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

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