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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
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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

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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)

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