title: Cathepsin L activity controls adipogenesis and glucose tolerance.
abstract: Cysteine proteases play an important part in human pathobiology. This report shows the participation of cathepsin L (CatL) in adipogenesis and glucose intolerance. In vitro studies demonstrate the role of CatL in the degradation of the matrix protein fibronectin, insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R), essential molecules for adipogenesis and glucose metabolism. CatL inhibition leads to the reduction of human and murine pre-adipocyte adipogenesis or lipid accumulation, protection of fibronectin from degradation, accumulation of IR and IGF-1R beta-subunits, and an increase in glucose uptake. CatL-deficient mice are lean and have reduced levels of serum glucose and insulin but increased levels of muscle IR beta-subunits, fibronectin and glucose transporter (Glut)-4, although food/water intake and energy expenditure of these mice are no less than their wild-type littermates. Importantly, the pharmacological inhibition of CatL also demonstrates reduced body weight gain and serum insulin levels, and increased glucose tolerance, probably due to increased levels of muscle IR beta-subunits, fibronectin and Glut-4 in both diet-induced obese mice and ob/ob mice. Increased levels of CatL in obese and diabetic patients suggest that this protease is a novel target for these metabolic disorders.
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jiehong
authors.initials: J
authors.lastname: Pan
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Katunuma
authors.forename: Odile D
authors.initials: OD
authors.lastname: Peroni
authors.forename: Michèle
authors.initials: M
authors.lastname: Guerre-Millo
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.forename: Karine
authors.initials: K
authors.lastname: Clement
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C402823:CLIK 148; D004852:Epoxy Compounds; D005353:Fibronectins; D047495:PPAR gamma; D011725:Pyridines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D005947:Glucose