CoChat
Sign Up
Cited by 110

The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.

Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis

Singh, Abhishek K., Aryal, Binod, Chaube, Balkrishna, Rotllan, Noemi, Varela, Luis, Horvath, Tamas L., Suárez, Yajaira, Fernández-Hernando, Carlos·2018·Molecular Metabolism
DOI 10.1016/j.molmet.2018.03.011PMC PMC6001401
Open this paper in CoChat — free account

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.molmet.2018.03.011

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Figures

Graphical abstract
Graphical abstract CC BY-NC-ND · PubMed Central
Figure 1 Generation of BAT conditional Angptl4 knockout mice. (A and B) Strategy for generating BAT Angptl4 knockout mice. A “Knock-out first/conditional ready” gene targeting vector was used to generate targeted cells (A). To delete the expression of Angptl4 in BAT Angptl4lox/lox mice were bred with Tg (Ucp1CRE/ERT2) mice and treated with tamoxifen for 5 days (B, upper panel). (B, bottom panel) qRT-PCR analysis of Angptl4 mRNA expression in eWAT, BAT, liver, muscle, and heart isolated from wild-type (WT; Angptl4lox/lox) and BAT-KO (Angptl4lox/loxUcp1CRE/ERT2) mice (n = 3). Angptl4 expression in all tissues is normalized to its expression in BAT from WT mice. (C and D) qRT-PCR analysis of Angptl3 (C) and Angptl8 (D) mRNA expression in eWAT, BAT and liver isolated from wild-type (WT; n = 3) and BAT-KO (n = 3) mice. Angptl8 expression in all tissues is normalized to its expression in BAT from WT mice. Data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.
Figure 1 Generation of BAT conditional Angptl4 knockout mice. (A and B) Strategy for generating BAT Angptl4 knockout mice. A “Knock-out first/conditional ready” gene targeting vector was used to generate targeted cells (A). To delete the expression of Angptl4 in BAT Angptl4lox/lox mice were bred with Tg (Ucp1CRE/ERT2) mice and treated with tamoxifen for 5 days (B, upper panel). (B, bottom panel) qRT-PCR analysis of Angptl4 mRNA expression in eWAT, BAT, liver, muscle, and heart isolated from wild-type (WT; Angptl4lox/lox) and BAT-KO (Angptl4lox/loxUcp1CRE/ERT2) mice (n = 3). Angptl4 expression in all tissues is normalized to its expression in BAT from WT mice. (C and D) qRT-PCR analysis of Angptl3 (C) and Angptl8 (D) mRNA expression in eWAT, BAT and liver isolated from wild-type (WT; n = 3) and BAT-KO (n = 3) mice. Angptl8 expression in all tissues is normalized to its expression in BAT from WT mice. Data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.CC BY-NC-ND · PubMed Central
Figure 2 Genetic loss of Angptl4 in BAT enhances plasma TAG clearance and tissue lipid uptake. (A) Fed and fasted plasma triacylglyceride (TAG) levels in WT and BAT-KO mice (n = 5). (B) Oral lipid tolerance test in 4 h fasted WT and BAT-KO mice followed by an oral gavage of olive oil (n = 5). (C) Radioactivity incorporation in indicated tissues after 2 h of oral gavage of [3H]-triolein in 6 h fasted WT or BAT-KO mice (n = 6). (D) qRT-PCR analysis of Cd36 and Lpl mRNA expression in BAT isolated from WT and BAT-KO mice (n = 3). (E) LPL activity in the indicated tissues isolated from WT and BAT-KO mice. Plasma LPL activity was assessed from blood isolated 5 min after heparin injection (n = 3). (F) Circulating TAG from WT and BAT-KO mice fasted for 4 h and treated with the LPL inhibitor, poloxamer 407 (n = 3). (G) Plasma 3H counts after injection of poloxamer 407 combined with an oral lipid gavage containing [3H-triolein (n = 3).
Figure 2 Genetic loss of Angptl4 in BAT enhances plasma TAG clearance and tissue lipid uptake. (A) Fed and fasted plasma triacylglyceride (TAG) levels in WT and BAT-KO mice (n = 5). (B) Oral lipid tolerance test in 4 h fasted WT and BAT-KO mice followed by an oral gavage of olive oil (n = 5). (C) Radioactivity incorporation in indicated tissues after 2 h of oral gavage of [3H]-triolein in 6 h fasted WT or BAT-KO mice (n = 6). (D) qRT-PCR analysis of Cd36 and Lpl mRNA expression in BAT isolated from WT and BAT-KO mice (n = 3). (E) LPL activity in the indicated tissues isolated from WT and BAT-KO mice. Plasma LPL activity was assessed from blood isolated 5 min after heparin injection (n = 3). (F) Circulating TAG from WT and BAT-KO mice fasted for 4 h and treated with the LPL inhibitor, poloxamer 407 (n = 3). (G) Plasma 3H counts after injection of poloxamer 407 combined with an oral lipid gavage containing [3H-triolein (n = 3).CC BY-NC-ND · PubMed Central
Figure 3 Lack of ANGPTL4 in BAT stimulates FA uptake in BAT and augments thermogenesis upon acute cold exposure. (A) Angptl4 mRNA in BAT lysates of WT mice exposed to 4 °C or RT for 4 h. (B) Plasma TAG levels during oral lipid tolerance test in fasted WT and BAT-KO mice during acute cold exposed setting (n = 5). (C) Tissue distribution of [3H] after 2 h oral gavage of [3H]-triolein (n = 3) in acute exposed condition. (D) Body temperature analysis in BAT-KO and WT mice in an acute cold exposed setting (n = 5). Mice had no access to food during the experiments performed in panel A–D. All data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.
Figure 3 Lack of ANGPTL4 in BAT stimulates FA uptake in BAT and augments thermogenesis upon acute cold exposure. (A) Angptl4 mRNA in BAT lysates of WT mice exposed to 4 °C or RT for 4 h. (B) Plasma TAG levels during oral lipid tolerance test in fasted WT and BAT-KO mice during acute cold exposed setting (n = 5). (C) Tissue distribution of [3H] after 2 h oral gavage of [3H]-triolein (n = 3) in acute exposed condition. (D) Body temperature analysis in BAT-KO and WT mice in an acute cold exposed setting (n = 5). Mice had no access to food during the experiments performed in panel A–D. All data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.CC BY-NC-ND · PubMed Central
Figure 4 Absence of ANGPTL4 in BAT reduces circulating TAG but does not influence body weight in mice fed a CD. (A–F) Body weight (A), plasma triglyceride (TAG) (B), total cholesterol (TC) (C), and high-density lipoprotein cholesterol (HDL-C) (D) from WT and BAT-KO mice fed a chow diet (CD) for 20 weeks (n = 5). (E and F) TAG (E) and TC (F) content of FPLC-fractionated lipoproteins from pooled plasma of WT and BAT-KO mice fed a CD for 20 weeks (n = 5). All data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.
Figure 4 Absence of ANGPTL4 in BAT reduces circulating TAG but does not influence body weight in mice fed a CD. (A–F) Body weight (A), plasma triglyceride (TAG) (B), total cholesterol (TC) (C), and high-density lipoprotein cholesterol (HDL-C) (D) from WT and BAT-KO mice fed a chow diet (CD) for 20 weeks (n = 5). (E and F) TAG (E) and TC (F) content of FPLC-fractionated lipoproteins from pooled plasma of WT and BAT-KO mice fed a CD for 20 weeks (n = 5). All data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.CC BY-NC-ND · PubMed Central
Figure 5 BAT depletion of ANGPTL4 reduces circulating TAG but does not affect body weight in mice fed a HFD. (A) Body weight from WT and BAT-KO mice fed a high-fat diet (HFD) for 20 weeks. Insert panel shows % fat mass in these mice after 20 weeks on HFD (n = 9). (B–D) Plasma TAG, (B) TC (C) and HDL-C (D) levels from mice fed a HFD for 20 weeks (n = 5). (E and F) TC (E) and TAG (F) content of FPLC-fractionated lipoproteins from pooled plasma of WT and BAT-KO mice fed a HFD for 20 weeks (n = 8). (G) Representative western blot analysis of plasma ApoB100, ApoB48, and ApoA1 in the FPLC-fractionated lipoproteins. Lanes 1–12 correspond to the following pooled fractions: 1 (28–30), 2 (31–33), 3 (34–36), 4 (37–39), 5 (40–42), 6 (43–45), 7 (46–48), 8 (49–51), 9 (52–54), 10 (55–57), 11 (58–60), and 12 (61–63). All data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.
Figure 5 BAT depletion of ANGPTL4 reduces circulating TAG but does not affect body weight in mice fed a HFD. (A) Body weight from WT and BAT-KO mice fed a high-fat diet (HFD) for 20 weeks. Insert panel shows % fat mass in these mice after 20 weeks on HFD (n = 9). (B–D) Plasma TAG, (B) TC (C) and HDL-C (D) levels from mice fed a HFD for 20 weeks (n = 5). (E and F) TC (E) and TAG (F) content of FPLC-fractionated lipoproteins from pooled plasma of WT and BAT-KO mice fed a HFD for 20 weeks (n = 8). (G) Representative western blot analysis of plasma ApoB100, ApoB48, and ApoA1 in the FPLC-fractionated lipoproteins. Lanes 1–12 correspond to the following pooled fractions: 1 (28–30), 2 (31–33), 3 (34–36), 4 (37–39), 5 (40–42), 6 (43–45), 7 (46–48), 8 (49–51), 9 (52–54), 10 (55–57), 11 (58–60), and 12 (61–63). All data represent the mean ± S.E.M. and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.CC BY-NC-ND · PubMed Central
Figure 6 Lack of ANGPTL4 expression in BAT improves glucose and insulin tolerance. (A–F) Glucose tolerance test (GTT) and insulin tolerance test (ITT) in WT and BAT-KO mice fed a CD (n = 5) (A and B), or a HFD for 4 weeks (n = 5) (C and D), or a HFD for 20 weeks (n = 5) (E and F). Inset represents the area under the curve (AUC). All data represent the mean ± S.E.M and * indicates P < 0.05 comparing BAT-KO mice with WT mice using unpaired t-test.
Figure 6 Lack of ANGPTL4 expression in BAT improves glucose and insulin tolerance. (A–F) Glucose tolerance test (GTT) and insulin tolerance test (ITT) in WT and BAT-KO mice fed a CD (n = 5) (A and B), or a HFD for 4 weeks (n = 5) (C and D), or a HFD for 20 weeks (n = 5) (E and F). Inset represents the area under the curve (AUC). All data represent the mean ± S.E.M and * indicates P < 0.05 comparing BAT-KO mice with WT mice using unpaired t-test.CC BY-NC-ND · PubMed Central
Figure 7 Loss of ANGPTL4 in BAT enhances the expression of genes associated to oxidative metabolism coupled with reduced endogenous lipogenesis. (A) Representative H&E stained sections of BAT isolated from WT and BAT-KO mice fed a HFD for 20 weeks. (B) FA oxidation in isolated BAT from WT and BAT-KO mice (n = 6). (C) Representative western blot analysis of indicated proteins in BAT from WT and BAT-KO mice fed a HFD for 20 weeks (n = 4) and densitometry analysis of the respective blots. (D) Measurement of FASN activity in isolated BAT of WT and BAT-KO mice (n = 6). (E) qRT-PCR analysis of Fasn expression in BAT isolated from WT and BAT-KO mice fed a HFD for 20 weeks (n = 3). All data represent the mean ± SEM and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.
Figure 7 Loss of ANGPTL4 in BAT enhances the expression of genes associated to oxidative metabolism coupled with reduced endogenous lipogenesis. (A) Representative H&E stained sections of BAT isolated from WT and BAT-KO mice fed a HFD for 20 weeks. (B) FA oxidation in isolated BAT from WT and BAT-KO mice (n = 6). (C) Representative western blot analysis of indicated proteins in BAT from WT and BAT-KO mice fed a HFD for 20 weeks (n = 4) and densitometry analysis of the respective blots. (D) Measurement of FASN activity in isolated BAT of WT and BAT-KO mice (n = 6). (E) qRT-PCR analysis of Fasn expression in BAT isolated from WT and BAT-KO mice fed a HFD for 20 weeks (n = 3). All data represent the mean ± SEM and * indicates P < 0.05 comparing BAT-KO with WT mice using unpaired t-test.CC BY-NC-ND · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Research works printed but not linked: 41

  1. Waki, 2007, Endocrine functions of adipose tissue, Annual Review of Pathology Mechanisms of Disease, 2, 31, 10.1146/annurev.pathol.2.010506.091859 · DOI
  2. Friedman, 2016, The long road to leptin, Journal of Clinical Investigation, 126, 4727, 10.1172/JCI91578 · DOI
  3. Kusminski, 2016, Targeting adipose tissue in the treatment of obesity-associated diabetes, Nature Reviews Drug Discovery, 15, 639, 10.1038/nrd.2016.75 · DOI · Paper page
  4. Bremer, 2013, Adipose tissue dysfunction in nascent metabolic syndrome, Journal of Obestics, 2013, 393192
  5. Bluher, 2009, Adipose tissue dysfunction in obesity, Experimental and Clinical Endocrinology & Diabetes, 117, 241, 10.1055/s-0029-1192044 · DOI
  6. Cannon, 2017, What ignites UCP1?, Cell Metabolism, 26, 697, 10.1016/j.cmet.2017.10.012 · DOI
  7. Stern, 2015, Adipose tissue biology in 2014: advances in our understanding of adipose tissue homeostasis, Nature Reviews Endocrinology, 11, 71, 10.1038/nrendo.2014.219 · DOI
  8. Villarroya, 2017, Brown adipose tissue as a secretory organ, Nature Reviews Endocrinology, 13, 26, 10.1038/nrendo.2016.136 · DOI
  9. Fedorenko, 2012, Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria, Cell, 151, 400, 10.1016/j.cell.2012.09.010 · DOI · Paper page
  10. Goldberg, 2009, Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways, The Journal of Lipid Research, 50
  11. Merkel, 2002, Lipoprotein lipase: genetics, lipid uptake, and regulation, The Journal of Lipid Research, 43, 1997, 10.1194/jlr.R200015-JLR200 · DOI
  12. Kersten, 2014, Physiological regulation of lipoprotein lipase, Biochimica et Biophysica Acta, 1841, 919, 10.1016/j.bbalip.2014.03.013 · DOI
  13. Unal, 2008, Translational regulation of lipoprotein lipase in adipocytes: depletion of cellular protein kinase Calpha activates binding of the C subunit of protein kinase A to the 3'-untranslated region of the lipoprotein lipase mRNA, Biochemical Journal, 413, 315, 10.1042/BJ20071559 · DOI
  14. Kersten, 2000, Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene, Journal of Biological Chemistry, 275, 28488, 10.1074/jbc.M004029200 · DOI · Paper page
  15. Zhu, 2012, Angiopoietin-like 4: a decade of research, Bioscience Reports, 32, 211, 10.1042/BSR20110102 · DOI
  16. Sukonina, 2006, Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue, Proceedings of the National Academy of Sciences of the U S A, 103, 17450, 10.1073/pnas.0604026103 · DOI · Paper page
  17. Zhang, 2016, The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking, Open Biology, 6, 150272, 10.1098/rsob.150272 · DOI
  18. Mandard, 2006, The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity, Journal of Biological Chemistry, 281, 934, 10.1074/jbc.M506519200 · DOI · Paper page
  19. Georgiadi, 2013, Overexpression of angiopoietin-like protein 4 protects against atherosclerosis development, Arteriosclerosis Thrombosis and Vascular Biology, 33, 1529, 10.1161/ATVBAHA.113.301698 · DOI · Paper page
  20. Aryal, 2016, ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression, Nature Communications, 7, 12313, 10.1038/ncomms12313 · DOI · Paper page
  21. Dijk, 2014, Regulation of lipoprotein lipase by Angptl4, Trends in Endocrinology and Metabolism, 25, 146, 10.1016/j.tem.2013.12.005 · DOI
  22. Desai, 2007, Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice, Proceedings of the National Academy of Sciences of the U S A, 104, 11766, 10.1073/pnas.0705041104 · DOI · Paper page
  23. Kotas, 2013, Role of caspase-1 in regulation of triglyceride metabolism, Proceedings of the National Academy of Sciences of the U S A, 110, 4810, 10.1073/pnas.1301996110 · DOI
  24. Camporez, 2015, ApoA5 knockdown improves whole-body insulin sensitivity in high-fat-fed mice by reducing ectopic lipid content, The Journal of Lipid Research, 56, 526, 10.1194/jlr.M054080 · DOI
  25. Iqbal, 2013, Lipid absorption defects in intestine-specific microsomal triglyceride transfer protein and ATP-binding cassette transporter A1-deficient mice, Journal of Biological Chemistry, 288, 30432, 10.1074/jbc.M113.501247 · DOI
  26. Huynh, 2014, Measurement of fatty acid oxidation rates in animal tissues and cell lines, Methods Enzymology, 542, 391, 10.1016/B978-0-12-416618-9.00020-0 · DOI
  27. Bays, 2009, A simplified scintillation proximity assay for fatty acid synthase activity: development and comparison with other FAS activity assays, Journal of Biomolecular Screening, 14, 636, 10.1177/1087057109335746 · DOI
  28. Haller, 2017, ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance, The Journal of Lipid Research, 58, 1166, 10.1194/jlr.M075689 · DOI · Paper page
  29. Nakajima, 2011, Postprandial lipoprotein metabolism: VLDL vs chylomicrons, Clinica Chimica Acta, 412, 1306, 10.1016/j.cca.2011.04.018 · DOI
  30. Cedikova, 2016, Mitochondria in white, brown, and beige adipocytes, Stem Cells International, 2016, 10.1155/2016/6067349 · DOI
  31. Festuccia, 2011, Control of brown adipose tissue glucose and lipid metabolism by PPARgamma, Frontiers in Endocrinology, 2, 84, 10.3389/fendo.2011.00084 · DOI
  32. McKee, 1990, Brown adipose tissue lipid is the main source of energy during arousal of the golden hamster (Mesocricetus auratus), Comparative Biochemistry and Physiology A Comparative Physiology, 96, 485, 10.1016/0300-9629(90)90666-G · DOI
  33. Cannon, 2010, Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans), International Journal of Obesity (London), 34, S7, 10.1038/ijo.2010.177 · DOI
  34. Thoonen, 2016, Brown adipose tissue: the heat is on the heart, American Journal of Physiology Heart and Circulatory Physiology, 310, H1592, 10.1152/ajpheart.00698.2015 · DOI
  35. Blondin, 2017, Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men, Nature Communications, 8, 14146, 10.1038/ncomms14146 · DOI
  36. Dijk, 2015, ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure, Elife, 4, 10.7554/eLife.08428 · DOI · Paper page
  37. Townsend, 2014, Brown fat fuel utilization and thermogenesis, Trends in Endocrinology and Metabolism, 25, 168, 10.1016/j.tem.2013.12.004 · DOI
  38. Winn, 2017, Loss of UCP1 exacerbates Western diet-induced glycemic dysregulation independent of changes in body weight in female mice, American Journal of Physiology Regulatory Integrative and Comparative Physiology, 312, R74, 10.1152/ajpregu.00425.2016 · DOI
  39. Xu, 2005, Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice, Proceedings of the National Academy of Sciences of the U S A, 102, 6086, 10.1073/pnas.0408452102 · DOI · Paper page
  40. Chen, 2017, The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCzeta, Science Signaling, 10, 10.1126/scisignal.aai7905 · DOI
  41. Lichtenstein, 2010, Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages, Cell Metabolism, 12, 580, 10.1016/j.cmet.2010.11.002 · DOI · Paper page

Cited by

Sorted by citations

See all 110

Metadata

Authors
Singh, A. K., Aryal, B., Chaube, B., Rotllan, N., Varela, L., Horvath, T. L., Suárez, Y., & Fernández-Hernando, C.
ORCID
Rotllan, Noemi
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2018-05
Volume
11
Pages
59-69
ISSN
2212-8778
DOI
10.1016/j.molmet.2018.03.011
PMC
PMC6001401
Cited by
110
References
7
Language
en
Licence
Funders
  • National Institutes of Health (R01HL135012, R35HL135820, R01HL105945)
  • American Heart Association (16EIA27550005, 17SDG33110002, 16GRNT26420047)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review