TY - JOUR
T1 - Obesity-and aging-induced excess of central transforming growth factor-β 2 potentiates diabetic development via an RNA stress response
AU - Yan, Jingqi
AU - Zhang, Hai
AU - Yin, Ye
AU - Li, Juxue
AU - Tang, Yizhe
AU - Purkayastha, Sudarshana
AU - Li, Lianxi
AU - Cai, Dongsheng
N1 - Publisher Copyright:
© 2014 Nature America, Inc.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - The brain, in particular the hypothalamus, plays a role in regulating glucose homeostasis; however, it remains unclear whether this organ is causally and etiologically involved in the development of diabetes. Here, we found that hypothalamic transforming growth factor-β 2 (TGF-β 2) production is excessive under conditions of not only obesity but also aging, which are two general etiological factors of type 2 diabetes. Pharmacological and genetic approaches revealed that central TGF-β 2 excess caused hyperglycemia and glucose intolerance independent of a change in body weight. Further, using cell-specific genetic analyses in vivo, we found that astrocytes and proopiomelanocortin neurons are responsible for the production and prodiabetic effect of central TGF-β 2, respectively. Mechanistically, TGF-β 2 excess induced a hypothalamic RNA stress response, resulting in accelerated mRNA decay of Iβ° Bβ±, an inhibitor of proinflammatory nuclear factor-β° B. These results reveal an atypical, mRNA metabolism-driven hypothalamic nuclear factor-β B activation, a mechanism that links obesity as well as aging to hypothalamic inflammation and ultimately to type 2 diabetes.
AB - The brain, in particular the hypothalamus, plays a role in regulating glucose homeostasis; however, it remains unclear whether this organ is causally and etiologically involved in the development of diabetes. Here, we found that hypothalamic transforming growth factor-β 2 (TGF-β 2) production is excessive under conditions of not only obesity but also aging, which are two general etiological factors of type 2 diabetes. Pharmacological and genetic approaches revealed that central TGF-β 2 excess caused hyperglycemia and glucose intolerance independent of a change in body weight. Further, using cell-specific genetic analyses in vivo, we found that astrocytes and proopiomelanocortin neurons are responsible for the production and prodiabetic effect of central TGF-β 2, respectively. Mechanistically, TGF-β 2 excess induced a hypothalamic RNA stress response, resulting in accelerated mRNA decay of Iβ° Bβ±, an inhibitor of proinflammatory nuclear factor-β° B. These results reveal an atypical, mRNA metabolism-driven hypothalamic nuclear factor-β B activation, a mechanism that links obesity as well as aging to hypothalamic inflammation and ultimately to type 2 diabetes.
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U2 - 10.1038/nm.3616
DO - 10.1038/nm.3616
M3 - Article
C2 - 25086906
AN - SCOPUS:84908344159
SN - 1078-8956
VL - 20
SP - 1001
EP - 1008
JO - Nature Medicine
JF - Nature Medicine
IS - 9
ER -