Inositol 1,4,5-trisphosphate receptor type II (InsP3R-II) is reduced in obese mice, but metabolic homeostasis is preserved in mice lacking InsP3R-II

Am J Physiol Endocrinol Metab. 2014 Dec 1;307(11):E1057-64. doi: 10.1152/ajpendo.00236.2014. Epub 2014 Oct 14.

Abstract

Inositol 1,4,5-trisphosphate receptor type II (InsP3R-II) is the most prevalent isoform of the InsP3R in hepatocytes and is concentrated under the canalicular membrane, where it plays an important role in bile secretion. We hypothesized that altered calcium (Ca(2+)) signaling may be involved in metabolic dysfunction, as InsP3R-mediated Ca(2+) signals have been implicated in the regulation of hepatic glucose homeostasis. Here, we find that InsP3R-II, but not InsP3R-I, is reduced in the livers of obese mice. In our investigation of the functional consequences of InsP3R-II deficiency, we found that organic anion secretion at the canalicular membrane and Ca(2+) signals were impaired. However, mice lacking InsP3R-II showed no deficits in energy balance, glucose production, glucose tolerance, or susceptibility to hepatic steatosis. Thus, our results suggest that reduced InsP3R-II expression is not sufficient to account for any disruptions in metabolic homeostasis that are observed in mouse models of obesity. We conclude that metabolic homeostasis is maintained independently of InsP3R-II. Loss of InsP3R-II does impair secretion of bile components; therefore, we suggest that conditions of obesity would lead to a decrease in this Ca(2+)-sensitive process.

Keywords: InsP3R; bile secretion; calcium; gluconeogenesis; glucose homeostasis; hepatic steatosis; insulin sensitivity.

Publication types

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

MeSH terms

  • Animals
  • Bile / metabolism
  • Body Composition / physiology
  • Calcium Signaling / genetics
  • Cholesterol / metabolism
  • Diet, High-Fat
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Glucose Tolerance Test
  • Hepatocytes / physiology
  • Homeostasis / genetics*
  • Inositol 1,4,5-Trisphosphate Receptors / genetics*
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Obese / metabolism*

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Cholesterol