1587-P: The NADPH Oxidase 4 Regulates Anti-inflammatory Signals to Modulate Lipid Depot Distribution between Adipose Tissue and Liver

Abstract

Excessive white adipose tissue (WAT) expansion and lipid load is associated with the onset of insulin resistance and Type 2 diabetes. In addition, lipid storage may “overflow” into the liver triggering the apparition of nonalcoholic fatty liver disease (NAFLD). Two major components linking white adipose tissue (WAT) dysfunction and NAFLD to insulin resistance are the deregulation of cellular redox homeostasis and the onset of chronic, low-grade inflammation. NADPH oxidases (NOX-es) produce oxidant molecules that control redox homeostasis and cytokine signaling in inflammatory cells. In particular, NOX4 is essential for the signal transduction of the transcription factor, Stat6 that mediates anti-inflammatory actions of IL-4 and IL-13. In order to elucidate the in vivo interaction between NOX4 and Stat6 and to assess their relevance in the onset of “obese” WAT and NAFLD, we created mice with double knock-out for NOX4 and Stat6 (DKO) and compared their metabolic phenotype to littermates with single NOX4 deletion (NOX4KO) upon a 13-week high-fat diet feeding (60 % of calorie from fat). DKO and NOX4KO mice displayed similar food intake. By contrast, DKO mice displayed less body weight gain than NOX4KO mice due to lower energy efficiency leading to reduced WAT accumulation. DKO mice shifted lipid deposition away from the WAT and enhanced lipid storage in the liver. DKO mice displayed similar fed and starved glucose levels with no alterations in glucose tolerance assessed by intra-peritoneal glucose tolerance tests. Gene expression analysis confirmed a less inflammatory state of both WAT and liver of DKO mice. Our results demonstrate that anti-inflammatory signaling is modulated by NOX4-derived signals in vivo in mice, and that NOX4 and IL-4/IL-13 interaction is a critical component in the regulation surplus lipid storage distribution between WAT and the liver. Disclosure I. Szanto: None. Funding Insuleman Foundation (ISZ-1); Foundation for the Innovation in Research in Cancer and Biological Sciences