Obesity-associated extracellular mtDNA activates central TGFβ pathway to cause blood pressure increase

Albert Alé, Yalin Zhang, Cheng Han, Dongsheng Cai

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-β (TGFβ) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ is sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.

Original languageEnglish (US)
Pages (from-to)E161-E174
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume312
Issue number3
DOIs
StatePublished - 2017

Fingerprint

Transforming Growth Factors
Mitochondrial DNA
Obesity
Blood Pressure
Growth Factor Receptors
Hypertension
Pro-Opiomelanocortin
Cerebrospinal Fluid
Inflammation
Neurons
Brain

Keywords

  • Brain
  • Hypertension
  • Hypothalamus
  • Inflammation
  • Mitochondrial DNA
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Obesity-associated extracellular mtDNA activates central TGFβ pathway to cause blood pressure increase. / Alé, Albert; Zhang, Yalin; Han, Cheng; Cai, Dongsheng.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 312, No. 3, 2017, p. E161-E174.

Research output: Contribution to journalArticle

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AU - Han, Cheng

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N2 - Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-β (TGFβ) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ is sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.

AB - Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-β (TGFβ) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ is sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.

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