Obesity-and aging-induced excess of central transforming growth factor-β 2 potentiates diabetic development via an RNA stress response

Jingqi Yan, Hai Zhang, Ye Yin, Juxue Li, Yizhe Tang, Sudarshana Purkayastha, Lianxi Li, Dongsheng Cai

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1001-1008
Number of pages8
JournalNature Medicine
Volume20
Issue number9
DOIs
StatePublished - Sep 1 2014

Fingerprint

Transforming Growth Factors
Medical problems
Obesity
Aging of materials
RNA
Type 2 Diabetes Mellitus
Glucose
Pro-Opiomelanocortin
Messenger RNA
Body Weight Changes
Glucose Intolerance
RNA Stability
Metabolism
Astrocytes
Hyperglycemia
Hypothalamus
Neurons
Brain
Homeostasis
Chemical activation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Obesity-and aging-induced excess of central transforming growth factor-β 2 potentiates diabetic development via an RNA stress response. / Yan, Jingqi; Zhang, Hai; Yin, Ye; Li, Juxue; Tang, Yizhe; Purkayastha, Sudarshana; Li, Lianxi; Cai, Dongsheng.

In: Nature Medicine, Vol. 20, No. 9, 01.09.2014, p. 1001-1008.

Research output: Contribution to journalArticle

Yan, Jingqi ; Zhang, Hai ; Yin, Ye ; Li, Juxue ; Tang, Yizhe ; Purkayastha, Sudarshana ; Li, Lianxi ; Cai, Dongsheng. / Obesity-and aging-induced excess of central transforming growth factor-β 2 potentiates diabetic development via an RNA stress response. In: Nature Medicine. 2014 ; Vol. 20, No. 9. pp. 1001-1008.
@article{2c1a259ba8fa47ceb776ef9dbc3cd35c,
title = "Obesity-and aging-induced excess of central transforming growth factor-β 2 potentiates diabetic development via an RNA stress response",
abstract = "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.",
author = "Jingqi Yan and Hai Zhang and Ye Yin and Juxue Li and Yizhe Tang and Sudarshana Purkayastha and Lianxi Li and Dongsheng Cai",
year = "2014",
month = "9",
day = "1",
doi = "10.1038/nm.3616",
language = "English (US)",
volume = "20",
pages = "1001--1008",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "9",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84908344159&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84908344159&partnerID=8YFLogxK

U2 - 10.1038/nm.3616

DO - 10.1038/nm.3616

M3 - Article

C2 - 25086906

AN - SCOPUS:84908344159

VL - 20

SP - 1001

EP - 1008

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 9

ER -