Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice

Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, ‘browning’ of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27 -null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare example where adipose inflammation and hepatic insulin resistance are disassociated. Fsp27 mediates ‘fusion’ of lipid droplets in mouse adipose tissue. Here, the authors investigate the physiological consequences of loss of Fsp27 in three different mouse models of ‘energetic overload’, and observe hepatic steatosis and insulin resistance but reduced adipose tissue inflammation.