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van Eenige, R.* ; In Het Panhuis, W.* ; Schönke, M.* ; Jouffe, C. ; Devilee, T.H.* ; Siebeler, R.* ; Streefland, T.C.M.* ; Sips, H.C.M.* ; Pronk, A.C.M.* ; Vorderman, R.H.P.* ; Mei, H.* ; van Klinken, J.B.* ; van Weeghel, M.* ; Uhlenhaut, N.H.* ; Kersten, S.* ; Rensen, P.C.N.* ; Kooijman, S.*

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

Mol. Metab. 60:101497 (2022)

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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. To gain insight in the diurnal regulation of metabolic BAT activity, we employed RNA-sequencing and lipidomics in murine BAT and identified pronounced enrichment of oscillating genes involved in extracellular lipolysis 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. Chromatin immunoprecipitation (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 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.

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