| First Author | Yan J | Year | 2014 |
| Journal | Nat Med | Volume | 20 |
| Issue | 9 | Pages | 1001-8 |
| PubMed ID | 25086906 | Mgi Jnum | J:227600 |
| Mgi Id | MGI:5701604 | Doi | 10.1038/nm.3616 |
| Citation | Yan J, et al. (2014) Obesity- and aging-induced excess of central transforming growth factor-beta potentiates diabetic development via an RNA stress response. Nat Med 20(9):1001-8 |
| abstractText | 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 IkappaBalpha, an inhibitor of proinflammatory nuclear factor-kappaB. These results reveal an atypical, mRNA metabolism-driven hypothalamic nuclear factor-kappaB activation, a mechanism that links obesity as well as aging to hypothalamic inflammation and ultimately to type 2 diabetes. |
