Work

RLIP76 Protein Knockdown Attenuates Obesity Due to a High-fat Diet

Year: 2013

Type: article

Abstract: Feeding a Western high-fat diet (HFD) to C57BL/6 mice induces obesity, associated with a chronic inflammatory state, lipid transport, and metabolic derangements, and organ system effects that particularly prominent in the kidneys. Here, we report that RLIP76 homozygous knock-out ( RLIP76 −/− ) mice are highly resistant to obesity as well as these other features of metabolic syndrome caused by HFD. The normal increase in pro-inflammatory and fibrotic markers associated with HFD induced obesity in wild-type C57B mice was broadly and nearly completely abrogated in RLIP76 −/− mice. This is a particularly striking finding because chemical markers of oxidative stress including lipid hydroperoxides and alkenals were significantly higher in RLIP76 −/− mice. Whereas HFD caused marked suppression of AMPK in wild-type C57B mice, RLIP76 −/− mice had baseline activation of AMP-activated protein kinase, which was not further affected by HFD. The baseline renal function was reduced in RLIP76 −/− mice as compared with wild-type, but was unaffected by HFD, in marked contrast to severe renal impairment and glomerulopathy in the wild-type mice given HFD. Our findings confirm a fundamental role of RLIP76 in regulating the function of obesity-promoting pro-inflammatory cytokines, and provide a novel mechanism for targeted therapy of obesity and metabolic syndrome. Background: RLIP76 homozygous knock-out mice ( RLIP76 −/− ) display a partially anti-metabolic syndrome phenotype characterized by insulin sensitivity, hypoglycemia, and hypolipidemia. Results: RLIP76 −/− mice are highly resistant to obesity as well as these other features of metabolic syndrome (MetS) caused by a high-fat diet. Conclusion: Our findings confirm a fundamental role of RLIP76 in regulating the function of obesity-promoting pro-inflammatory cytokines. Significance: Present studies provide a novel mechanism for targeted therapy of obesity and MetS.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m113.480194