title: Nedd4 haploinsufficient mice display moderate insulin resistance, enhanced lipolysis, and protection against high-fat diet-induced obesity.
abstract: Neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) is the prototypical protein in the Nedd4 ubiquitin ligase (E3) family, which governs ubiquitin-dependent endocytosis and/or degradation of plasma membrane proteins. Loss of Nedd4 results in embryonic or neonatal lethality in mice and reduced insulin/IGF-1 signaling in embryonic fibroblasts. To delineate the roles of Nedd4 in vivo, we examined the phenotypes of heterozygous knockout mice using a high-fat diet-induced obesity (HFDIO) model. We observed that Nedd4+/- mice are moderately insulin resistant but paradoxically protected against HFDIO. After high-fat diet feeding, Nedd4+/- mice showed less body weight gain, less fat mass, and smaller adipocytes vs the wild type. Despite ameliorated HFDIO, Nedd4+/- mice did not manifest improvement in glucose tolerance vs the wild type in both genders. Nedd4+/- male, but not female, mice displayed significantly lower fasting blood glucose levels and serum insulin levels. Under obesogenic conditions, Nedd4+/- mice displayed elevated stimulated lipolytic activity, primarily through a β2-adrenergic receptor. Combined, these data support novel complex roles for Nedd4 in metabolic regulation involving altered insulin and β-adrenergic signaling pathways.
authors.affiliation: Departments of Pharmacology (J.J.L., S.D., S.W.B., F.-F.L.) and Pediatrics (R.J.F.), University of Tennessee Health Science Center, Memphis, Tennessee 38163; Department of Psychology (R.J.F), University of Memphis, Memphis, Tennessee 38152; and Department of Biology (B.X.), Georgia State University, Atlanta, Georgia 30302.
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Li
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferry
authors.forename: Shiyong
authors.initials: S
authors.lastname: Diao
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.forename: Suleiman W
authors.initials: SW
authors.lastname: Bahouth
authors.forename: Francesca-Fang
authors.initials: FF
authors.lastname: Liao
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000235:genetics*; D059305:Diet, High-Fat; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057895:Haploinsufficiency; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008066:Lipolysis / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000075702:Nedd4 Ubiquitin Protein Ligases; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D056827:Endosomal Sorting Complexes Required for Transport; D007328:Insulin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases