Angiopoietin-like 4 governs diurnal lipoprotein lipase activity in brown adipose tissue

• Published in: Molecular metabolism (Germany) 2022-06, Vol.60, p.101497-101497, Article 101497
• Main Authors: van Eenige, Robin, In het Panhuis, Wietse, Schönke, Milena, Jouffe, Céline, Devilee, Thomas H., Siebeler, Ricky, Streefland, Trea C.M., Sips, Hetty C.M., Pronk, Amanda C.M., Vorderman, Ruben H.P., Mei, Hailiang, van Klinken, Jan Bert, van Weeghel, Michel, Uhlenhaut, Nina H., Kersten, Sander, Rensen, Patrick C.N., Kooijman, Sander
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; Angiopoietin-like 4; Angiopoietin-Like Protein 4 - metabolism; Angiopoietins; Animals; Brown adipose tissue; Circadian/diurnal rhythms; Lipoprotein lipase; Lipoprotein Lipase - genetics; Lipoprotein Lipase - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Original; Peroxisome proliferator-activated receptor gamma; PPAR gamma - metabolism; Transcriptomics; Triglycerides - metabolism
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2022.101497

Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity. RNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing, and lipidomics analyses were performed on BAT samples of wild type C57BL/6J mice collected at 3-hour intervals throughout the day. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT. We identified pronounced enrichment of oscillating genes involved in extracellular lipolysis in BAT, accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. ChIP-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL activity and TG-derived FA-uptake by BAT. Our findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health. [Display omitted] •The transcriptome and lipidome of brown fat show clusters with distinct circadian phases.•The peak in metabolic brown fat activity is defined by activation of lipolytic processes.•PPARγ shows oscillating binding to lipolytic genes and may drive diurnal brown fat activity.•Genetic modulation of the lipoprotein lipase inhibitor Angptl4 flattens rhythmic activity in brown fat.•Time of day should be considered when studying the metabolic benefits of targeting brown fat.