TY - JOUR
T1 - Angiopoietin-like 4 governs diurnal lipoprotein lipase activity in brown adipose tissue
AU - van Eenige, Robin
AU - in het Panhuis, Wietse
AU - Schönke, Milena
AU - Jouffe, C. line
AU - Devilee, Thomas H.
AU - Siebeler, Ricky
AU - Streefland, Trea C. M.
AU - Sips, Hetty C. M.
AU - Pronk, Amanda C. M.
AU - Vorderman, Ruben H. P.
AU - Mei, Hailiang
AU - van Klinken, Jan Bert
AU - van Weeghel, Michel
AU - Uhlenhaut, Nina H.
AU - Kersten, Sander
AU - Rensen, Patrick C. N.
AU - Kooijman, Sander
N1 - Funding Information: This work is supported by the Netherlands Cardiovascular Research Initiative : an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE to P.C.N.R. and S.KE and CVON2017-20-GENIUS-II to P.C.N.R. and a CVON-GENIUS-II talent grant to R.V.E.), Dutch Federation of University Medical Centers , the Netherlands Organisation for Health Research and Development , and the Royal Netherlands Academy of Sciences . M.S. is supported by the Novo Nordisk Foundation ( NNF18OC0032394 ). S.KO is supported by the Dutch Heart Foundation ( 2017T016 ). C.J. and N.H.U. are supported by the Deutsche Forschungsgemeinschaft ( CRC1064 chromatin dynamics and Trans-Regio TRR333 BATenergy). Publisher Copyright: © 2022 The Author(s)
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Objective: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Objective: 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. Methods: 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. Results: 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. Conclusions: 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.
KW - Angiopoietin-like 4
KW - Brown adipose tissue
KW - Circadian/diurnal rhythms
KW - Lipoprotein lipase
KW - Peroxisome proliferator-activated receptor gamma
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85128482764&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.molmet.2022.101497
DO - https://doi.org/10.1016/j.molmet.2022.101497
M3 - Article
C2 - 35413480
SN - 2212-8778
VL - 60
JO - Molecular metabolism
JF - Molecular metabolism
M1 - 101497
ER -