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

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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
Issue number9
StatePublished - Sep 1 2014


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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