title: Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes.
abstract: Dipeptidyl peptidase 4 (DPP4) is the target of the gliptins, a recent class of oral antidiabetics. DPP4 (also called CD26) was previously characterized in immune cells but also has important metabolic functions which are not yet fully understood. Thus, we investigated the function of DPP4 in human white preadipocytes and adipocytes. We found that both cell types express DPP4 in high amounts; DPP4 release markedly increased during differentiation. In preadipocytes, lentiviral DPP4 knockdown caused significant changes in gene expression as determined by whole-genome DNA-array analysis. Metabolic genes were increased, e.g. PDK4 18-fold and PPARγC1α (=PGC1α) 6-fold, and proliferation-related genes were decreased (e.g. FGF7 5-fold). These effects, contributing to differentiation, were not inhibited by the PPARγ antagonist T0070907. Vice versa, the PPARγ agonist pioglitazone induced a different set of genes (mainly FABP4). DPP4 knockdown also affected growth factor signaling and, accordingly, retarded preadipocyte proliferation. In particular, basal and insulin-induced ERK activation (but not Akt activation) was markedly diminished (by around 60%). This indicates that DPP4 knockdown contributes to adipocyte maturation by mimicking growth factor withdrawal, an early step in fat cell differentiation. In mature adipocytes, DPP4 becomes liberated so that adipose tissue may constitute a relevant source of circulating DPP4.
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Zilleßen
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Celner
authors.affiliation: Institute for Pharmacology and Toxicology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Kretschmann
authors.affiliation: Institute for Pharmacology and Toxicology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Institute for Pharmacology and Toxicology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Racké
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), 53175 Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Mayer
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D052436:Adipose Tissue, White / Q000201:enzymology / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D000077205:Pioglitazone; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D001549:Benzamides; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; C000631432:PDK4 protein, human; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011725:Pyridines; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034741:RNA, Small Interfering; C458508:T 0070907; D045162:Thiazolidinediones; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D018819:Dipeptidyl Peptidase 4; D000077205:Pioglitazone