title: Leptin enhances insulin sensitivity by direct and sympathetic nervous system regulation of muscle IGFBP-2 expression: evidence from nonrodent models.
abstract: Leptin is produced from white adipose tissue and acts primarily to regulate energy balance. Obesity is associated with leptin resistance and increased circulating levels of leptin. Leptin has recently been shown to influence levels of IGF binding protein-2 (IGFBP-2), a protein that is reduced in obesity and type 2 diabetes. Overexpression of IGFBP-2 protects against obesity and type 2 diabetes. As such, IGFBP-2 signaling may represent a novel pathway by which leptin regulates insulin sensitivity. We sought to investigate how leptin regulates skeletal muscle IGFBP-2 levels and to assess the impact of this on insulin signaling and glucose uptake. In vitro experiments were undertaken in cultured human skeletal myotubes, whereas in vivo experiments assessed the effect of intracerebroventricular leptin on peripheral skeletal muscle IGFBP-2 expression and insulin sensitivity in sheep. Leptin directly increased IGFBP-2 mRNA and protein in human skeletal muscle through both signal transducer and activator of transcription-3 and phosphatidylinositol 3-kinase signaling, in parallel with enhanced insulin signaling. Silencing IGFBP-2 lowered leptin- and insulin-stimulated protein kinase B phosphorylation and glucose uptake. In in vivo experiments, intracerebroventricular leptin significantly increased hind-limb skeletal muscle IGFBP-2, an effect completely blocked by concurrent peripheral infusion of a β-adrenergic blocking agent. Sheep receiving central leptin showed improvements in glucose tolerance and circulating insulin levels after an iv glucose load. In summary, leptin regulates skeletal muscle IGFBP-2 by both direct peripheral and central (via the sympathetic nervous system) mechanisms, and these likely impact on peripheral insulin sensitivity and glucose metabolism.
authors.affiliation: Centre for Hormone Research (S.W.Y., V.C.R., G.A.W., M.A.S.), Murdoch Childrens Research Institute and Royal Children's Hospital, and Department of Paediatrics (S.W.Y., V.C.R., G.A.W., M.A.S.), University of Melbourne, Melbourne, Victoria 3052, Australia; Department of Physiology (S.W.Y., B.A.H., I.J.C., M.A.S.), Monash University, Melbourne, Victoria 3800, Australia; and Institute of Sport, Exercise and Active Living and the College of Health and Biomedicine (G.K.M.), Victoria University, Melbourne, Victoria 3011, Australia.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Yau
authors.forename: Belinda A
authors.initials: BA
authors.lastname: Henry
authors.forename: Vincenzo C
authors.initials: VC
authors.lastname: Russo
authors.forename: Glenn K
authors.initials: GK
authors.lastname: McConell
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Clarke
authors.forename: George A
authors.initials: GA
authors.lastname: Werther
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sabin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D018482:Muscle, Skeletal; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D012756:Sheep; D013564:Sympathetic Nervous System / Q000187:drug effects*
chemical_list: D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2; D020738:Leptin; D034741:RNA, Small Interfering