title: Obesity- and aging-induced excess of central transforming growth factor-β potentiates diabetic development via an RNA stress response.
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.
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA. [4].
authors.forename: Jingqi
authors.initials: J
authors.lastname: Yan
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA. [4].
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yin
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Juxue
authors.initials: J
authors.lastname: Li
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Tang
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Sudarshana
authors.initials: S
authors.lastname: Purkayastha
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Lianxi
authors.initials: L
authors.lastname: Li
authors.affiliation: 1] Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA. [2] Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA. [3] Institute of Aging, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
mesh_terms: D000375:Aging / Q000502:physiology*; D001253:Astrocytes / Q000378:metabolism; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D006801:Humans; D007031:Hypothalamus / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012313:RNA / Q000378:metabolism*; D013312:Stress, Physiological; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D016212:Transforming Growth Factor beta; D012313:RNA; D011333:Pro-Opiomelanocortin
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