Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase

J Biol Chem. 2017 Oct 13;292(41):16833-16846. doi: 10.1074/jbc.M117.784256. Epub 2017 Aug 24.

Abstract

Nischarin (Nisch) is a key protein functioning as a molecular scaffold and thereby hosting interactions with several protein partners. To explore the physiological importance of Nisch, here we generated Nisch loss-of-function mutant mice and analyzed their metabolic phenotype. Nisch-mutant embryos exhibited delayed development, characterized by small size and attenuated weight gain. We uncovered the reason for this phenotype by showing that Nisch binds to and inhibits the activity of AMP-activated protein kinase (AMPK), which regulates energy homeostasis by suppressing anabolic and activating catabolic processes. The Nisch mutations enhanced AMPK activation and inhibited mechanistic target of rapamycin signaling in mouse embryonic fibroblasts as well as in muscle and liver tissues of mutant mice. Nisch-mutant mice also exhibited increased rates of glucose oxidation with increased energy expenditure, despite reduced overall food intake. Moreover, the Nisch-mutant mice had reduced expression of liver markers of gluconeogenesis associated with increased glucose tolerance. As a result, these mice displayed decreased growth and body weight. Taken together, our results indicate that Nisch is an important AMPK inhibitor and a critical regulator of energy homeostasis, including lipid and glucose metabolism.

Keywords: AMP-activated kinase (AMPK); calorimetry; cell metabolism; cell migration; glucose; obesity.

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Line
  • Energy Metabolism*
  • Gluconeogenesis*
  • Glucose / genetics
  • Glucose / metabolism
  • Humans
  • Imidazoline Receptors
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipid Metabolism*
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Oxidation-Reduction
  • Protein Binding

Substances

  • Imidazoline Receptors
  • Intracellular Signaling Peptides and Proteins
  • Nisch protein, mouse
  • AMP-Activated Protein Kinases
  • Glucose