Abstract
RIP140 (receptor-interacting protein 140) is highly expressed in mature adipocytes and functions as a co-repressor for gene expression involved in lipid and glucose metabolism. In adipocytes, activated PKCε (Protein kinase C epsilon) phosphorylates nuclear RIP140 which is then subsequently arginine methylated and exported to the cytoplasm. In the cytoplasm, RI140 can elicit additional activities. Here we report a new functional role for cytoplasmic RIP140 in adipocyte in regulating adiponectin secretion. Targeting cytoplasmic RIP140 by knocking down RIP140 itself or its nuclear export trigger, PKCε, promotes the secretion of adiponectin without affecting the production or oligomerization of adiponectin. Consequentially, conditioned media from either RIP140- or PKCε-silenced adipocytes, which contain higher levels of adiponectin, enhance glucose uptake in C2C12 cells and reduce gluconeogenesis in HepG2 cells. Further, these effects can be inhibited by an adiponectin-neutralizing antibody. The effect of cytoplasmic RIP140 in regulating adiponectin secretion is via interacting with AS160, a known RIP140-interacting protein. This study reveals a new functional role for cytoplasmic RIP140 in modulating adiponectin vesicle secretion, and suggests that targeting cytoplasmic RIP140 may be a potentially effective therapeutic strategy to improve adiponectin secretion and possibly to manage metabolic disorders.
Original language | English (US) |
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Pages (from-to) | 71-76 |
Number of pages | 6 |
Journal | Cellular Signalling |
Volume | 24 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2012 |
Bibliographical note
Funding Information:This study was supported in part by NIH grants DK60521 , DK060521-07S1 , DA11190 , DK54733 , DK054733-09S1 , K02-DA13926 and the Distinguished McKnight University Professorship to L.-N. W. P.-C. H. is supported by predoctoral fellowship of American Heart Association. We thank Gustav Lienhard for providing AS160 constructs, Malcolm Parker for providing RIP140-null MEF cells. We thank Shawna D. Persaud, C.-H. Hung, Y.-S. Chuang, A. Smith, F. A. Beyan and S.-C. Luo for technical help. We also thank Dr. Timothy Walseth for providing essential equipment.
Keywords
- Adiponectin
- Cytoplasmic
- Gluconeogenesis
- Glucose uptake
- Insulin sensitivity
- RIP140