MitoNEET-Mediated Effects on Browning of White Adipose Tissue

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 program 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.