Abstract
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.
Original language | English (US) |
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Pages (from-to) | 176-183 |
Number of pages | 8 |
Journal | Molecular and Cellular Endocrinology |
Volume | 351 |
Issue number | 2 |
DOIs | |
State | Published - Apr 4 2012 |
Bibliographical note
Funding Information:This work is supported by NIH Grants DK54733, DK054733-09S1, DK60521, DK060521-07S1, DA11190, K02-DA13926 and the Distinguished McKnight University Professorship to LNW. P.-C. H. is also supported by American Heart Association predoctoral fellowship. We thank A. Smith, C.-H. Hung, Y.-S. Chuang, F.A. Beyan and S.-C. Luo for technical help, and M Parker for RIP140-null MEF.
Keywords
- Ambrisentan
- Cytoplasm
- ET receptor
- Endothelin-1
- Insulin sensitivity
- RIP140