Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress

Publication date: 21 February 2017
Source:Cell Reports, Volume 18, Issue 8
Author(s): Yoko Yagishita, Akira Uruno, Toshiaki Fukutomi, Ritsumi Saito, Daisuke Saigusa, Jingbo Pi, Akiyoshi Fukamizu, Fumihiro Sugiyama, Satoru Takahashi, Masayuki Yamamoto
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 (Trsp^RIPKO) 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 (Trsp^Ins1KO) 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 Trsp^RIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.

Graphical abstract

Teaser

Yagishita et al. show that selenocysteine-tRNA (Trsp) knockout in hypothalamic cells elicits oxidative stress in hypothalamus and decreases proopiomelanocortin (POMC)-positive neurons, resulting in the development of general leptin and insulin resistance, obesity, and diabetes mellitus. Nrf2 induction by conditional Keap1 knockout prevents oxidative damage to POMC-positive neurons and ameliorates the metabolic phenotypes.


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