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 (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.
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Acknowledgements
The authors thank members of the Cai laboratory for providing technical assistance. This study was supported by US National Institutes of Health grants R01 DK078750, R01 AG031774, R01 HL113180 and R01 DK 099136 (all to D.C.).
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D.C. conceived and designed the study; J.Y., H.Z., Y.Y., J.L. and Y.T. performed experiments and data analyses with experimental assistance from S.P. and L.L.; and D.C. and J.Y. wrote the paper.
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Yan, J., Zhang, H., Yin, Y. et al. Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response. Nat Med 20, 1001–1008 (2014). https://doi.org/10.1038/nm.3616
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DOI: https://doi.org/10.1038/nm.3616
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