SNAP25 mutation disrupts metabolic homeostasis, steroid hormone production and central neurobehavior

Biochim Biophys Acta Mol Basis Dis. 2022 Feb 1;1868(2):166304. doi: 10.1016/j.bbadis.2021.166304. Epub 2021 Nov 24.

Abstract

Objective: SNAP-25 is one of the key proteins involved in formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes that are at the core of hormonal secretion and synaptic transmission. Altered expression or function of SNAP-25 can contribute to the development of neuropsychiatric and metabolic disease. A dominant negative (DN) I67T missense mutation in the b-isoform of SNAP-25 (DN-SNAP25mut) mice leads to abnormal interactions within the SNARE complex and impaired exocytotic vesicle recycling, yet the significance of this mutation to any association between the central nervous system and metabolic homeostasis is unknown.

Methods: Here we explored aspects of metabolism, steroid hormone production and neurobehavior of DN-SNAP25mut mice.

Results: DN-SNAP25mut mice displayed enhanced insulin function through increased Akt phosphorylation, alongside increased adrenal and gonadal hormone production. In addition, increased anxiety behavior and beigeing of white adipose tissue with increased energy expenditure were observed in mutants.

Conclusions: Our results show that SNAP25 plays an important role in bridging central neurological systems with peripheral metabolic homeostasis, and provide potential insights between metabolic disease and neuropsychiatric disorders in humans.

Keywords: Anxiety-like behavior; Beigeing; Brown adipose tissue; Glucose metabolism; Insulin secretion; Neurobehavior; SNAP25; Steroidogenesis; White adipose tissue.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal*
  • Female
  • Gonadal Steroid Hormones / metabolism*
  • Homeostasis*
  • Insulin Resistance*
  • Male
  • Metabolic Diseases / etiology
  • Metabolic Diseases / metabolism
  • Metabolic Diseases / pathology*
  • Mice
  • Mice, Inbred C3H
  • Mutation*
  • Synaptic Transmission
  • Synaptosomal-Associated Protein 25 / genetics*
  • Synaptosomal-Associated Protein 25 / physiology

Substances

  • Gonadal Steroid Hormones
  • Snap25 protein, mouse
  • Synaptosomal-Associated Protein 25