Deficiency of ER Ca2+ sensor STIM1 in AgRP neurons confers protection against dietary obesity

Cell Rep. 2021 Oct 19;37(3):109868. doi: 10.1016/j.celrep.2021.109868.

Abstract

Store-operated calcium entry (SOCE) is pivotal in maintaining intracellular Ca2+ level and cell function; however, its role in obesity development remains largely unknown. Here, we show that the stromal interaction molecule 1 (Stim1), an endoplasmic reticulum (ER) Ca2+ sensor for SOCE, is critically involved in obesity development. Pharmacological blockade of SOCE in the brain, or disruption of Stim1 in hypothalamic agouti-related peptide (AgRP)-producing neurons (ASKO), significantly ameliorates dietary obesity and its associated metabolic disorders. Conversely, constitutive activation of Stim1 in AgRP neurons leads to an obesity-like phenotype. We show that the blockade of SOCE suppresses general translation in neuronal cells via the 2',5'-oligoadenylate synthetase 3 (Oas3)-RNase L signaling. While Oas3 overexpression in AgRP neurons protects mice against dietary obesity, deactivation of RNase L in these neurons significantly abolishes the effect of ASKO. These findings highlight an important role of Stim1 and SOCE in the development of obesity.

Keywords: AgRP neuron; Oas3-RNase L signaling; Stim1; obesity; store-operated calcium entry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / metabolism
  • Agouti-Related Protein / genetics
  • Agouti-Related Protein / metabolism*
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling*
  • Cell Line, Tumor
  • Diet, High-Fat
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism*
  • Endoribonucleases / metabolism
  • HEK293 Cells
  • Humans
  • Hypothalamus / metabolism*
  • Hypothalamus / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism*
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / physiopathology
  • Obesity / prevention & control*
  • Stromal Interaction Molecule 1 / deficiency*
  • Stromal Interaction Molecule 1 / genetics
  • Weight Gain

Substances

  • Agouti-Related Protein
  • Agrp protein, mouse
  • Stim1 protein, mouse
  • Stromal Interaction Molecule 1
  • 2',5'-Oligoadenylate Synthetase
  • Endoribonucleases
  • 2-5A-dependent ribonuclease
  • Calcium