Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):E4326-35. doi: 10.1073/pnas.1511951112. Epub 2015 Jul 20.

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.

Keywords: SNARE; glucose metabolism; hypothalamus; insulin secretion; regulated exocytosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipocytes / pathology
  • Adipose Tissue, White / metabolism
  • Adipose Tissue, White / pathology
  • Adiposity
  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Dyslipidemias / pathology
  • Energy Intake
  • Energy Metabolism
  • Feeding Behavior
  • Female
  • Homeostasis
  • Hypertrophy
  • Hypothalamus / metabolism
  • Insulin / metabolism
  • Insulin Secretion
  • Leptin / blood
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Metabolic Diseases / blood
  • Metabolic Diseases / metabolism*
  • Mice, Obese
  • Phenotype
  • Receptors, Leptin / metabolism
  • Synaptosomal-Associated Protein 25 / deficiency
  • Synaptosomal-Associated Protein 25 / metabolism*

Substances

  • Blood Glucose
  • Insulin
  • Leptin
  • Receptors, Leptin
  • Snap25 protein, mouse
  • Synaptosomal-Associated Protein 25