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

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-beta(TGF beta) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGF beta is sufficient to cause hypertension in mice. Knockout of the TGF beta receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGF beta but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGF beta receptor antagonist or genetically by TGF beta receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGF beta receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGF beta pathway to mediate a central inflammatory mechanism of obesity-related hypertension.