title: Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yagishita
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan. Electronic address: uruno@med.tohoku.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan; Organ Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukutomi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
authors.forename: Ritsumi
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Miyagi 980-8573, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.affiliation: Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.affiliation: Laboratory Animal Resource Center, University of Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan. Electronic address: masiyamamoto@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012345:RNA, Transfer, Amino Acid-Specific / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000975:Antioxidants; D007328:Insulin; D020738:Leptin; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012345:RNA, Transfer, Amino Acid-Specific; C036928:tRNA, selenocysteine-
keywords: Nrf2; Trsp; hypothalamus; insulin resistance; leptin resistance; oxidative stress; pancreatic beta-cells; proopiomelanocortin; selenoproteins