title: Regulation of mitochondrial biogenesis by lipoprotein lipase in muscle of insulin-resistant offspring of parents with type 2 diabetes.
abstract: Recent studies reveal a strong relationship between reduced mitochondrial content and insulin resistance in human skeletal muscle, although the underlying factors responsible for this association remain unknown. To address this question, we analyzed muscle biopsy samples from young, lean, insulin resistant (IR) offspring of parents with type 2 diabetes and control subjects by microarray analyses and found significant differences in expression of ~512 probe pairs. We then screened these genes for their potential involvement in the regulation of mitochondrial biogenesis using RNA interference and found that mRNA and protein expression of lipoprotein lipase (LPL) in skeletal muscle was significantly decreased in the IR offspring and was associated with decreased mitochondrial density. Furthermore, we show that LPL knockdown in muscle cells decreased mitochondrial content by effectively decreasing fatty acid delivery and subsequent activation of peroxisome proliferator-activated receptor (PPAR)-δ. Taken together, these data suggest that decreased mitochondrial content in muscle of IR offspring may be due in part to reductions in LPL expression in skeletal muscle resulting in decreased PPAR-δ activation.
authors.affiliation: Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA. gerald.shulman@yale.edu
authors.forename: Katsutaro
authors.initials: K
authors.lastname: Morino
authors.forename: Kitt Falk
authors.initials: KF
authors.lastname: Petersen
authors.forename: Saki
authors.initials: S
authors.lastname: Sono
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Aiping
authors.initials: A
authors.lastname: Lin
authors.forename: Amy
authors.initials: A
authors.lastname: Gallo
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference
chemical_list: D005227:Fatty Acids; D047494:PPAR delta; D008071:Lipoprotein Lipase