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

Nat Med. 2014 Sep;20(9):1001-8. doi: 10.1038/nm.3616. Epub 2014 Aug 3.


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 (TGF-β) 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 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, respectively. Mechanistically, TGF-β excess induced a hypothalamic RNA stress response, resulting in accelerated mRNA decay of IκBα, an inhibitor of proinflammatory nuclear factor-κB. These results reveal an atypical, mRNA metabolism-driven hypothalamic nuclear factor-κB activation, a mechanism that links obesity as well as aging to hypothalamic inflammation and ultimately to type 2 diabetes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / physiology*
  • Astrocytes / metabolism
  • Diabetes Mellitus / etiology
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / physiopathology*
  • Glucose Tolerance Test
  • Humans
  • Hypothalamus / physiopathology
  • NF-kappa B / metabolism
  • Obesity / physiopathology*
  • Pro-Opiomelanocortin / metabolism
  • RNA / metabolism*
  • Stress, Physiological*
  • Transforming Growth Factor beta / metabolism*


  • NF-kappa B
  • Transforming Growth Factor beta
  • RNA
  • Pro-Opiomelanocortin