Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress

Cell Rep. 2017 Feb 21;18(8):2030-2044. doi: 10.1016/j.celrep.2017.01.064.


The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout (KO) of selenocysteine-tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). These Trsp-KO (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β cells, leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals are suppressed, and numbers of proopiomelanocortin-positive neurons in the hypothalamus are decreased. In contrast, Trsp-KO mice (TrspIns1KO) expressing Cre specifically in pancreatic β cells, but not in the hypothalamus, do not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related factor 2) regulates antioxidant gene expression. Increased Nrf2 signaling suppresses hypothalamic oxidative stress and improves insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.

Keywords: Nrf2; Trsp; hypothalamus; insulin resistance; leptin resistance; oxidative stress; pancreatic beta-cells; proopiomelanocortin; selenoproteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Diabetes Mellitus / metabolism
  • Hypothalamus / metabolism*
  • Insulin / metabolism
  • Insulin Resistance / physiology*
  • Insulin-Secreting Cells / metabolism
  • Leptin / metabolism*
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / physiology*
  • Promoter Regions, Genetic / physiology
  • RNA, Transfer, Amino Acid-Specific / metabolism
  • Signal Transduction / physiology


  • Antioxidants
  • Insulin
  • Leptin
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • RNA, Transfer, Amino Acid-Specific
  • tRNA, selenocysteine-