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ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure
Abstract
Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL activity and uptake of plasma triglyceride-derived fatty acids. In contrast, cold up-regulates ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained cold.
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In the citing paper
“It is important to note that ANGPTL proteins are likely not the primary driver of the alterations in lipid partitioning that occur during thermogenesis.”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
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In the citing paper
“Consistent with a role for ANGPTL4 in thermogenic triglyceride partitioning, either whole body or BAT-specific deletion of ANGPTL4 resulted in increased LPL activity and triglyceride uptake in BAT (33, 71).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
Experimental — accuracy not yet measuredIn the citing paper
“With cold exposure, large amounts of triglyceride are funneled to brown adipose tissue in an LPL-dependent manner (68, 69, 71).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
In the citing paper
“With prolonged cold exposure, expression of ANGPTL4 decreases in BAT and increases in WAT (33, 70, 71).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
In the citing paper
“The resulting decrease in ANGPTL4 protein leads to increased LPL activity in BAT, increasing uptake of triglycerides for thermogenic oxidation (71).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
In the citing paper
“Dijk et al. (71) also observed that neither whole body knockout of ANGPTL4 nor ANGPTL4 overexpression had a significant effect on body temperature after prolonged cold exposure.”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
In the citing paper
“Cold exposure did not increase LPL activity in white adipose tissue, nor was ANGPTL4 expression decreased (71), indicating that these changes were specific to brown adipose tissue.”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
In the citing paper
“Angptl4 gene expression decreases in brown adipose tissue in the cold (33, 70, 71).”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
In the citing paper
“It is important to note, however, that modulation of ANGPTL4 expression is not essential for cold-induced thermogenesis or even cold-induced changes in triglyceride partitioning.”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
In the citing paper
“Dijk et al. (71) found that greater uptake of TGs into BAT was induced by cold both in ANGPTL4-deficient mice and in mice overexpressing ANGPTL4.”
From Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8 (2021) · cites this paper as [71]
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Citations
Cites
Brown Adipose Tissue: Function and Physiological Significance
CANNON, B., & NEDERGAARD, J. (2004) · Physiological Reviews · doi:10.1152/physrev.00015.2003 · Cited by 6,433
Cold-Activated Brown Adipose Tissue in Healthy Men
van Marken Lichtenbelt, W. D., Vanhommerig, J. W., Smulders, N. M., Drossaerts, J. M. A. F. L., Kemerink, G. J., Bouvy, N. D., Schrauwen, P., & Teule, G. J. J. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808718 · Cited by 3,452
Functional Brown Adipose Tissue in Healthy Adults
Virtanen, K. A., Lidell, M. E., Orava, J., Heglind, M., Westergren, R., Niemi, T., Taittonen, M., Laine, J., Savisto, N.-J., Enerbäck, S., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808949 · Cited by 3,058
Dyslipidemia in obesity: Mechanisms and potential targets
Klop, B., Elte, J., & Cabezas, M. (2013) · Nutrients · doi:10.3390/nu5041218 · Cited by 1,665
Brown adipose tissue activity controls triglyceride clearance
Bartelt, A., Bruns, O. T., Reimer, R., Hohenberg, H., Ittrich, H., Peldschus, K., Kaul, M. G., Tromsdorf, U. I., Weller, H., Waurisch, C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2297 · Cited by 1,608
Self-citationKöster, A., Chao, Y. B., Mosior, M., Ford, A., Gonzalez-DeWhitt, P. A., Hale, J. E., Li, D., Qiu, Y., Fraser, C. C., Yang, D. D., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0476 · Cited by 427
AMPK inhibition in health and disease
Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M., Giri, S., & Andreelli, F. (2010) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2010.488215 · Cited by 383
AMPK: Lessons from transgenic and knockout animals
Viollet, B. (2009) · Frontiers in bioscience · doi:10.2741/3229 · Cited by 314
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Metadata
- Authors
- Dijk, W., Heine, M., Vergnes, L., Boon, M. R., Schaart, G., Hesselink, M. K., Reue, K., van Marken Lichtenbelt, W. D., Olivecrona, G., Rensen, P. C., Heeren, J., & Kersten, S.
- Affiliations
- Nutrition, Metabolism and Genomics group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
- Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Human Movement Sciences, Maastricht University, Maastricht, The Netherlands
- Department of Human Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2015-10-17
- Volume
- 4
- ISSN
- 2050-084X
- PMC
- PMC4709329
- Cited by
- 114
- References
- 8
- Language
- en
- Licence
- Funders
- Fondation Leducq (12CVD04)
- Forskningsrådet om Hälsa, Arbetsliv och Välfärd (12203)
- Hartstichting (2009T038)
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