4-(5-benzo(1-3)dioxol-5-yl-4-pyridin-2-yl-1h-imidazol-2-yl)benzamide and Obesity

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.

Topics: Animals; Benzamides; Blood Pressure; Blotting, Western; Diet, High-Fat; Dioxoles; DNA, Mitochondrial; Hypertension; Hypothalamus; Male; Mice; Mice, Knockout; Neurons; Obesity; Pro-Opiomelanocortin; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Third Ventricle; Transforming Growth Factor beta; Transforming Growth Factor beta1

Obesity results in reduced differentiation potential of adipocytes leading to adipose tissue insulin resistance. Elevated proinflammatory cytokines from adipose tissue in obesity, such as TNFα have been implicated in the reduced adipocyte differentiation. Other mediators of reduced adipocyte differentiation include TGFβ and wnt proteins. Although some overlap exists in the signaling cascades of the wnt and TGFβ pathways it is unknown if TGFβ or wnt proteins reciprocally induce the expression of each other to maximize their biological effects in adipocytes. Therefore, we investigated the possible involvement of TGFβ signaling in wnt induced gene expression and vice versa in 3T3-L1 adipocyte. Effect of TGFβ and Wnt pathways on differentiation was studied in preadipocytes induced to differentiate in the presence of Wnt3a or TGFβ1 and their inhibitors (FZ8-CRD and SB431542, respectively). Regulation of intracellular signaling and gene expression was also studied in mature adipocytes. Our results show that both TGFβ1 and Wnt3a lead to increased accumulation of β-catenin, phosphorylation of AKT and p44/42 MAPK. However, differences were found in the pattern of gene expression induced by the two proteins suggesting that distinct, but complex, signaling pathways are activated by TGFβ and wnt proteins to independently regulate adipocyte function.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Benzamides; beta Catenin; Blotting, Western; Cell Differentiation; Dioxoles; DNA Primers; Gene Expression Profiling; Gene Expression Regulation; Mice; Obesity; Phosphorylation; Real-Time Polymerase Chain Reaction; Receptor Cross-Talk; RNA, Small Interfering; Transforming Growth Factor beta; Wnt Signaling Pathway