression of cytokines such as TNFα, IFNγ and IL1β. We conclude that FGF21 acts to limit islet hyperplasia and may also prevent pancreatic inflammation.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 02215, United States of America.
authors.forename: Garima
authors.initials: G
authors.lastname: Singhal
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 02215, United States of America.
authors.forename: Ffolliott Martin
authors.initials: FM
authors.lastname: Fisher
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 02215, United States of America.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Chee
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, 02215, United States of America.
authors.forename: Tze Guan
authors.initials: TG
authors.lastname: Tan
authors.affiliation: Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Boston, Massachusetts, 02215, United States of America.
authors.forename: Abdelfattah
authors.initials: A
authors.lastname: El Ouaamari
authors.affiliation: Lilly Research Laboratories, Diabetes Research, Indianapolis, Indiana, 46225, United States of America.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02215, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Najarian
authors.affiliation: Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Boston, Massachusetts, 02215, United States of America.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, 02215, United States of America.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 02215, United States of America.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 02215, United States of America.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
mesh_terms: D061354:Acinar Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000009:adverse effects; D005215:Fasting; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006965:Hyperplasia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D010195:Pancreatitis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018800:Thy-1 Antigens; D014409:Tumor Necrosis Factor-alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D007371:Interferon-gamma; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3