期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 31, 页码 E4326-E4335出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1511951112
关键词
SNARE; insulin secretion; glucose metabolism; hypothalamus; regulated exocytosis
资金
- Swedish Research Council
- Family Erling-Persson Foundation
- Karolinska Institutet funds
- Magnus Bergvalls Foundation
- Gun and Bertil Stohnes Foundation
- Langmanska Kulturfonden
- Peter and Augusta Hedlund's Foundation
- Novo Nordisk Foundation
- Fogelstroms Foundation
- Sven Mattssons Foundation
- Alzheimers Research UK [ART-EG2009A-1] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0010695, NNF15OC0015964] Funding Source: researchfish
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 Ca2+-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.
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