title: Replacing SNAP-25b with SNAP-25a expression results in metabolic disease.
abstract: Synaptosomal-associated protein of 25 kDa (SNAP-25) is a key molecule in the soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE) complex mediating fast Ca(2+)-triggered release of hormones and neurotransmitters, and both splice variants, SNAP-25a and SNAP-25b, can participate in this process. Here we explore the hypothesis that minor alterations in the machinery mediating regulated membrane fusion can increase the susceptibility for metabolic disease and precede obesity and type 2 diabetes. Thus, we used a mouse mutant engineered to express normal levels of SNAP-25 but only SNAP-25a. These SNAP-25b-deficient mice were exposed to either a control or a high-fat/high-sucrose diet. Monitoring of food intake, body weight, hypothalamic function, and lipid and glucose homeostases showed that SNAP-25b-deficient mice fed with control diet developed hyperglycemia, liver steatosis, and adipocyte hypertrophy, conditions dramatically exacerbated when combined with the high-fat/high-sucrose diet. Thus, modified SNARE function regulating stimulus-dependent exocytosis can increase the vulnerability to and even provoke metabolic disease. When combined with a high-fat/high-sucrose diet, this vulnerability resulted in diabesity. Our SNAP-25b-deficient mouse may represent a diabesity model.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden; Ismael.Valladolid.Acebes@ki.se tomas.hokfelt@ki.se Christina.Bark@ki.se.
authors.forename: Ismael
authors.initials: I
authors.lastname: Valladolid-Acebes
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden;
authors.forename: Teresa
authors.initials: T
authors.lastname: Daraio
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.affiliation: Division of Molecular Neurosciences, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden;
authors.forename: Sven Ove
authors.initials: SO
authors.lastname: Ögren
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden; Ismael.Valladolid.Acebes@ki.se tomas.hokfelt@ki.se Christina.Bark@ki.se.
authors.forename: Tomas G M
authors.initials: TG
authors.lastname: Hökfelt
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden; Ismael.Valladolid.Acebes@ki.se tomas.hokfelt@ki.se Christina.Bark@ki.se.
authors.forename: Christina
authors.initials: C
authors.lastname: Bark
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism / Q000473:pathology; D050154:Adiposity; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D050171:Dyslipidemias / Q000473:pathology; D002149:Energy Intake; D004734:Energy Metabolism; D005247:Feeding Behavior; D005260:Female; D006706:Homeostasis; D006984:Hypertrophy; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008659:Metabolic Diseases / Q000097:blood / Q000378:metabolism*; D008820:Mice, Obese; D010641:Phenotype; D054411:Receptors, Leptin / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; C494209:Snap25 protein, mouse; D050825:Synaptosomal-Associated Protein 25
keywords: SNARE; glucose metabolism; hypothalamus; insulin secretion; regulated exocytosis