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

Nature Medicine volume 20, pages 1001–1008 (2014)Cite this article

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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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Figure 1: Excess brain TGF-β1 induces a systemic glucose disorder.
Figure 2: Astrocyte-specific TGF-β1 transgenic expression leads to metabolic dysfunction.
Figure 3: Cell-specific TGF-β1 inhibition reduces diet-induced metabolic dysfunction.
Figure 4: Effect of TGF-β1 excess on hypothalamic inflammation.
Figure 5: Effects of TGF-β1 on hypothalamic RNA SGs and IκBα mRNA decay.
Figure 6: Hypothalamic TGF-β and RNA SGs and PBs link aging to metabolic dysfunction.

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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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  1. Jingqi Yan and Hai Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA

    Jingqi Yan, Hai Zhang, Ye Yin, Juxue Li, Yizhe Tang, Sudarshana Purkayastha, Lianxi Li & Dongsheng Cai

  2. Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA

    Jingqi Yan, Hai Zhang, Ye Yin, Juxue Li, Yizhe Tang, Sudarshana Purkayastha, Lianxi Li & Dongsheng Cai

  3. Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA

    Jingqi Yan, Hai Zhang, Ye Yin, Juxue Li, Yizhe Tang, Sudarshana Purkayastha, Lianxi Li & Dongsheng Cai

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Contributions

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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Correspondence to Dongsheng Cai.

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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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