lu-208075 and Obesity

The physiological signal activating cytoplasmic accumulation of nuclear receptor interacting protein 140 (RIP140) in adipocytes was unclear. We uncover that endothelin-1 (ET-1) promotes cytoplasmic accumulation of RIP140 in 3T3-L1 adipocytes. We determine ET-1's signal transduction pathway in adipocytes, which is by activating ET(A) receptor-PLCβ-nuclear PKCε. Blocking this pathway in 3T3-L1 adipocyte cultures, by treating cells with an ET(A) antagonist, inhibiting PLCβ, or silencing PKCε, reduces ET-1-stimulated cytoplasmic accumulation of RIP140. In a HFD-fed obese mouse model, administration of a selective ET(A) antagonist, ambrisentan, effectively dampens cytoplasmic accumulation of RIP140 in the epididymal adipose tissue and reduces HFD-caused adipocyte dysfunctions. Importantly, ambrisentan improves blood glucose control and reduces the severity of hepatic steatosis in HFD-fed mice. This study reports a physiological signal that stimulates nuclear export of RIP140 in adipocytes and provides evidence for a strategy using selective ET(A) antagonist to treat obesity-induced insulin resistance and, possibly, other metabolic disorders.

Topics: 3T3-L1 Cells; Adaptor Proteins, Signal Transducing; Adipocytes; Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Experimental; Diet, High-Fat; Endothelin A Receptor Antagonists; Endothelin-1; Fatty Liver; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Nuclear Proteins; Nuclear Receptor Interacting Protein 1; Obesity; Phenylpropionates; Phosphoinositide Phospholipase C; Phospholipase C beta; Pyridazines; Receptor, Endothelin A; RNA Interference; RNA, Small Cytoplasmic