Angiopoietin-like 4 dictates the day-night rhythm of metabolic brown adipose tissue activity

Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and interestingly shows a strong day-night rhythm in glucose and triglyceride (TG)-derived FA-uptake (Van den Berg, Cell Rep 2018), peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity. BAT was collected from chow-fed male C57BL/6J mice at 3-hour intervals throughout the day, and RNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing, and lipidomics analyses were performed. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT. Our findings highlight involvement of PPARγ and a crucial role of angiopoietin-like 4 (ANGPTL4) in mediating the day-night rhythm of TG-derived FA-uptake by BAT, and implicate that time of day should be considered when studying the metabolic benefits of targeting brown fat.