MitoNEET-mediated effects on browning of white adipose tissue

Abstract

MitoNEET is an outer mitochondrial membrane protein that, upon overexpression in white adipose tissue (WAT), exerts a positive impact on tissue expansion and whole-body lipid and carbohydrate homeostasis by altering mitochondrial matrix iron metabolism. Here we determine the key transcriptional events in subcutaneous WAT of mice in response to mitoNEET overexpression and a high-fat diet (HFD). Microarray analyses at key points during weight gain upon body weight divergence with wild-type mice demonstrate that mitoNEET-enriched sWAT early on, upregulates a browning signature programme that limits WAT expansion in transgenic mice for a period of up to 12 weeks of HFD. This compensatory browning phenotype is subsequently lost, resulting in rapid WAT expansion and body weight gain. Exposure to thermoneutral temperatures during HFD prompts weight gain significantly earlier. Similar WAT expansion is achieved upon infection with an adeno-associated virus expressing mitoNEET. Collectively, the mitoNEET-enriched fat pads feature a more vascularized, anti-inflammatory and less fibrotic environment.