Mitochondrial dysfunction in white adipose tissue has been demonstrated to play a role in metabolic disorders. Recent evidence indicates that carbon monoxide (CO) modulates mitochondria bioenergetic. However, whether CO promotes beneficial effects in adipocytes during metabolic disorders by affecting mitochondrial functions is currently unknown.

The aim of this study was to investigate the effects of CO on metabolism and insulin-sensitivity in adipocytes and evaluate the therapeutic impact of CORM-401, CO-releasing agent, on adipose tissue dysfunction in obese mice.

3T3-L1 adipocytes were treated with CORM-401 and cellular bioenergetic was determined by a seahorse analyzer while insulin-sensitivity was assessed by AKT-phosphorylation. Dietary induced obese mice were treated with CORM-401 three times a week for 8 weeks while maintained on a high fat diet. Glucose metabolism was assessed by metabolic tests and fasting blood glucose and insulin.

We found that CORM-401 induced a simultaneous uncoupling of mitochondrial respiration and an increased in glycolysis in 3T3-L1 adipocytes in vitro as well as in mouse adipose tissue ex-vivo. This was accompanied by an increase of insulin-induced AKT-phosphorylation in adipocytes pre-treated with CORM-401 compared to untreated adipocytes suggesting that CO increases insulin-sensitivity in adipocytes. We confirmed these results in vivo by showing that mice pre-treated with CORM-401 displayed a higher insulin-sensitivity (lower glycemia after insulin injection) compared to untreated mice. Finally, we found that a prolonged treatment (8 weeks) of mice with CORM-401 improves glycemic profiles and insulin tolerance tests in high fat diet-induced obesity.

Our results demonstrate that CO prevents the dysfunction of adipose tissue metabolism during obesity and indicate that the beneficial effects of CO involve uncoupling of mitochondrial respiration and an increase in glycolysis.