Brown Adipose Tissue Derived ANGPTL4 Controls Glucose and Lipid Metabolism and Regulates Thermogenesis

Overview

Journal Mol Metab

Specialty Cell Biology

Date 2018 Apr 9

PMID 29627378

Citations 55

Authors

Abhishek K Singh

Binod Aryal

Balkrishna Chaube

Noemi Rotllan

Luis Varela

Tamas L Horvath

Yajaira Suarez

Carlos Fernandez-Hernando

Affiliations

Soon will be listed here.

Abstract

Objectives: Brown adipose tissue (BAT) controls triglyceride-rich lipoprotein (TRL) catabolism. This process is mediated by the lipoprotein lipase (LPL), an enzyme that catalyzed the hydrolysis of triglyceride (TAG) in glycerol and fatty acids (FA), which are burned to generate heat. LPL activity is regulated by angiopoietin-like 4 (ANGPTL4), a secretory protein produced in adipose tissues (AT), liver, kidney, and muscle. While the role of ANGPTL4 in regulating lipoprotein metabolism is well established, the specific contribution of BAT derived ANGPTL4 in controlling lipid and glucose homeostasis is not well understood.

Methods And Results: We generated a novel mouse model lacking ANGPTL4 specifically in brown adipose tissue (BAT-KO). Here, we report that specific deletion of ANGPTL4 in BAT results in enhanced LPL activity, circulating TAG clearance and thermogenesis. Absence of ANGPTL4 in BAT increased FA oxidation and reduced FA synthesis. Importantly, we observed that absence of ANGPTL4 in BAT leads to a remarkable improvement in glucose tolerance in short-term HFD feeding.

Conclusion: Our findings demonstrate an important role of BAT derived ANGPTL4 in regulating lipoprotein metabolism, whole-body lipid and glucose metabolism, and thermogenesis during acute cold exposure.

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References

Cannon B, Nedergaard J . What Ignites UCP1?. Cell Metab. 2017; 26(5):697-698. DOI: 10.1016/j.cmet.2017.10.012. View

Cannon B, Nedergaard J . Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans). Int J Obes (Lond). 2010; 34 Suppl 1:S7-16. DOI: 10.1038/ijo.2010.177. View

Xu A, Lam M, Chan K, Wang Y, Zhang J, Hoo R . Angiopoietin-like protein 4 decreases blood glucose and improves glucose tolerance but induces hyperlipidemia and hepatic steatosis in mice. Proc Natl Acad Sci U S A. 2005; 102(17):6086-91. PMC: 1087912. DOI: 10.1073/pnas.0408452102. View

Chen T, Benjamin D, Kuo T, Lee R, Li M, Mar D . The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ. Sci Signal. 2017; 10(489). PMC: 6218395. DOI: 10.1126/scisignal.aai7905. View

Stanford K, Middelbeek R, Townsend K, An D, Nygaard E, Hitchcox K . Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2012; 123(1):215-23. PMC: 3533266. DOI: 10.1172/JCI62308. View

Zhang R . The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open Biol. 2016; 6(4):150272. PMC: 4852456. DOI: 10.1098/rsob.150272. View

Bartelt A, Bruns O, Reimer R, Hohenberg H, Ittrich H, Peldschus K . Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011; 17(2):200-5. DOI: 10.1038/nm.2297. View

Lichtenstein L, Mattijssen F, de Wit N, Georgiadi A, Hooiveld G, van der Meer R . Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab. 2010; 12(6):580-92. PMC: 3387545. DOI: 10.1016/j.cmet.2010.11.002. View

Blondin D, Tingelstad H, Noll C, Frisch F, Phoenix S, Guerin B . Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men. Nat Commun. 2017; 8:14146. PMC: 5290270. DOI: 10.1038/ncomms14146. View

10.

Huynh F, Green M, Koves T, Hirschey M . Measurement of fatty acid oxidation rates in animal tissues and cell lines. Methods Enzymol. 2014; 542:391-405. PMC: 4154315. DOI: 10.1016/B978-0-12-416618-9.00020-0. View

11.

Bays N, Hill A, Kariv I . A simplified scintillation proximity assay for fatty acid synthase activity: development and comparison with other FAS activity assays. J Biomol Screen. 2009; 14(6):636-42. DOI: 10.1177/1087057109335746. View

12.

Friedman J . The long road to leptin. J Clin Invest. 2016; 126(12):4727-4734. PMC: 5127673. DOI: 10.1172/JCI91578. View

13.

Haller J, Mintah I, Shihanian L, Stevis P, Buckler D, Alexa-Braun C . ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. J Lipid Res. 2017; 58(6):1166-1173. PMC: 5454515. DOI: 10.1194/jlr.M075689. View

14.

Zhu P, Goh Y, Chin H, Kersten S, Tan N . Angiopoietin-like 4: a decade of research. Biosci Rep. 2012; 32(3):211-9. DOI: 10.1042/BSR20110102. View

15.

Bluher M . Adipose tissue dysfunction in obesity. Exp Clin Endocrinol Diabetes. 2009; 117(6):241-50. DOI: 10.1055/s-0029-1192044. View

16.

Merkel M, Eckel R, Goldberg I . Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res. 2002; 43(12):1997-2006. DOI: 10.1194/jlr.r200015-jlr200. View

17.

Festuccia W, Blanchard P, Deshaies Y . Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ. Front Endocrinol (Lausanne). 2012; 2:84. PMC: 3356105. DOI: 10.3389/fendo.2011.00084. View

18.

Kersten S, Mandard S, Tan N, Escher P, Metzger D, Chambon P . Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem. 2000; 275(37):28488-93. DOI: 10.1074/jbc.M004029200. View

19.

Dijk W, Heine M, Vergnes L, Boon M, Schaart G, Hesselink M . ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure. Elife. 2015; 4. PMC: 4709329. DOI: 10.7554/eLife.08428. View

20.

McKee G, Andrews J . Brown adipose tissue lipid is the main source of energy during arousal of the golden hamster (Mesocricetus auratus). Comp Biochem Physiol A Comp Physiol. 1990; 96(4):485-8. DOI: 10.1016/0300-9629(90)90666-g. View