Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans.
BACKGROUND
Nuclear factor-κB (NF-κB) signaling plays critical roles in physiological and pathological processes such as responses to inflammation and oxidative stress.


RESULTS
To examine the role of endothelial NF-κB signaling in vivo, we generated transgenic mice expressing dominant-negative IκB under the Tie2 promoter/enhancer (E-DNIκB mice). These mice exhibited functional inhibition of NF-κB signaling specifically in endothelial cells. Although E-DNIκB mice displayed no overt phenotypic changes when young and lean, they were protected from the development of insulin resistance associated with obesity, whether diet- or genetics-induced. Obesity-induced macrophage infiltration into adipose tissue and plasma oxidative stress markers were decreased and blood flow and mitochondrial content in muscle and active-phase locomotor activity were increased in E-DNIκB mice. In addition to inhibition of obesity-related metabolic deteriorations, blockade of endothelial NF-κB signaling prevented age-related insulin resistance and vascular senescence and, notably, prolonged life span. These antiaging phenotypes were also associated with decreased oxidative stress markers, increased muscle blood flow, enhanced active-phase locomotor activity, and aortic upregulation of mitochondrial sirtuin-related proteins.


CONCLUSIONS
The endothelium plays important roles in obesity- and age-related disorders through intracellular NF-κB signaling, thereby ultimately affecting life span. Endothelial NF-κB signaling is a potential target for treating the metabolic syndrome and for antiaging strategies.
Department of Metabolic Diseases, Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
Yutaka
Y
Hasegawa
Tokuo
T
Saito
Takehide
T
Ogihara
Yasushi
Y
Ishigaki
Tetsuya
T
Yamada
Junta
J
Imai
Kenji
K
Uno
Junhong
J
Gao
Keizo
K
Kaneko
Tatsuo
T
Shimosawa
Tomoichiro
T
Asano
Toshiro
T
Fujita
Yoshitomo
Y
Oka
Hideki
H
Katagiri
D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000235:genetics* / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009765:Obesity / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology
D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha