Dataset Information

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

ABSTRACT:

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-h 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.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase, Liquid Chromatography MS - alternating

SUBMITTER: Robin van Eenige

PROVIDER: MTBLS4082 | MetaboLights | 2023-11-15

REPOSITORIES: MetaboLights

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Dataset's files

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			Action	DRS
	MTBLS4082	Other
	FILES	Other
	a_MTBLS4082_LC-MS_alternating_normal-phase_metabolite_profiling.txt	Txt
	a_MTBLS4082_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Publications

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

van Eenige Robin R In Het Panhuis Wietse W Schönke Milena M Jouffe Céline C Devilee Thomas H TH Siebeler Ricky R Streefland Trea C M TCM Sips Hetty C M HCM Pronk Amanda C M ACM Vorderman Ruben H P RHP Mei Hailiang H van Klinken Jan Bert JB van Weeghel Michel M Uhlenhaut Nina H NH Kersten Sander S Rensen Patrick C N PCN Kooijman Sander S

Molecular metabolism 20220410

<h4>Objective</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 35413480

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Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.

Dataset Information

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

Dataset's files

Publications

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

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